An Open-Label Study of Brentuximab Vedotin + Adriamycin, Vinblastine, and Dacarbazine in Pediatric Patients With Advanced Stage Newly Diagnosed Hodgkin Lymphoma
Phase: PHASE1
Conditions: Hodgkin Disease
Sponsor: Takeda




Title: An Open-Label Study of Brentuximab Vedotin+Adriamycin, Vinblastine, and Dacarbazine 
in Pediatric Patients With Advanced Stage Newly Diagnosed Hodgkin Lymphoma
NCT Number: NCT02979522
Protocol Approve Date: 11 June 2021
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.

1.0 TITLE PAGE
PROTOCOL
An Open-Label Study of Brentuximab Vedotin+Adriamycin, Vinblastine, and Dacarbazine in 
Pediatric Patients With Advanced Stage Newly Diagnosed Hodgkin Lymphoma
Brentuximab Vedotin+Adriamycin, Vinblastine, and Dacarbazine in Pediatric patients with 
Advanced Stage Newly Diagnosed Hodgkin Lymphoma
Sponsor:
Takeda Development Center (TDC) Americas, Inc.
95 Hayden Avenue, Lexington, Massachusetts 02421 USA
Please note: TDC Americas, Inc. may be referred to in this protocol as 
“sponsor” or “Takeda”.
Study Number:
C25004
IND Number:
110,636
EudraCT Number:
2015-004112-38
Compound:
Brentuximab vedotin (ADCETRIS)
Date:
11 June 2021
Version/Amendment 
Number
04
Amendment History
Date
Amendment Number
Amendment Type
Region
12 August 2016
Initial protocol
Global
27 July 2017
01
Nonsubstantial
Global
03 January 2019
02
Nonsubstantial
Global
10 December 2019
03
Substantial
Global
11 June 2021
04
Substantial
Global
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1.0
ADMINISTRATIVE 
1.1
Contacts 
A separate contact information list will be provided to each site.
Serious adverse event (SAE) and pregnancy reporting information is presented in Section 10.0, as 
is information on reporting product complaints. 
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site. 
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1.2
Approval 
REPRESENTATIVES OF TAKEDA 
This study will be conducted with the highest respect for the individual participants in accordance 
with the requirements of this clinical study protocol and also in accordance with the following:
The ethical principles that have their origin in the Declaration of Helsinki.
International Council on Harmonisation E6 Good Clinical Practice: Consolidated Guideline.
All applicable laws and regulations, including, without limitation, data privacy laws, clinical trial 
disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures may be found on the last page of this document.
PPD
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dance
ance
wing:
wing:
Guidel
Guide
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r signat
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docum
mmercial Use Only and 

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1.3
Protocol Amendment 04 Summary of Changes
This document describes the changes in reference to the protocol incorporating Amendment 04. 
The primary reasons for this amendment are to describe the modifications in study conduct 
because of the coronavirus disease 2019 (COVID-19) pandemic, clarify the time points for 
analysis of study data, provide additional guidance on long-term follow-up procedures, and 
provide an update to the sponsor’s name. In addition, the protocol signatories are updated. 
As all patients have completed the treatment period of the study, the protocol will confirm that 
study participation is not restricted by administration of the COVID-19 vaccine. Where permitted 
by local regulations, the study will allow remote monitoring due to COVID-19 impact. Guidance 
is also provided for handling of delayed or missed protocol visits due to the pandemic.
With the agreement of the European Medicines Agency (EMA) Paediatric Committee (PDCO), 
and as prespecified in the study’s approved statistical analysis plan, the analyses for reporting the 
results of the study’s primary endpoints in the clinical study report (CSR) were performed after all 
enrolled patients had the opportunity to be followed for 15 months after enrollment of the last 
patient in the main study. Efficacy analyses included all evaluable patients treated at the 
recommended dose.
All enrolled patients will continue to be followed for survival and disease status every 12 weeks 
(1 week) for 12 months, and then every 24 weeks (2 weeks) until death or study closure or for 
up to 2 years after enrollment of the last patient in the main study. An updated analysis of 
time-to-event efficacy endpoints and other selected endpoints will be performed after all enrolled 
patients have had the opportunity to be followed for up to 2 years after enrollment of the last 
patient, denoting the end of the main study. This updated analysis may include data from the 
long-term follow-up period. Results of the updated analysis performed at the end of the main study 
will be presented in an addendum to the CSR. A separate CSR addendum is planned to present the 
results for participating patients at the end of the 10-year optional long-term follow-up. 
This protocol amendment provides an update to the sponsor name, now Takeda Development 
Center (TDC) Americas, Inc.
Minor grammatical, editorial, and formatting changes are included, if applicable for clarification 
purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix J.
Changes in Amendment 04
1. Modifications in study conduct instituted in response to the COVID-19 pandemic. 
2. Clarification of time points for analysis and reporting of study results.
3. Additional guidance pertaining to the long-term follow-up procedures.
4. Updated sponsor name and protocol signatories.
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INVESTIGATOR AGREEMENT 
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, package 
insert and any other product information provided by the sponsor. I agree to conduct this study in 
accordance with the requirements of this protocol and also to protect the rights, safety, privacy, 
and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Council on Harmonisation E6 Good Clinical Practice: Consolidated Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting SAEs defined in Section 10.0 of this protocol.

Terms outlined in the Clinical Study Site Agreement.

Appendix B Responsibilities of the Investigator.
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix C of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Province)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE.......................................................................................................2
1.1
Contacts.....................................................................................................................2
1.2
Approval....................................................................................................................3
1.3
Protocol Amendment 04 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................12
3.0
STUDY REFERENCE INFORMATION ......................................................................19
3.1
Study-Related Responsibilities.................................................................................19
3.2
Principal Investigator/Coordinating Investigator ......................................................19
3.3
List of Abbreviations ...............................................................................................20
3.4
Corporate Identification...........................................................................................22
4.0
INTRODUCTION.........................................................................................................23
4.1
Background .............................................................................................................23
4.1.1
Disease Under Treatment.................................................................................23
4.1.2
Study Drug ......................................................................................................23
4.2
Nonclinical Experience............................................................................................24
4.3
Clinical Experience..................................................................................................24
4.4
Potential Risks in Children.......................................................................................25
4.5
Rationale for the Proposed Study.............................................................................26
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................28
5.1
Objectives................................................................................................................28
5.1.1
Phase 1 Primary Objective...............................................................................28
5.1.2
Phase 1 Secondary Objectives..........................................................................28
5.1.3
5.1.4
Phase 2 Primary Objectives .............................................................................29
5.1.5
Phase 2 Secondary Objectives..........................................................................29
5.1.6
5.2
Endpoints.................................................................................................................30
5.2.1
Phase 1 Primary Endpoints ..............................................................................30
5.2.2
Phase 1 Secondary Endpoints ..........................................................................30
5.2.3
5.2.4
Phase 2 Primary Endpoints ..............................................................................31
5.2.5
Phase 2 Secondary Endpoints ..........................................................................31
5.2.6
6.0
STUDY DESIGN..........................................................................................................32
CCI
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.1.6
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6.1
Overview of Study Design.......................................................................................32
6.2
Number of Patients ..................................................................................................35
6.3
Duration of Study ....................................................................................................35
6.3.1
Duration of an Individual Patient’s Study Participation....................................35
6.3.2
End of Study/Study Completion Definition and Planned Reporting..................35
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures ......36
6.3.4
Total Study Duration .......................................................................................40
7.0
STUDY POPULATION................................................................................................40
7.1
Inclusion Criteria .....................................................................................................40
7.2
Exclusion Criteria ....................................................................................................42
8.0
PROTOCOL THERAPY...............................................................................................43
8.1
Protocol Therapy Administration.............................................................................43
8.2
Definitions of DLT ..................................................................................................44
8.3
Regimen De-Intensification Rules............................................................................44
8.4
Dose Modification Guidelines..................................................................................44
8.4.1
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity........................................................................44
8.4.2
Reference Therapy Dose Modifications ...........................................................45
8.4.3
Criteria for Dose Administration......................................................................45
8.5
Excluded Concomitant Medications and Procedures ................................................46
8.6
Permitted Concomitant Medications and Procedures................................................46
8.7
Precautions and Restrictions ....................................................................................47
8.7.1
Infusion-Related Reactions..............................................................................47
8.7.2
Pregnancy........................................................................................................47
8.8
Management of Clinical Events ...............................................................................48
8.8.1
Nausea and/or Vomiting ..................................................................................48
8.8.2
Diarrhea...........................................................................................................48
8.8.3
Infusion-Related Reactions..............................................................................48
8.8.4
Peripheral Neuropathy.....................................................................................48
8.8.5
Suspected PML................................................................................................49
8.9
Blinding and Unblinding..........................................................................................49
8.10
Description of Investigational Agents ......................................................................49
8.10.1
Brentuximab Vedotin.......................................................................................49
8.10.2
Doxorubicin.....................................................................................................50
8.10.3
Vinblastine ......................................................................................................50
8.10.4
Dacarbazine.....................................................................................................50
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8.11
Preparation, Reconstitution, and Dispensation..........................................................50
8.11.1
Brentuximab Vedotin.......................................................................................50
8.11.2
Doxorubicin.....................................................................................................50
8.11.3
Vinblastine ......................................................................................................50
8.11.4
Dacarbazine.....................................................................................................51
8.12
Packaging and Labeling...........................................................................................51
8.13
Storage, Handling, and Accountability.....................................................................51
8.13.1
Brentuximab Vedotin.......................................................................................51
8.13.2
Doxorubicin.....................................................................................................51
8.13.3
Vinblastine ......................................................................................................51
8.13.4
Dacarbazine.....................................................................................................51
9.0
STUDY CONDUCT......................................................................................................51
9.1
Study Personnel and Organizations..........................................................................51
9.2
Arrangements for Recruitment of Patients................................................................52
9.3
Treatment Group Assignments.................................................................................52
9.4
Study Procedures.....................................................................................................52
9.4.1
Informed Consent ............................................................................................52
9.4.2
Patient Demographics......................................................................................52
9.4.3
Medical History...............................................................................................52
9.4.4
Enrollment.......................................................................................................53
9.4.5
Patient Height, Weight and Body Surface Area................................................53
9.4.6
Physical Examination ......................................................................................53
9.4.7
Pregnancy Test ................................................................................................53
9.4.8
Vital Signs.......................................................................................................53
9.4.9
Lansky Play-Performance or Karnofsky Performance Status............................53
9.4.10
Development Assessment ................................................................................53
9.4.11
Clinical Chemistry and Hematology ................................................................54
9.4.12
Electrocardiogram ...........................................................................................54
9.4.13
Echocardiogram...............................................................................................54
9.4.14
9.4.15
9.4.16
Concomitant Medications and Procedures........................................................55
9.4.17
Adverse Events................................................................................................55
9.4.18
Disease Assessment.........................................................................................55
9.4.19
PK Measurements............................................................................................56
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9.4.20
Immunogenicity...............................................................................................56
9.4.21
Immune Reconstitution....................................................................................57
9.5
Completion of Treatment .........................................................................................57
9.6
Completion of Study................................................................................................57
9.7
Completion of Optional Long-term Follow-up.........................................................57
9.8
Discontinuation of Treatment With Protocol Therapy and Patient Replacement .......57
9.9
Withdrawal of Patients From Study .........................................................................58
9.10
Withdrawal of Patients from Optional Long-term Follow-up ...................................58
9.11
Study Compliance....................................................................................................59
9.12
Posttreatment Follow-up Assessments (PFS and OS)...............................................59
9.13
Optional Long-term Follow-up ................................................................................59
9.14
COVID-19 Considerations.......................................................................................61
10.0
ADVERSE EVENTS ....................................................................................................62
10.1
Definitions...............................................................................................................62
10.1.1
PTE Definition ................................................................................................62
10.1.2
AE Definition ..................................................................................................62
10.1.3
SAE Definition................................................................................................63
10.2
Procedures for Recording and Reporting AEs and SAEs..........................................63
10.3
Monitoring of AEs and Period of Observation .........................................................64
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events.........65
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose) ................................................................................................................65
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities...........66
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................66
12.0
DATA HANDLING AND RECORDKEEPING............................................................66
12.1
eCRFs......................................................................................................................66
12.2
Record Retention .....................................................................................................67
13.0
STATISTICAL METHODS..........................................................................................68
13.1
Statistical and Analytical Plans ................................................................................68
13.1.1
Analysis Sets ...................................................................................................68
13.1.2
Analysis of Demographics and Other Baseline Characteristics.........................68
13.1.3
Efficacy Analysis.............................................................................................69
13.1.4
13.1.5
PK Analysis.....................................................................................................69
13.1.6
Immunogenicity Analysis ................................................................................69
13.1.7
Immune Reconstitution Analysis .....................................................................69
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13.1.8
PK Modeling ...................................................................................................69
13.1.9
Safety Analysis................................................................................................70
13.2
Interim Analysis and Criteria for Early Termination ................................................70
13.3
Time Points for Additional Analyses........................................................................71
13.4
Determination of Sample Size..................................................................................71
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................71
14.1
Study-Site Monitoring Visits ...................................................................................71
14.2
Protocol Deviations..................................................................................................72
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................72
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................72
15.1
IRB and/or IEC Approval ........................................................................................73
15.2
Subject Information, Informed Consent and Assent, and Subject Authorization .......73
15.3
Subject Confidentiality ............................................................................................74
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................75
15.4.1
Publication and Disclosure...............................................................................75
15.4.2
Clinical Trial Registration................................................................................75
15.4.3
Clinical Trial Results Disclosure......................................................................76
15.5
Insurance and Compensation for Injury....................................................................76
16.0
REFERENCES..............................................................................................................76
LIST OF IN-TEXT TABLES
Table 6.a
Primary and Secondary Endpoints for Disclosures .............................................36
Table 8.a
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity ..........................................................................45
Table 9.a
Clinical Chemistry and Hematology Tests..........................................................54
LIST OF IN-TEXT FIGURES
Figure 6.a
Dosing Schema ..................................................................................................33
LIST OF APPENDICES
Appendix A
Schedule of Events.............................................................................................79
Appendix B
Responsibilities of the Investigator.....................................................................87
Appendix C
Investigator Consent to Use of Personal Information..........................................89
Appendix D
Deauville Criteria for PET .................................................................................90
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Appendix E
Ann Arbor Staging System for Hodgkin Lymphoma..........................................91
Appendix F
Lansky Play-Performance Scale for Children .....................................................92
Appendix G
Karnofsky Performance Status ...........................................................................93
Appendix H
New York Heart Association Classification of Cardiac Disease..........................94
Appendix I
Tanner Scale ......................................................................................................95
Appendix J
Detailed Description of Amendments to Text Changes.......................................96
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2.0
STUDY SUMMARY
Name of Sponsor(s):
Takeda Development Center (TDC) Americas, Inc.
Compound:
Brentuximab vedotin (ADCETRIS)
Title of Protocol: An Open-Label Study of Brentuximab 
Vedotin+Adriamycin, Vinblastine, and Dacarbazine in 
Pediatric Patients With Advanced Stage Newly Diagnosed 
Hodgkin Lymphoma
IND No.: 110,636
EudraCT No.:
2015-004112-38
Study Number: C25004
Phase: 1/2 
Study Design:
This phase 1/2, open-label, multiagent, multicenter study has the primary objectives of assessing the safety, 
tolerability, and recommended dose of brentuximab vedotin (A) in combination with a multiagent chemotherapy 
regimen, Adriamycin (doxorubicin), vinblastine, and dacarbazine, (referred to as AVD), in pediatric patients with 
advanced stage, newly diagnosed, classical CD30+ Hodgkin lymphoma (HL) and to evaluate the antitumor activity of 
this combination in pediatric patients. 
The study will enroll at least 55 evaluable patients. In the phase 1 portion of the study, at least 6 patients will be 
enrolled into up to 2 planned dose cohorts (48 and 36 mg/m2, 3-6 patients per cohort) to determine the recommended 
dose according to a modified 3+3 design. Once the recommended dose is identified, additional patients will be 
enrolled into phase 2 so that the total number of evaluable patients will be approximately 55, including the patients 
treated at the recommended dose in phase 1. 
A+AVD will be administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles.
In phase 1, the study will enroll up to 6 dose-limiting toxicity (DLT)-evaluable patients at a brentuximab vedotin dose 
of 48 mg/m2 to determine the recommended dose. The first 3 patients enrolled in the study will be monitored for DLTs 
during the DLT observation period (Cycle 1+28 days [from first dose through Study Day 56]). If 0 or 1 DLT occurs in 
the first 3 patients, 3 additional patients will be enrolled and monitored for DLTs. If the first 6 patients complete the 
DLT observation period with 0 or 1 patient experiencing a DLT, 48 mg/m2 will be the recommended dose of 
brentuximabvedotin, and approximately 49 additional patients will receive the protocol therapy in phase 2 to further 
assess safety and efficacy, for a total of at least 55 evaluable patients at the recommended dose in the study. Available 
pharmacokinetics (PK) data will be reviewed together with the safety data to guide the final decision on the 
recommended dose.
Given the known safety profile of this regimen in adult patients and the importance of dose intensity in the first-line 
treatment of HL, this study will begin with a dose that is expected to deliver equivalent brentuximab vedotin exposure
to that in the adult regimen (see Section 4.5). If at any time more than 1 patient out of a maximum of 6 DLT-evaluable 
patients treated with the protocol therapy experiences a DLT, the brentuximab vedotin dose will be reduced to 
36 mg/m2. If 0 or 1 patient experiences a DLT among the 6 patients treated at 36 mg/m2, approximately an additional 
49 patients will be enrolled into the de-intensified dosing regimen to ensure a total of at least 55 evaluable patients at 
the recommended dose (36 mg/m2). If more than 1 patient experiences a DLT in the first 6 patients treated at 
36 mg/m2, the study will be discontinued (pending review of available PK data to verify that exposures achieved at 
these doses are consistent with expectations), as both the 36 mg/m2 dose and the 48 mg/m2 dose will be deemed too 
toxic.
Response to treatment and disease status assessments will be evaluated according to the International Working Group 
(IWG) Revised Criteria for Response Assessment for Malignant Lymphoma [1]. These disease assessments will be 
performed by investigators and an independent review facility (IRF) at times specified in the Schedule of Events 
(SOE). Evaluations will be performed per the SOE until progressive disease is documented by the investigator, death 
occurs, or the study ends. 
Restaging will be performed to assess the status of the patient’s underlying disease after completion of Cycle 2 
treatment and at End of Treatment (EOT). Involved site radiotherapy (ISRT) should be employed (at EOT) in patients 
who are positron emission tomography (PET) positive (PET+) at the end of Cycle 2 at the node sites that were PET+ at 
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diagnosis with a boost to sites that are still PET+ at EOT.
Survival will be assessed until the sooner of death, study closure, or up to 2 years after enrollment of the last patient. 
The main study will be considered to be complete when all study patients have had the opportunity to be followed for 
up to 2 years after enrollment of the last patient. All patients will be offered the opportunity to participate in an 
optional long-term follow-up, for at least 10 years after their date of enrollment in the main study.
Phase 1 Primary Objective:
To assess the safety and tolerability, and to identify the recommended dose of brentuximab vedotin when combined 
with multiagent chemotherapy regimen AVD for first-line treatment of advanced stage HL in pediatric patients.
Phase 1 Secondary Objectives:

To describe the maximum observed concentration (Cmax), area under the concentration-time curve from time 0 to 
15 days (AUC0-15), and time of first time of occurrence of Cmax (Tmax) of brentuximab vedotin, monomethyl 
auristatin E (MMAE), and total (free and conjugated) therapeutic antibody (TAb).

To evaluate the complete remission (CR) rate of pediatric patients with advanced stage HL at the end of protocol 
therapy.

To evaluate the partial remission (PR) rate of pediatric patients with advanced stage HL at the end of protocol 
therapy.

To evaluate the overall response rate (ORR) of pediatric patients with advanced stage HL at the end of protocol 
therapy.

To determine the percentage of patients who are PET negative (PET-) after 2 cycles of protocol therapy.

To determine the percentage of patients who are PET+ after 6 cycles of protocol therapy.

To determine the immunogenicity of brentuximab vedotin.
Phase 2 Primary Objectives:

To evaluate the CR rate of pediatric patients with advanced stage HL at the end of protocol therapy.

To determine the percentage of patients who are PET- after 2 cycles of protocol therapy.

To evaluate the PR rate of pediatric patients with advanced stage HL at the end of protocol therapy.

To evaluate the ORR of pediatric patients with advanced stage HL at the end of protocol therapy.

To determine the percentage of patients who are able to complete 6 cycles of protocol therapy at the 
recommended dose.
Phase 2 Secondary Objectives:

To evaluate the progression-free survival (PFS), event-free survival (EFS), overall survival (OS), and duration of 
response (DOR) in pediatric patients with advanced stage HL treated with protocol therapy.

To determine the percentage of patients receiving irradiation for HL following study treatment.

To assess the safety and tolerability of brentuximab vedotin when combined with multiagent chemotherapy 
regimen AVD for first-line treatment of advanced stage HL in pediatric patients.

To determine the immunogenicity of brentuximab vedotin.

To evaluate the effect of antitherapeutic antibodies (ATA) and ATA status on the safety, efficacy, and PK of 
brentuximab vedotin.

To describe the Cmax, AUC0-15, and Tmax of brentuximab vedotin, MMAE, and TAb.

To describe the frequency, severity, and time to resolution of peripheral neuropathy events. 

To assess immune reconstitution. 
Subject Population: Male or female patients aged 5 to <18 years with newly diagnosed classical CD30+ advanced 
(Ann Arbor Stage III or Stage IV) HL who are treatment naïve with Karnofsky Performance Status or Lansky 
Play-Performance ≥50.
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Number of Subjects:
A total of at least 55 evaluable patients will be enrolled. In 
the phase 1 portion of the study, at least 6 patients will be 
enrolled into up to 2 planned dose cohorts dose cohorts (48 
and 36 mg/m2, 3-6 patients per cohort) to determine the 
recommended dose according to a modified 3+3 design. 
Once the recommended dose is identified, additional 
patients will be enrolled into phase 2 so that the total 
number of evaluable patients will be at least 55, including 
the patients treated at the recommended dose in phase 1.
Number of Sites: 
There are 14 study centers globally.
Dose Level(s):
Brentuximab vedotin 48 or 36 mg/m2, plus doxorubicin 
25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 
375 mg/m2.
Route of Administration:
All protocol therapy will be administered by 
intravenous infusion on Days 1 and 15 of each 28-day 
cycle.
Brentuximab vedotin infusion is to start approximately 
1 hour after the conclusion of the dacarbazine 
administration.
Duration of Treatment:
Patients will be treated for a maximum of six 28-day cycles.
Period of Evaluation:
Patients will have an EOT assessment visit 307 days 
after receiving their final dose of protocol therapy. 
Survival will be assessed until the sooner of death, 
study closure, or up to 2 years after enrollment of the 
last patient. All patients will be offered the opportunity 
to participate in an optional long-term follow-up, for at 
least 10 years from their date of enrollment in the main 
study.
Main Criteria for Inclusion:
Male or female patients aged 5 to <18 years with newly diagnosed classical CD30+ advanced stage (Stage III and 
Stage IV) HL who are treatment naïve with Karnofsky Performance Status or Lansky Play-Performance ≥50.
Main Criteria for Exclusion:
Patients may not have nodular lymphocyte-predominant HL, known active cerebral meningeal disease, including 
signs or symptoms of progressive multifocal leukoencephalopathy (PML) or any history of PML, sensory or motor 
peripheral neuropathy, or known hypersensitivity to brentuximab vedotin or any component of AVD. 
Main Criteria for Evaluation and Analyses:
Phase 1 primary endpoints for this study are: 

Determination of the recommended dose of brentuximab vedotin in combination with AVD in a pediatric 
population.

Percentage of patients who experience adverse events (AEs) from the first dose of protocol therapy through 
30 days after administration of the last dose of protocol therapy.

Percentage of patients who experience serious adverse events (SAEs) from the first dose of protocol therapy 
through 30 days after administration of the last dose of protocol therapy.
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Phase 1 secondary endpoints for this study are:

Mean Cmax and mean AUC0-15 of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma).

Median Tmax of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma). 

Percentage of patients who achieve a CR per IRF assessment at EOT per IWG criteria [1].

Percentage of patients who achieve a PR per IRF assessment at EOT per IWG criteria [1].

Percentage of patients who achieve an overall response (OR) per IRF assessment at EOT per IWG criteria [1].

Percentage of patients whose disease is PET- after 2 cycles of protocol therapy per IRF assessment.

Percentage of patients whose disease is PET+ after 6 cycles of protocol therapy per IRF assessment.

Percentage of patients who are ATA positive, persistently positive, or transiently positive, ATA titer and 
neutralizing ATA (nATA) positive at baseline, predose Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, or at 
termination if treatment is terminated before Cycle 6, and at EOT. 

Impact of ATA and nATA on the primary safety, secondary efficacy, and PK endpoints.
Phase 2 primary endpoints for this study are:

Percentage of patients who achieve a CR per IRF assessment at EOT per IWG criteria [1].

Percentage of patients whose disease is PET- after 2 cycles of protocol therapy per IRF assessment.

Percentage of patients who achieve a PR per IRF assessment at EOT per IWG criteria [1].

Percentage of patients who achieve an OR per IRF assessment at EOT per IWG criteria [1].

Percentage of patients who are able to complete 6 cycles of protocol therapy at the recommended dose.
Phase 2 secondary endpoints for this study are:

PFS, EFS, OS, DOR. 

Percentage of patients receiving irradiation for HL following study treatment. 

Percentage of patients who experience AEs from first dose of protocol therapy through 30 days after 
administration of the last dose of protocol therapy.

Percentage of patients who experience SAEs from first dose of protocol therapy through 30 days after 
administration of the last dose of protocol therapy.

Percentage of patients who are ATA positive, persistently positive, or transiently positive, ATA titer and nATA 
positive at baseline, predose Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 Day 1, or at termination if treatment is 
terminated before Cycle 6, and at EOT. 

Impact of ATA and nATA on the primary safety, secondary efficacy, and PK endpoints.

Mean Cmax and mean AUC0-15 of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma).

Median Tmax of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma). 

Percentage of patients who experience peripheral neuropathy, regardless of seriousness, from the first dose of 
protocol therapy through study closure.

Time to onset and time to resolution for all peripheral neuropathy events.

Immune reconstitution (peripheral blood CD34+ count; enumeration of the total lymphocyte count and 
lymphocyte subsets; total immunoglobulin [Ig] and IgG, IgM, and IgA levels; and levels of the antibodies to 
tetanus, hemophilus influenza type B [HiB], and polio serotypes) at baseline, EOT, and at 6, 12, and 18 months 
(±1 month) after last dose, until the start of subsequent anticancer therapy (with the exception of radiotherapy 
administered as part of first-line therapy).
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Statistical Considerations: 
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from baseline in the 
patient’s vital signs, neuropathy assessment, and clinical laboratory results using the Safety Population. Exposure to 
protocol therapy, including percentage of patients who are able to complete 6 cycles of treatment and reasons for 
discontinuation, will be tabulated. Treatment-emergent AEs (TEAEs) that occur after administration of the first dose 
of protocol therapy and through 30 days after the last dose of protocol therapy will be tabulated. AEs will be tabulated 
according to the Medical Dictionary for Regulatory Activities and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

SAEs.
A listing of TEAEs resulting in protocol therapy discontinuation will be provided. The individual patient’s 
information on the DLTs will also be presented in a listing.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from baseline in clinical 
laboratory parameters) will be presented for all scheduled measurements over time. Mean laboratory values over time 
will also be plotted for key laboratory parameters. Shift tables for laboratory parameters will be generated based on 
changes in National Cancer Institute Common Terminology Criteria for Adverse Events grade from baseline to the 
worst postbaseline value. Graphical displays of key safety parameters, such as scatter plots of baseline versus worst 
postbaseline values, may be used to understand the brentuximab vedotin safety profile.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs, weight, and development 
assessment results over time will be tabulated by scheduled time point. The results of lymphoma assessment and 
Lansky Play-Performance/Karnofsky Performance Status over time will also be tabulated.
All concomitant medications collected from Screening throughout the study period will be classified to generic terms 
according to the World Health Organization Drug Dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to further define the 
safety profile of brentuximab vedotin.
PK, Immune Reconstitution, and Immunogenicity Analysis
Descriptive statistics (eg, number of patients, arithmetic mean, geometric mean, standard deviation, median, 
percentage of coefficient of variation, minimum, and maximum) will be used to summarize brentuximab vedotin and 
TAb concentrations in serum, and concentrations of MMAE in plasma, by dose group. Mean plasma concentration 
data will be plotted over time by dose group. PK parameters (Cmax, AUC0-15, Tmax) will be calculated from individual 
plasma (MMAE) or serum (brentuximab vedotin, TAb) concentration-time data using noncompartmental methods 
and summarized descriptively by analyte and dose group. Immune reconstitution (peripheral blood CD34+ count, 
enumeration of the total lymphocyte count and lymphocyte subsets, total Ig and IgG, IgM, and IgA levels, levels of 
antibodies to tetanus, HiB, and polio serotypes) over time will be summarized. Immunogenicity parameters (ATA titer 
and nATA titer in serum) will be summarized using descriptive statistics. The relationship of immunogenicity 
responses to efficacy and safety will be explored.
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Efficacy Analysis
Analysis of efficacy measures will be descriptive. ORR, CR rate, and PR rate at EOT will be assessed by an IRF and 
by investigators per IWG criteria. The percentage of patients whose disease is PET- after 2 cycles of A+AVD 
chemotherapy and the percentage of patients whose disease is PET+ after 6 cycles will also be evaluated. Other 
efficacy endpoints including PFS, EFS, OS, and DOR will also be explored. The percentage of patients receiving 
irradiation for HL following study treatment will be summarized.
Sample Size Justification: A total of at least 55 evaluable patients treated at the recommended dose will be enrolled 
in this study. In phase 1, up to 12 DLT-evaluable patients will be enrolled into up to 2 planned dose cohorts (48 and 
36 mg/m2, 3-6 patients per cohort) according to a modified 3+3 design. Once the recommended dose is identified, 
additional patients will be enrolled into phase 2 so that the total number of evaluable patients will be at least 55, 
including the patients treated at the recommended dose in phase 1. Assuming that the true ORR for the A+AVD 
regimen is 90%, with 55 evaluable patients and a 2-sided type I error of α=0.2, the study would have approximately 
78% power to state that the ORR is greater than 80%. An interim futility analysis will be conducted after 25 patients 
have completed 6 cycles of study therapy and had their EOT response assessment. The study may be terminated early 
in the case of inferior efficacy. Analyses will be primarily descriptive in nature. No formal statistical tests will be 
performed.
Planned Reporting: As prespecified in the approved SAP, the analyses for reporting the results of the study’s primary 
endpoints in the clinical study report (CSR) were performed after all enrolled patients had the opportunity to be 
followed for 15 months after enrollment of the last patient in the main study. Efficacy results are presented by study 
phase, and for all evaluable patients treated at the recommended dose.
Patients will continue to be followed for survival and disease status every 12 weeks (!1 week) for 12 months, and then 
every 24 weeks (!2 weeks) until death or study closure or for up to 2 years from the date of the last patient enrolled. 
An updated analysis of the time-to-event efficacy endpoints and other selected study endpoints will be performed after 
all enrolled patients have had the opportunity to be followed for up to 2 years after enrollment of the last patient, 
denoting the end of the main study. This updated analysis may include data from the long-term follow-up period. 
Results of the updated analysis will be presented in an addendum to the CSR.
Data from the optional long-term follow-up will be analyzed after all participating patients have had the opportunity to 
complete 10 years of follow up from their date of enrollment in the main study and those results will be presented in a 
separate CSR addendum.
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Study Overview Diagram
AVD+A: brentuximab vedotin, Adriamycin, vinblastine, and dacarbazine; C2D25: Cycle 2 Day 25; CT: computed 
tomography; EOT: End of Treatment; MRI: magnetic resonance imaging; PET: positron emission tomography; XRT: 
radiotherapy.
AVD+A indicates the actual order of drug administration.
* 30 days (7 days) after completion of last dose of protocol therapy.
PET, CT, and MRI at C2D25 and 3-7 weeks after last dose of protocol therapy.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities 
The sponsor will perform all study-related activities with the exception of those identified in the 
Clinical Study Supplier List. The identified vendors in the template for specific study-related 
activities will perform these activities in full or in partnership with the sponsor.
3.2
Principal Investigator/Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator from the investigators who participate in 
the study. Selection criteria for this investigator will include significant knowledge of the study 
protocol, the study medication, their expertise in the therapeutic area and the conduct of clinical 
research as well as study participation. The Signatory Coordinating Investigator will be required to 
review and sign the clinical study report and by doing so agrees that it accurately describes the 
results of the study.
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3.3
List of Abbreviations
A+ABVD
brentuximab vedotin with standard doses of Adriamycin (doxorubicin), bleomycin, 
vinblastine, and dacarbazine
A+AVD
brentuximab vedotin with Adriamycin (doxorubicin), vinblastine, and dacarbazine
ABVD
Adriamycin (doxorubicin), bleomycin, vinblastine, and dacarbazine
AE
adverse event
ALCL
anaplastic large-cell lymphoma
ASCT
autologous stem cell transplant
ATA
antitherapeutic antibody
AUC
area under the concentration-time curve
AUC0-15
area under the concentration-time curve from Day 0 to Day 15
AVD
Adriamycin (doxorubicin) vinblastine, and dacarbazine
BSA
body surface area
cAC10
CD30-directed monoclonal antibody
CDC
Centers for Disease Control and Prevention
Cmax
maximum observed concentration
cHL
classical Hodgkin lymphoma
COVID-19
coronavirus disease 2019
CR
complete remission
CRO
contract research organization
CT
computed tomography
CYP
cytochrome P450
DLT
dose-limiting toxicity
DOR
duration of response
ECG
electrocardiogram
eCRF
electronic case report form
EFS
event-free survival
EMA
European Medicines Agency
EOT
End of Treatment (visit)
EU
European Union
FDA
Food and Drug Administration
GCP
Good Clinical Practice
HiB
hemophilus influenza type B
HL
Hodgkin lymphoma
HRS
Hodgkin Reed-Sternberg
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council on Harmonisation
IEC
independent ethics committee
CCI
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Ig
immunoglobulin
IRB
institutional review board
IRF
independent review facility
ISRT
involved site radiotherapy
IV
intravenous(ly)
IWG
International Working Group
JCV
John Cunningham virus
MedDRA
Medical Dictionary for Regulatory Activities
MMAE
monomethyl auristatin E
MRI
magnetic resonance imaging
MUGA
multiple-gated acquisition scan
nATA
neutralizing antitherapeutic antibody
NCI CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NK
natural killer
OR
overall response
ORR
overall response rate
OS
overall survival
OSFU
overall survival follow-up
PD
progressive disease
PET
positron emission tomography
PET-
positron emission tomography negative
PET+
positron emission tomography positive
PFS
progression-free survival
PFSFU
progression-free survival follow-up
PK
pharmacokinetic(s)
PML
progressive multifocal leukoencephalopathy
PR
partial remission
PTE
pretreatment event
Q2W
every 2 weeks
RP2D
recommended phase 2 dose
SAE
serious adverse event
sALCL
systemic anaplastic large-cell lymphoma
SAP
statistical analysis plan
SOC
standard of care
SOE 
Schedule of Events
SUSAR
suspected unexpected serious adverse reaction
TAb
total (free and conjugated) therapeutic antibody
TDC Americas Inc.
Takeda Development Center, Americas, Inc.
TEAE
treatment-emergent adverse event
Tmax
time of first time of occurrence of Cmax
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Property of Takeda: For Non-Commercial Use 
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ULN
upper limit of the normal range
US
United States
WHO
World Health Organization
3.4
Corporate Identification 
TDC Americas
Takeda Development Center Americas, Inc.
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe
Takeda Development Centre Europe Ltd
TDC Japan
Takeda Development Center Japan
Takeda
Millennium Pharmaceuticals, Inc, TDC Americas, TDC Asia, TDC Europe, TDC Japan
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4.0
INTRODUCTION
4.1
Background
4.1.1
Disease Under Treatment
Hodgkin lymphoma (HL), a neoplasm of lymphoid tissue, is 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 2013 alone, it was 
estimated that approximately 9290 new cases of HL were diagnosed in the United States (US) [2]. 
In 2012, approximately 12,431 new cases of HL were diagnosed in the 28 major European Union 
(EU) countries [3], and approximately 898 new cases of HL were diagnosed in Canada [3]. 
Pediatric HL has an annual incidence of approximately 0.7 to 1.0 cases per 100,000 children in the 
US and in the EU [4] and is the childhood cancer with the highest cure rates, with historical overall 
survival (OS) rates of more than 90% in early-stage disease and up to 70% for advanced stage 
disease [5-8]. Five-year event-free survival (EFS) in pediatric HL is approximately 80% to 85% 
[9]. Pediatric patients aged less than 10 years had a significantly improved freedom from relapse 
and survival compared with adolescents, and a highly significant improved outcome compared 
with adults. Although pediatric patients present high cure rates, many multiagent regimens confer 
significant morbidity, including secondary malignancies, cardiovascular disease, thyroid function 
impairment, male infertility, pulmonary diseases, and infections [10-13]. Some of the serious 
sequelae of radiation and alkylating chemotherapy are most pronounced in younger patients, in 
whom growth and development are particularly active when therapy is administered. In addition, 
cardiac toxicity appears to be age related, with younger patients at the highest risk. Secondary 
malignancies, including breast cancer in female patients and secondary myeloid neoplasms, 
represent the leading cause of mortality in survivors of HL [14,15].
The proposed pediatric study has been designed to evaluate brentuximab vedotin as a component 
of a multiagent frontline chemotherapy regimen in patients with advanced stage, newly diagnosed 
HL, here defined as Stage III and Stage IV and a ≥50 Lansky Play-Performance or Karnofsky 
Performance Status. The primary objective of the study is to evaluate the safety and determine the 
recommended dose, and the secondary objectives include evaluation of efficacy, pharmacokinetics 
(PK), immunogenicity, the percentage of patients who have a negative positron emission 
tomography (PET) result (PET-; Deauville score 3) after 2 cycles of treatment, and the 
percentage of patients who have a positive PET result (PET+; Deauville score >3) after 6 cycles of 
treatment (see Appendix D).
4.1.2
Study Drug
Brentuximab vedotin (ADCETRIS, the first “A” in the treatment regimen acronym) is an 
antibody-drug conjugate. It consists of a CD30-directed monoclonal antibody (cAC10) covalently 
linked, via an enzyme-cleavable linker, to the antimitotic small molecule monomethyl auristatin E 
(MMAE). cAC10 binds to the CD30 antigen, which has very low expression on normal cells but is 
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found at higher levels of expression on the HRS cells of HL, on anaplastic large-cell lymphoma 
(ALCL) cells, and on tumor cells of other varied lymphoproliferative disorders.
The European Medicines Agency (EMA) granted brentuximab vedotin conditional marketing 
authorization as ADCETRIS on 25 October 2012 for the treatment of adult patients with relapsed 
or refractory CD30HL after autologous stem cell transplant (ASCT) or after at least 2 previous 
treatments when ASCT or multiagent chemotherapy is not a treatment option, and for the 
treatment of adult patients with relapsed or refractory systemic anaplastic large-cell lymphoma 
(sALCL). In 2016, the EMA further approved ADCETRIS for the treatment of (1) adult patients 
with HL or sALCL who previously responded to ADCETRIS and who later relapse, and (2) adult 
patients with CD30+ HL at increased risk of relapse or progression following ASCT.
On 19 August 2011, the US Food and Drug Administration (FDA) granted accelerated approval to 
brentuximab vedotin as ADCETRIS for the treatment of patients with sALCL after failure of at 
least 1 prior multiagent chemotherapy regimen and for the treatment of patients with HL after 
failure of ASCT or after failure of at least 2 prior multiagent chemotherapy regimens in patients 
who are not ASCT candidates. In 2015, the US FDA further approved ADCETRIS for the 
treatment of patients with classical Hodgkin lymphoma (cHL) at high risk of relapse or 
progression as post–autologous hematopoietic stem cell transplantation consolidation.
4.2
Nonclinical Experience 
Brentuximab vedotin has the potential to target and selectively deliver a potent cytotoxic agent to 
CD30+ tumor cells. It induces cell death of both HL and ALCL cell lines in vitro with 
subnanomolar concentrations producing 50% inhibition and has demonstrated antitumor activity 
in xenograft models of the same tumors.
Multiple-dose brentuximab vedotin toxicity studies have been performed in monkeys and rats. In 
both species, hypocellularity of the bone marrow and lymphoid depletion of the thymus were 
observed. In addition, lesions were seen in the kidneys, liver, and spleen in monkeys and in the 
liver and testes in rats. Reversibility of toxicity was demonstrated for all the findings with the 
exception of the testicular changes in rats. At the recovery sacrifice 4 weeks following the last dose 
of brentuximab vedotin, testicular changes (diffuse seminiferous tubule degeneration) were still 
evident. The no observed adverse effect level for brentuximab vedotin was defined at 1.0 mg/kg in 
monkeys and 0.5 mg/kg in rats. Human equivalent doses are 0.32 and 0.08 mg/kg, respectively.
Detailed information regarding the nonclinical pharmacology and toxicology of brentuximab 
vedotin may be found in the Investigator’s Brochure (IB).
4.3
Clinical Experience 
More than 700 patients have received brentuximab vedotin monotherapy in 10 completed clinical 
studies. Six studies formed the basis for initial marketing authorizations of brentuximab vedotin 
for relapsed HL and systemic ALCL in the US, Europe, Canada, and additional countries. 
Study SGN35-009 is a completed, phase 1, 2-arm, open-label, multicenter study in adults to 
evaluate the safety of brentuximab vedotin when administered in combination with standard 
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therapy, doxorubicin (Adriamycin), bleomycin, vinblastine, and dacarbazine (ABVD), or a 
modified standard therapy, Adriamycin (doxorubicin), vinblastine, and dacarbazine (AVD). Adult 
patients received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of 
ABVD (A+ABVD) or 1.2 mg/kg brentuximab vedotin with AVD (A+AVD), depending upon 
cohort assignment. 
A total of 47 of 51 patients (92%) completed first-line therapy. At the completion of first-line 
therapy, 45 of the 47 patients (96%) achieved complete remission (CR), 21 of 22 patients (95%) in 
the A+ABVD regimen and 24 of 25 patients (96%) in the A+AVD regimen. A 3-year failure-free 
survival analysis showed 92% of patients treated in the A+AVD arm versus 79% of patients 
treated in the A+ABVD arm [16]. Of the 51 patients, 50 (98%) experienced at least 
1 treatment-emergent adverse event (TEAE); 24 patients (96%) in the A+ABVD regimen and 
26 patients (100%) in the A+AVD regimen. Overall, a total of 43 patients (84%) experienced at 
least 1 Grade ≥3 event; 22 of 25 patients (88%) in the A+ABVD regimen and 21 of 26 patients 
(81%) in the A+AVD regimen.
Fifty-one patients received at least 1 dose of A+ABVD (n=25) or A+AVD (n=26). Whereas no 
pulmonary toxicity was reported for patients who received A+AVD, noninfectious pulmonary 
toxicity was reported for patients who received A+ABVD, and the rate was higher than historical 
incidence reported with ABVD alone. Brentuximab vedotin combined with bleomycin was 
subsequently listed as contraindicated in the US Prescribing Information and in the EU Summary 
of Product Characteristics. The A+AVD regimen was well tolerated, and the CR rate among 
patients who received the combination was favorable.
Clinical Study C25002 is an ongoing phase 1/2 study of brentuximab vedotin in pediatric patients 
with relapsed or refractory sALCL or HL. The primary objectives of the study are to assess the 
safety and PK, and determine the pediatric maximum tolerated dose and/or recommended phase 2 
dose (RP2D) of brentuximab vedotin in pediatric patients. Approximately 42 patients will be 
enrolled in the study. The phase 1 dose escalation arm of the study was planned to enroll 
12 patients with any relapsed or refractory CD30+ hematologic malignancy. The 2 phase 2 arms of 
the study will enroll at least 15 evaluable patients diagnosed with relapsed or refractory sALCL 
and HL, respectively. 
4.4
Potential Risks in Children 
As detailed in Section 4.3, brentuximab vedotin monotherapy and multiagent therapy have 
demonstrated therapeutic activity in CD30+ hematological malignancies. 
Brentuximab vedotin recognizes the CD30 antigen on tumor cells and normal activated T cells. In 
nonclinical toxicology studies, hypocellularity of the bone marrow and lymphoid depletion of the 
thymus were observed in rats and monkeys. It is possible that binding of brentuximab vedotin to 
normal CD30+ T cells could render these cells ineffective, thus leading to alterations in immune 
function. To date, the effect of brentuximab vedotin on the immune system of pediatric patients 
and the extent or duration of immune dysfunction following the completion of brentuximab 
vedotin therapy is unknown. Pediatric patients have rapidly developing immune systems 
characterized by continual exposure to neoantigens and a large thymus where T-cell selection is 
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actively engaged. CD30 is expressed on medullary cells of the thymus; however, the role of CD30 
in T-cell selection is controversial [17,18]. Nonclinical data suggest a potential impact of 
brentuximab vedotin on thymic cell populations. Additionally, younger patients are more likely to 
have immune suppression after completion of chemotherapy, including the loss of protective 
serum antibody concentrations against vaccines. There is a reduction in vaccine-antigen-specific 
antibody concentrations after completion of chemotherapy [19].
The extent and duration of immune dysfunction following the completion of standard-dose 
chemotherapy will depend on the antineoplastic agent used and its dose intensity, and can 
therefore vary widely. This may influence immunity to vaccine antigens and responses to 
vaccination. Total B and T lymphocytes usually recover fully, quantitatively and functionally, 
6 months after completion of chemotherapy; although in some cases, recovery may take up to 
1 year. There is a reduction of immunoglobulin (Ig) levels after completion of chemotherapy, 
particularly of IgG2 levels. Normalization of Ig levels can take up to 1 year after completion of 
treatment. A recent study looking at immunity to vaccines at a median time of 7 months after 
completion of treatment for acute leukemia in British children demonstrated protective antibody 
concentrations for all patients to tetanus, 87% to hemophilus influenza type B (HiB), 71% to 
measles, 12% to Neisseria meningitidis group C (meningococcus C), and 11% to all 3 poliovirus 
serotypes. Therefore, to assess the effect of brentuximab vedotin on pediatric immune function, 
the duration of any changes to the levels of immunoglobulins (including IgG, IgA, and IgM), and 
the number and subsets of lymphocytes, such as T cell, B cell, and natural killer (NK) cell subsets, 
peripheral blood CD34+ cell counts, and vaccine-specific antibody levels (tetanus, HiB, and 
poliovirus) will be examined at baseline and at 6, 12, and 18 months (±1 month) after treatment is 
completed.
To address safety concerns regarding growth and development in children treated with 
brentuximab vedotin, Centers for Disease Control and Prevention (CDC)-recommended growth 
charts for persons aged 2 to 19 years will be used. Clinical charts are available for boys and for 
girls at cdc.gov/growthcharts/clinical_charts.htm. A sexual maturity scale such as the one 
developed by Tanner is used to assess the physical developmental stage of a patient. This scale 
assigns a Tanner stage of 1 (prepubertal) to 5 (adult) to girls based on breasts and pubic hair and to 
boys based on genitalia and pubic hair.
For specific risks associated with brentuximab vedotin, refer to Section 6 of the IB.
4.5
Rationale for the Proposed Study
Including brentuximab vedotin as a component of multiagent chemotherapy in pediatric patients 
with newly diagnosed HL may provide clinical benefit by decreasing the need for radiotherapy 
following chemotherapy, thereby reducing the risks of late effects associated with radiotherapy, 
including secondary malignancies, cardiac toxicity, and thyroid dysfunction. The safety, 
tolerability, recommended dosing, PK, immunogenicity, and antitumor activity of brentuximab 
vedotin alone or in a multiagent chemotherapy regimen have not been studied for first-line 
treatment of HL in a pediatric population. ABVD treatment of advanced stage HL is associated 
with a 5-year progression-free survival (PFS) rate of 76%. [20] This standard of care (SOC) 
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generally includes involved-field radiation therapy following chemotherapy in patients with a 
suboptimal response to chemotherapy alone. Because of the increased risk of late effects 
associated with radiotherapy, including secondary malignancies, cardiac and pulmonary toxicities, 
and endocrine dysfunction, a focus of research in pediatric HL has been on minimizing the need 
for radiotherapy. 
The single-agent activity of brentuximab vedotin has been demonstrated in adult (SG035-0003) 
relapsed/refractory HL, and the pediatric RP2D for brentuximab vedotin is being investigated in 
clinical Study C25002 (safety and dose escalation) in pediatric patients diagnosed with relapsed or 
refractory HL and sALCL. Safety and feasibility of brentuximab vedotin administered at 
1.2 mg/kg every 2 weeks have been demonstrated in a phase 1 study in adult first-line HL 
(SGN35-009) as part of a combination chemotherapy regimen with AVD. Because the PK of
brentuximab vedotin is linear, the administration of 1.2 mg/kg intravenously (IV) every 2 weeks 
or 1.8 mg/kg IV every 3 weeks should result in similar time-averaged exposures. Furthermore, no 
dose-limiting toxicities (DLTs) were observed in the 1.2 mg/kg dose cohort of Study SGN35-009. 
Additionally, of the 4 agents in the ABVD regimen, bleomycin is most associated with 
unpredictable, life-threatening pulmonary toxicity [21]. For patients on ABVD therapy who 
develop pulmonary toxicity, standard practice is to continue first-line therapy with AVD while 
omitting bleomycin. The replacement of brentuximab vedotin for bleomycin in an AVD 
combination regimen may provide an improvement in PFS over the standard ABVD regimen and 
eliminate the risk of bleomycin-associated pulmonary toxicity. 
Therefore, brentuximab vedotin at 1.2 mg/kg every 2 weeks in combination with multiagent 
chemotherapy AVD is being evaluated for safety and efficacy in a phase 3 study, ECHELON-1 
(C25003), in adults with newly diagnosed, advanced stage, cHL. The ECHELON-1 A+AVD 
regimen arm in adult patients with newly diagnosed, advanced stage HL will serve as a basis for 
extrapolation for this pediatric study of safety and tolerability of brentuximab vedotin at doses to 
achieve exposures in pediatric patients with newly diagnosed, advanced stage cHL comparable to 
adults. The pediatric dose that will provide a similar exposure to that seen in the adult population 
was estimated in a preliminary analysis of brentuximab vedotin exposure in the pediatric 
Study C25002. In that study, the area under the concentration-time curve (AUC) of brentuximab 
vedotin in pediatric patients was found to be lower than that seen in adults after the same 
1.8 mg/kg dose. (Preliminary estimates of Geomean AUC were 76 and 63, respectively, for adults 
in Study SG035-0001 and for pediatric patients in Study C25002). At the lower pediatric age of 
4 years with a typical body weight of 16 kg, the AUC of brentuximab vedotin was estimated to be 
approximately 43 µg/mL*day. Simulations from a population PK analysis of the data showed that 
dosing pediatric patients based on body surface area normalizes the difference in exposure in adult
and pediatric patients. Based on the adult exposure from the 1.8 mg/kg dose, 71.5 mg/m2 was 
found to provide a similar exposure in pediatric patients across the age range of 4 to 17 years. 
Extrapolation of the above single-agent exposure experience to the dosing in the multiagent 
first-line setting in which adult brentuximab vedotin dosing was 1.2 mg/kg every 2 weeks (Q2W), 
the pediatric dosing is calculated to be approximately 48 mg/m2 Q2W.
Although excessive toxicity of A+AVD is not expected, this study will include a plan to 
de-escalate the brentuximab vedotin dose if patients show excessive toxicity to the regimen. 
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Replacing bleomycin with brentuximab vedotin in ABVD therapy may provide clinical benefit to 
pediatric patients with newly diagnosed HL by decreasing the risks of pulmonary toxicity and of 
late undesirable effects associated with radiotherapy.
The recommended dose of brentuximab vedotin in adult patients with relapsed/refractory HL or 
ALCL is 1.8 mg/kg administered IV every 3 weeks until a maximum of 16 cycles, disease 
progression, or unacceptable toxicity. At this dose and schedule, the most common adverse events 
(AEs) were peripheral sensory neuropathy, fatigue, nausea, diarrhea, pyrexia, upper respiratory 
tract infection, neutropenia, and vomiting. These events have been primarily mild or moderate in 
severity. The planned dose of brentuximab vedotin in this study is 48 mg/m2 Q2W, which should 
provide the same exposure as the adult dose of 1.2 mg/kg Q2W, based on population PK modeling 
and simulation, as described earlier.
5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Phase 1 Primary Objective
The primary objective is:

To assess the safety and tolerability, and to identify the recommended dose of brentuximab 
vedotin when combined with multiagent chemotherapy regimen AVD for first-line treatment 
of advanced stage HL in pediatric patients.
5.1.2
Phase 1 Secondary Objectives
The secondary objectives are:

To describe the maximum observed concentration (Cmax), area under the concentration-time 
curve from time 0 to 15 days (AUC0-15), and time of first time of occurrence of Cmax (Tmax) of 
brentuximab vedotin, MMAE, and total (free and conjugated) therapeutic antibody (TAb).

To evaluate the CR rate of pediatric patients with advanced stage HL at the end of protocol 
therapy.

To evaluate the partial remission (PR) rate of pediatric patients with advanced stage HL at the 
end of protocol therapy.

To evaluate the overall response rate (ORR) of pediatric patients with advanced stage HL at the 
end of protocol therapy.

To determine the percentage of patients who are PET- after 2 cycles of protocol therapy.

To determine the percentage of patients who are PET+ after 6 cycles of protocol therapy.

To determine the immunogenicity of brentuximab vedotin.
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5.1.4
Phase 2 Primary Objectives
∀
To evaluate the CR rate of pediatric patients with advanced stage HL at the end of protocol
therapy.
∀
To determine the percentage of patients who are PET- after 2 cycles of protocol therapy.
∀
To evaluate the PR rate of pediatric patients with advanced stage HL at the end of protocol 
therapy.
∀
To evaluate the ORR of pediatric patients with advanced stage HL at the end of protocol 
therapy.
∀
To determine the percentage of patients who are able to complete 6 cycles of protocol therapy 
at the recommended dose.
5.1.5
Phase 2 Secondary Objectives
∀
To evaluate the PFS, EFS, OS, and DOR in pediatric patients with advanced stage HL treated 
with protocol therapy.
∀
To determine the percentage of patients receiving irradiation for HL following study treatment. 
∀
To assess the safety and tolerability of brentuximab vedotin when combined with multiagent 
chemotherapy regimen AVD for first-line treatment of advanced stage HL in pediatric 
patients.
∀
To determine the immunogenicity of brentuximab vedotin.
∀
To evaluate the effect of ATA and ATA status on the safety, efficacy, and PK of brentuximab 
vedotin.
∀
To describe the Cmax, AUC0-15, and Tmax of brentuximab vedotin, MMAE, and TAb.
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∀
To describe the frequency, severity, and time to resolution of peripheral neuropathy events. 
∀
To assess immune reconstitution. 
5.2
Endpoints
5.2.1
Phase 1 Primary Endpoints
∀
Determination of the recommended dose of brentuximab vedotin in combination with AVD in 
a pediatric population.
∀
Percentage of patients who experience AEs from the first dose of protocol therapy through 
30 days after administration of the last dose of protocol therapy.
∀
Percentage of patients who experience serious adverse events (SAEs) from the first dose of 
protocol therapy through 30 days after administration of the last dose of protocol therapy.
5.2.2
Phase 1 Secondary Endpoints
∀
Mean Cmax and mean AUC0-15 of brentuximab vedotin (serum), TAb (serum), and MMAE 
(plasma).
∀
Median Tmax of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma). 
∀
Percentage of patients who achieve a CR per independent review facility (IRF) assessment at 
End of Treatment (EOT) per International Working Group (IWG) criteria [1].
∀
Percentage of patients who achieve a PR per IRF assessment at EOT per IWG criteria [1].
∀
Percentage of patients who achieve an overall response (OR) per IRF assessment at EOT per 
IWG criteria [1].
∀
Percentage of patients whose disease is PET- after 2 cycles of protocol therapy per IRF 
assessment.
∀
Percentage of patients whose disease is PET+ after 6 cycles of protocol therapy per IRF 
assessment.
∀
Percentage of patients who are ATA positive, persistently positive, or transiently positive, 
ATA titer and neutralizing ATA (nATA) positive at baseline, predose Cycle 2 Day 1, Cycle 4 
Day 1, Cycle 6 Day 1, or at termination if treatment is terminated before Cycle 6, and at EOT. 
∀
Impact of ATA and nATA on the safety, efficacy, and PK endpoints.
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5.2.4
Phase 2 Primary Endpoints
∀
Percentage of patients who achieve a CR per IRF assessment at EOT per IWG criteria [1].
∀
Percentage of patients whose disease is PET- after 2 cycles of protocol therapy per IRF 
assessment.
∀
Percentage of patients who achieve a PR per IRF assessment at EOT per IWG criteria [1].
∀
Percentage of patients who achieve an OR per IRF assessment at EOT per IWG criteria [1].
∀
Percentage of patients who are able to complete 6 cycles of protocol therapy at the 
recommended dose.
5.2.5
Phase 2 Secondary Endpoints
∀
PFS, EFS, OS, DOR.
∀
Percentage of patients receiving irradiation for HL following study treatment.
∀
Percentage of patients who experience AEs from the first dose of protocol therapy through 
30 days after administration of the last dose of protocol therapy.
∀
Percentage of patients who experience SAEs from the first dose of protocol therapy through 
30 days after administration of the last dose of protocol therapy.
∀
Percentage of patients who are ATA positive, persistently positive, or transiently positive, 
ATA titer and nATA positive at baseline, predose Cycle 2 Day 1, Cycle 4 Day 1, Cycle 6 
Day 1, or at termination if treatment is terminated before Cycle 6, and at EOT. 
∀
Impact of ATA and nATA on the safety, efficacy, and PK endpoints.
∀
Mean Cmax and mean AUC0-15 of brentuximab vedotin (serum), TAb (serum), and MMAE 
(plasma).
∀
Median Tmax of brentuximab vedotin (serum), TAb (serum), and MMAE (plasma). 
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∀
Percentage of patients who experience peripheral neuropathy, regardless of seriousness, from 
the first dose of protocol therapy through study closure.
∀
Time to onset and time to resolution for all peripheral neuropathy events.
∀
Immune reconstitution (peripheral blood CD34+ count; enumeration of the total lymphocyte 
count and lymphocyte subsets; total Ig and IgG, IgM, and IgA levels; and levels of the 
antibodies to tetanus, HiB, and polio serotypes) at baseline, EOT, and at 6, 12, and 18 months 
(±1 month) after last dose, until the start of subsequent anticancer therapy (with the exception 
of radiotherapy administered as part of first-line therapy).
6.0
STUDY DESIGN
6.1
Overview of Study Design
This is a phase 1/2, open-label, multiagent, multicenter study of brentuximab vedotin in pediatric 
patients diagnosed with advanced stage, classical CD30+, first-line HL. The primary objectives of 
the study are to assess the safety and feasibility of combining brentuximab vedotin with a 
multiagent chemotherapy regimen that is based on a current SOC first-line treatment regimen for 
newly diagnosed HL, and to evaluate the antitumor activity of this combination in pediatric 
patients. A current widely used SOC regimen for this population is multiagent therapy ABVD. The 
proposed regimen for this study is identical to the current SOC except that in this study B 
(bleomycin) will be replaced with A (brentuximab vedotin) for A+AVD multiagent therapy
(protocol therapy). This study will be the first company-sponsored study to administer 
brentuximab vedotin as a combination component for pediatric patients. 
The study will enroll at least 55 evaluable patients. In the phase 1 portion of the study, at least 
6 patients will be enrolled into up to 2 planned dose cohorts (48 and 36 mg/m2, 3-6 patients per 
cohort) to determine the recommended dose according to a modified 3+3 design. Patients will be 
administered A+AVD on Days 1 and 15 of every 28-day cycle for up to 6 cycles. An 
End-of-Cohort meeting scheduled by the sponsor will occur after the last patient in each cohort has 
completed the DLT observation period. Enrollment will be on hold pending the documented 
outcome of this meeting. Once the recommended dose is identified, additional patients will be 
enrolled in the phase 2 portion as described below, so that the total number of evaluable patients 
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will be at least 55, including the patients treated at the recommended dose in phase 1. The Dosing 
Schema is presented in Figure 6.a.
Figure 6.a
Dosing Schema
DLT: dose-limiting toxicity; Pts: patients.
The phase 1 portion of the study will enroll up to 6 DLT-evaluable patients at a brentuximab 
vedotin dose of 48 mg/m2 to determine the recommended dose. The first 3 patients enrolled in the 
study will be monitored for DLTs during the DLT observation period (Cycle 1+28 days [from the 
first dose through Study Day 56]). If 0 or 1 DLTs occur in the first 3 patients, 3 additional patients 
will be enrolled and monitored for DLTs. If the first 6 patients complete the DLT observation with 
0 or 1 patient experiencing a DLT, 48 mg/m2 will be the recommended dose of brentuximab 
vedotin, and approximately 49 additional patients will be enrolled in the phase 2 portion of the 
study to receive the protocol therapy to further assess safety and efficacy for a total of at least 
55 evaluable patients at the recommended dose in the study. Available PK data will be reviewed 
together with the safety data to guide the final decision on the recommended dose. Refer to 
Section 8.1 for a description of the protocol therapy.
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Given the known safety profile of this regimen in adult patients and the importance of dose 
intensity in the first-line treatment of HL, this study will begin with a dose that is expected to 
deliver equivalent brentuximab vedotin exposure to that in the adult regimen (see Section 4.5). If at 
any time more than 1 patient out of a maximum of 6 DLT-evaluable patients treated with the 
protocol therapy experiences a DLT, the brentuximab vedotin dose will be reduced to 36 mg/m2. 
Refer to Section 8.3 for dose de-intensification rules. If 0 or 1 patient experiences a DLT among 
the 6 patients treated at 36 mg/m2, approximately an additional 49 patients will be enrolled into the 
de-intensified dosing regimen to ensure a total of at least 55 evaluable patients at the 
recommended dose (36 mg/m2), including the patients treated at the recommended dose in 
phase 1. If more than 1 patient experiences a DLT in the first 6 patients treated at 36 mg/m2, the 
study will be discontinued (pending review of available PK data to verify that exposures achieved 
at these doses are consistent with expectations), as both the 36 mg/m2 dose and the 48 mg/m2 dose 
will be deemed too toxic. 
Toxicity will be evaluated according to the National Cancer Institute Common Terminology 
Criteria for Adverse Events (NCI CTCAE), Version 4.03, effective date 14 June 2010 [22]. DLTs 
are defined in Section 8.2.
Study treatment will be discontinued due to completion of 6 cycles of protocol therapy, occurrence 
of unacceptable AE, progressive disease (PD), patient withdrawal, or study termination (see 
Section 9.8). Patients may discontinue protocol therapy at any time. 
AEs will be assessed, and laboratory values and vital signs will be obtained to evaluate the safety 
and tolerability of protocol therapy.
Serial blood samples will be obtained at prespecified time points as described in the Schedule of 
Events (SOE) (Appendix A) for determination of the serum concentration of brentuximab vedotin 
and TAb, plasma concentrations of MMAE, and to determine if patients are positive for ATA and 
nATA.
Response to treatment and disease status assessments will be evaluated according to the IWG 
Revised Criteria for Response Assessment for Malignant Lymphoma [1]. These disease 
assessments will be performed by investigators and an IRF at times specified in the SOE. 
Evaluations will be performed per the SOE until PD is documented by the investigator, death 
occurs, or the study ends. 
Restaging will be performed to assess the status of the patient’s underlying disease after 
completion of Cycle 2 treatment. Involved site radiotherapy (ISRT) should be employed at EOT in 
those patients who are PET+ at the end of Cycle 2 at the node sites that were PET+ at diagnosis. 
Additionally, restaging to determine if there is a need for additional radiotherapy will also be 
performed at the EOT disease assessment. Only residual lymph nodes >1 cm that are still PET+ at 
EOT should be considered for radiotherapy. Extranodal lesions should require radiotherapy only if 
they are PET+ at the end of Cycle 2 or EOT. Whenever possible, pericardial and liver irradiation 
should be avoided. The use of radiotherapy is not permitted until patients have completed their 
EOT disease assessment.
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For patients receiving radiation at EOT, the following guidance is provided: ISRT will consist of 
2100cGy in 14 fractions of 150cGy per day. Treatment should be given 5 days per week. All fields 
should be treated once per day. Treatment should begin no later than 4 weeks after completion of 
the last cycle of chemotherapy provided that the blood count recovery has occurred. Patients 
requiring radiation above and below the diaphragm should be treated with sequential rather than 
concurrent fields. The site of bulkiest involvement should be treated first, and the second field 
should be treated with adequate hematologic recovery.
Patients will be followed for survival until the sooner of death, study closure, or up to 2 years after 
enrollment of the last patient. 
All patients will be offered the opportunity to participate in an optional long-term follow-up, for at 
least 10 years after patient enrollment. For each patient electing to participate, the optional 
long-term follow-up will start 2 years after the date of the specific patient’s EOT visit. Regardless 
of participation in the optional 10-year long-term follow-up study, patients will continue with the 
main study for up to 2 years after enrollment of the last patient, as specified in Section 9.5.
6.2
Number of Patients
At least 55 evaluable patients will be enrolled in this study from 14 study centers globally. 
Enrollment is defined as the date of first dose of protocol therapy.
Patients who are withdrawn from the study before the completion of the DLT observation period 
for reasons other than DLTs will be replaced. Additional patients may be enrolled to ensure a total 
of at least 55 evaluable patients at the recommended dose. 
6.3
Duration of Study
6.3.1
Duration of an Individual Patient’s Study Participation
Patients will receive a maximum of 6 cycles of treatment with protocol therapy.
Following the last dose of protocol therapy, patients will be followed for a minimum of 30 days to 
permit the detection of any delayed TEAEs. Patients will be followed for survival until the sooner 
of death or study closure or up to 2 years after enrollment of the last patient.
All patients will be offered the opportunity to participate in an optional long-term follow-up, 
which focuses on the collection of long-term safety and survival data (refer to Section 9.13).
6.3.2
End of Study/Study Completion Definition and Planned Reporting
Primary Completion Study Completion
As prespecified in the approved SAP, the analyses for reporting the results of the study’s primary 
endpoints in the CSR were performed after all patients had the opportunity to be followed for 
15 months after enrollment of the last patient in the main study. 
Patients will continue to be followed for survival and disease status every 12 weeks (1 week) for 
12 months, and then every 24 weeks (2 weeks) until death or study closure or for up to 2 years 
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from the date of the last patient enrolled. An updated analysis of the time-to-event efficacy 
endpoints and other selected study endpoints will be performed after all enrolled patients have had 
the opportunity to be followed for up to 2 years after enrollment of the last patient, denoting the 
end of the main study. This updated analysis may include data from the long-term follow-up
period. Results of this updated analysis will be presented in an addendum to the CSR. 
Data from the optional long-term follow-up will be analyzed after all participating patients have 
had the opportunity to complete 10 years of follow-up from their date of enrollment in the main 
study and those results will be presented in a separate CSR addendum. 
6.3.3
Timeframes for Primary and Secondary Endpoints to Support Disclosures
Refer to Table 6.a for disclosures information for all primary and secondary endpoints.
Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a
Phase 1 Primary

Determination of the 
recommended dose of 
brentuximab vedotin in 
combination with AVD in a 
pediatric population.
The recommended dose of brentuximab 
vedotin in combination with AVD for a 
pediatric population on the basis of the 
safety, tolerability, and preliminary PK and 
efficacy data (if available).
Up to 6 months

Percentage of patients who 
experience AEs from the first 
dose of protocol therapy through 
30 days after administration of 
the last dose of protocol therapy.
The percentage of patients in the Safety 
Population who experience TEAEs for up to 
6 months of treatment plus 30 days 
following the end of study treatment.
Up to 7 months

Percentage of patients who 
experience SAEs from the first 
dose of protocol therapy through 
30 days after administration of 
the last dose of protocol therapy.
The percentage of patients in the Safety 
Population who experience 
treatment-emergent SAEs for up to 
6 months of treatment plus 30 days 
following the end of study treatment.
Up to 7 months
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a
Phase 1 Secondary

Mean Cmax and mean AUC0-15 of 
brentuximab vedotin (serum), 
TAb (serum), and MMAE 
(plasma).
Mean maximum concentration and AUC 
from Day 0 to Day 15 for brentuximab 
vedotin and TAb in serum and MMAE in 
plasma based on data from the PK 
Population.
Up to 15 days

Median Tmax of brentuximab 
vedotin (serum), TAb (serum), 
and MMAE (plasma).
First time of occurrence of maximum (peak) 
concentration for a single dose of 
brentuximab vedotin for patients in the PK 
Population.
Up to 15 days

Percentage of patients who 
achieve a CR per IRF 
assessment at EOT per IWG 
criteria.
Percentage of patients in the 
Response-Evaluable Population who 
achieve a complete response based on the 
IRF assessment at the EOT visit based on 
the IWG criteria.
Up to 7 months

Percentage of patients who 
achieve a PR per IRF assessment 
at EOT per IWG criteria.
Percentage of patients in the 
Response-Evaluable Population who 
achieve a partial response based on the IRF 
assessment at the EOT visit based on the 
IWG criteria.
Up to 7 months

Percentage of patients who 
achieve an OR per IRF 
assessment at EOT per IWG 
criteria.
Percentage of patients in the 
Response-Evaluable Population who 
achieve an overall response based on the 
IRF assessment at the EOT visit based on 
the IWG criteria.
Up to 7 months

Percentage of patients whose 
disease is PET- after 2 cycles of 
protocol therapy per IRF 
assessment.
Percentage of patients in the 
Response-Evaluable Population whose 
disease is negative per PET after 2 cycles of 
protocol therapy per IRF assessment.
Up to 2 months

Percentage of patients whose 
disease is PET+ after 6 cycles of 
protocol therapy per IRF 
assessment.
Percentage of patients in the 
Response-Evaluable Population whose 
disease is positive per PET after 6 cycles of 
protocol therapy per IRF assessment.
Up to 6 months

Percentage of patients who are 
ATA positive, persistently 
positive, or transiently positive, 
ATA titer and nATA positive at 
baseline, predose Cycle 2 Day 1, 
Cycle 4 Day 1, Cycle 6 Day 1, or 
at termination if treatment is 
terminated before Cycle 6, and 
at EOT. 
Percentage of patients in the safety 
population who are ATA positive, 
persistently positive, or transiently positive, 
ATA titer and nATA positive at baseline, 
predose Cycle 2 Day 1, Cycle 4 Day 1, 
Cycle 6 Day 1, or at termination if treatment 
is terminated before Cycle 6, and at EOT.
Up to 7 months

Impact of ATA and nATA on 
the safety, efficacy, and PK 
endpoints.
Impact of ATA and nATA on the safety, 
efficacy, and PK endpoints.
Up to 24 months
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a
Phase 2 Primary

Percentage of patients who 
achieve a CR per IRF 
assessment at EOT per IWG 
criteria.
Percentage of patients in the 
Response-Evaluable Population who 
achieve a complete response based on the 
IRF assessment at the EOT visit based on 
the IWG criteria.
Up to 7 months

Percentage of patients whose 
disease is PET- after 2 cycles of 
protocol therapy per IRF 
assessment.
Percentage of patients in the 
Response-Evaluable Population whose 
disease is negative per PET after 2 cycles of 
protocol therapy per IRF assessment.
Up to 2 months

Percentage of patients who 
achieve a PR per IRF assessment 
at EOT per IWG criteria.
Percentage of patients in the 
Response-Evaluable Population who 
achieve a partial response based on the IRF 
assessment at the EOT visit based on the 
IWG criteria.
Up to 7 months

Percentage of patients who 
achieve an OR per IRF 
assessment at EOT per IWG 
criteria.
Percentage of patients in the 
Response-Evaluable Population who 
achieve an overall response based on the 
IRF assessment at the EOT visit based on 
the IWG criteria.
Up to 7 months

Percentage of patients who are 
able to complete 6 cycles of 
protocol therapy at the 
recommended dose.
Percentage of patients in the 
Response-Evaluable Population who are 
able to complete six 28-day cycles of 
treatment at the recommended dose.
Up to 6 months
Phase 2 Secondary

PFS, EFS, OS, DOR.
Progression- and event-free survival, overall 
survival, and duration of response.
Up to 24 months

Percentage of patients receiving 
irradiation for HL following 
study treatment.
Percentage of patients receiving irradiation 
for HL after up to 6 months of study 
treatment.
Up to 24 months.

Percentage of patients who 
experience AEs from the first 
dose of protocol therapy through 
30 days after administration of 
the last dose of protocol therapy.
The percentage of patients in the Safety 
Population who experience TEAEs for up to 
6 months of treatment plus 30 days 
following the end of study treatment.
Up to 7 months

Percentage of patients who 
experience SAEs from the first 
dose of protocol therapy through 
30 days after administration of 
the last dose of protocol therapy.
The percentage of patients in the Safety 
Population who experience 
treatment-emergent SAEs for up to 
6 months of treatment plus 30 days 
following the end of study treatment.
Up to 7 months
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a

Percentage of patients who are 
ATA positive, persistently 
positive, or transiently positive, 
ATA titer and nATA positive at 
baseline, predose Cycle 2 Day 1, 
Cycle 4 Day 1, Cycle 6 Day 1, or 
at termination if treatment is 
terminated before Cycle 6, and 
at EOT. 
Percentage of patients in the safety 
population who are ATA positive, 
persistently positive, or transiently positive, 
ATA titer and nATA positive at baseline, 
predose Cycle 2 Day 1, Cycle 4 Day 1, 
Cycle 6 Day 1, or at termination if treatment 
is terminated before Cycle 6, and at EOT.
Up to 7 months

Impact of ATA and nATA on 
the safety, efficacy, and PK 
endpoints.
Impact of ATA and nATA on the safety, 
efficacy, and PK endpoints.
Up to 24 months

Mean Cmax and mean AUC0-15 of 
brentuximab vedotin (serum), 
TAb (serum), and MMAE 
(plasma).
Mean maximum concentration and AUC 
from Day 0 to Day 15 for brentuximab 
vedotin and TAb in serum and MMAE in 
plasma based on data from the PK 
Population.
Up to 15 days

Median Tmax of brentuximab 
vedotin (serum), TAb (serum), 
and MMAE (plasma).
First time of occurrence of maximum (peak) 
concentration for a single dose of 
brentuximab vedotin for patients in the PK 
Population.
Up to 15 days

Percentage of patients who 
experience peripheral 
neuropathy, regardless of 
seriousness, from the first dose 
of protocol therapy through 
study closure.
Percentage of patients who experience 
peripheral neuropathy, regardless of 
seriousness, from the first dose of protocol 
therapy through study closure.
Up to 24 months

Time to onset and time to 
resolution for all peripheral 
neuropathy events.
Time from first dose of protocol therapy to 
onset, and time from onset to resolution for 
all peripheral neuropathy events.
Up to 24 months

Immune reconstitution 
(peripheral blood CD34+ count; 
enumeration of the total 
lymphocyte count and 
lymphocyte subsets; total Ig and 
IgG, IgM, IgA levels; and levels 
of antibodies to tetanus, HiB, 
and polio serotypes) at baseline, 
EOT, and at 6, 12, and 
18 months (±1 month) after last 
dose, until the start of 
subsequent anticancer therapy 
(with the exception of 
radiotherapy administered as 
part of first-line therapy).
Immune reconstitution (peripheral blood 
CD34+ count; enumeration of the total 
lymphocyte count and lymphocyte subsets; 
total immunoglobulin and IgG, IgM, IgA 
levels; levels of antibodies to tetanus, HiB, 
and polio serotypes) at baseline, EOT, and at 
6, 12, and 18 months (±1 month) after last 
dose, until the start of subsequent anticancer 
therapy (with the exception of radiotherapy 
administered as part of first-line therapy).
Up to 24 months
AE: adverse event; ATA: antitherapeutic antibody; AVD: Adriamycin (doxorubicin), vinblastine, and dacarbazine; 
AUC: area under the concentration-time curve; AUC0-15: area under the concentration-time curve from Day 0 to Day 
1; Cmax: maximum observed concentration; CR: complete remission; DOR: duration of response; EFS: event-free 
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Table 6.a
Primary and Secondary Endpoints for Disclosures
Endpoint
Definition
Maximum Time Frame a
survival; EOT: End of Treatment (visit); HiB: hemophilus influenza type B; HL: Hodgkin lymphoma; Ig: 
immunoglobulin; IRF: independent review facility; IWG: International Working Group; MMAE: monomethyl 
auristatin E; nATA: neutralizing antitherapeutic antibody; OR: overall response; PET: positron emission tomography; 
PFS: progression-free survival; PK: pharmacokinetic(s); PR: partial remission; SAE: serious adverse event; TAb: total 
(free and conjugated) therapeutic antibody; TEAE: treatment-emergent adverse event; Tmax: time of occurrence of 
maximum (peak) concentration. 
a Time to last assessment for that endpoint for an individual patient.
6.3.4
Total Study Duration
It is anticipated that this study, including the follow-up period, will last approximately 55 months. 
All patients will be offered the opportunity to participate in an optional long-term follow-up that is 
for at least 10 years from the individual patient’s enrollment. 
7.0
STUDY POPULATION
Male or female patients aged 5 to <18 years with newly diagnosed, classical CD30+, advanced 
stage (Stage III or Stage IV) HL who are treatment naïve with Karnofsky Performance Status or 
Lansky Play-Performance ≥50.
7.1
Inclusion Criteria
Each patient must meet all the following inclusion criteria to be enrolled in the study:
1. Male or female patients aged 5 to <18 years.
2. Histologically confirmed CD30+ cHL.
3. Advanced stage, newly diagnosed HL (Stage III and Stage IV disease) (refer to Appendix E).
4. Treatment-naïve HL.
5. Have performance scores of ≥50 for Lansky Play-Performance or Karnofsky Performance 
Status (refer to Appendix F and Appendix G, respectively).
6. Patients must have bidimensional measurable disease as documented by radiographic 
technique per IWG criteria [1]. 
7. Female patients who:

Are surgically sterile, OR

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing the informed consent through 6 months after the last dose of protocol therapy, or
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
Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy), who:

Agree to practice effective barrier contraception during the entire study treatment period 
and through 6 months after the last dose of protocol therapy, OR

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle 
of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
8. Voluntary written consent (and institution-specific assent as appropriate based upon patient 
comprehension) must be given before the performance of any study-related procedure not part 
of standard medical care, with the understanding that consent/assent may be withdrawn by the 
patient or patient guardian at any time without prejudice to future medical care.
9. Suitable venous access for the study-required procedures.
10. Clinical laboratory values within 4 days before the first dose of protocol therapy as follows:

Absolute neutrophil count ≥1,500/μL unless there is known HL marrow involvement.

Platelet count ≥75,000/μL unless there is known HL marrow involvement.

Total bilirubin 1.5the upper limit of the normal range (ULN) for age or 3ULN for 
patients with indirect hyperbilirubinemia due to Gilbert’s syndrome.

Alanine aminotransferase or aspartate aminotransferase ≤2.5 ULN for age. 

Creatinine clearance or radioisotope glomerular filtration rate ≥70 mL/min/1.73m2 or a 
serum creatinine based on age/gender as follows:
–
Age
–
Maximum serum creatinine (mg/dL)*
–
–
Male
–
Female
–
2 to <6 years
–
0.8
–
0.8
–
6 to <10 years
–
1
–
1
–
10 to <13 years
–
1.2
–
1.2
–
13 to <16 years
–
1.5
–
1.4
–
≥16 years
–
1.7
–
1.4
*Derived from the Schwartz formula for estimating, utilizing child length and stature data published by the 
CDC.

Hemoglobin 8 g/dL (patients may be transfused to meet eligibility criteria).
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7.2
Exclusion Criteria
1. Nodular lymphocyte predominant HL.
2. Known active cerebral/meningeal disease, including signs or symptoms of progressive 
multifocal leukoencephalopathy (PML) or any history of PML.
3. Any sensory or motor peripheral neuropathy.
4. Female patients who are breastfeeding or have a positive serum or urine pregnancy test during 
the Screening period or a positive serum or urine pregnancy test on Day 1 before the first dose 
of protocol therapy.
5. Any serious medical or psychiatric illness that could, in the investigator’s or medical monitor’s 
opinion, potentially interfere with the completion of treatment according to this protocol.
6. Symptomatic neurologic disease compromising normal activities of daily living or requiring 
medications.
7. Any active systemic viral, bacterial, or fungal infection requiring systemic antibiotics within 
2 weeks before the first study protocol therapy.
8. Known hypersensitivity to recombinant proteins, murine proteins, or to any excipient 
contained in the drug formulation of brentuximab vedotin or any component of AVD.
9. Known human immunodeficiency virus positive.
10. Known hepatitis B surface antigen positive or known or suspected active hepatitis C infection, 
as determined by hepatitis B DNA or hepatitis C RNA, respectively, in blood.
11. Diagnosed or treated for another malignancy within 3 years before the first dose or previously 
diagnosed with another malignancy and have any evidence of residual disease. Patients with 
nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have 
undergone complete resection.
12. Use of any strong or listed moderate cytochrome P450 (CYP) 3A4 inhibitors <2 weeks before 
the first dose of protocol therapy (please refer to the Study Manual for an example list of 
prohibited CYP3A4 inhibitors).
13. Any of the following cardiovascular conditions or values within 6 months before the first dose 
of protocol therapy: 

Shortening fraction of <27% by echocardiogram or, if echocardiogram not feasible, 
ejection fraction of <50% by radionuclide angiogram (RNA or MUGA [multiple-gated 
acquisition scan]).

New York Heart Association Class III or IV heart failure (see Appendix H).

Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, 
congestive heart failure, angina, or electrocardiographic evidence of acute ischemia or 
active conduction system abnormalities.
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8.0
PROTOCOL THERAPY
8.1
Protocol Therapy Administration
All protocol-specific criteria for administration of protocol therapy must be met and documented 
before drug administration. Protocol therapy will be administered only to eligible patients under 
the supervision of the investigator or identified subinvestigator(s). The components of A+AVD 
used in this study are considered investigational medicinal products and will be supplied by the 
study sponsor, as outlined in Section 8.10.
A+AVD consists of brentuximab vedotin (ADCETRIS) 48 or 36 mg/m2, plus doxorubicin 
25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2.

A: Doxorubicin: 25 mg/m2 will be administered by IV infusion on Days 1 and 15 of each 
28-day cycle.

V: Vinblastine: 6 mg/m2 will be administered by IV infusion on Days 1 and 15 of each 28-day 
cycle.

D: Dacarbazine: 375 mg/m2 will be administered by IV infusion on Days 1 and 15 of each 
28-day cycle.
AVD is to be administered first, in the stated order, per institutional guidelines. If an investigator 
needs to choose a different order of administration of the protocol therapy components, this must 
first be discussed with the contract research organization (CRO) and/or the Takeda medical 
monitor. 
Brentuximab vedotin is to be administered after AVD:

A: brentuximab vedotin (ADCETRIS): 48 or 36 mg/m2 will be administered by IV infusion 
over approximately 30 minutes on Days 1 and 15 of each 28-day cycle; the infusion is to start 
approximately 1 hour after the conclusion of the dacarbazine administration. 
In the absence of infusion toxicities, the infusion rate for all patients must be calculated to 
achieve a 30-minute (approximate) brentuximab vedotin infusion period.
Brentuximab vedotin must not be administered as an IV push or bolus. It must be administered 
through a dedicated IV line and cannot be mixed with other medications. 
Dosing is based on patients’ body surface area (BSA) according to the institutional standard; 
however, doses must be adjusted for patients who experience a ≥10% change in BSA from the 
most recent dose calculation. For patients with a BSA of >2.5 m2, the dose will be calculated 
based on a BSA of 2.5 m2 for these individuals, as the maximum dose of brentuximab vedotin 
that a patient can receive is 120 mg. The dose will be rounded to the nearest whole number of 
milligrams. 
Further brentuximab vedotin administration information can be found in the Pharmacy 
Manual.
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8.2
Definitions of DLT
Toxicity will be evaluated according to the NCI CTCAE, Version 4.03, effective 14 June 2010 
[23]. These criteria are provided in the Study Manual. 
The DLT observation period comprises Cycle 1+28 days (from first dose through Study Day 56). 
Patients who receive study treatment in Cycles 1 and 2 without dose delay will be observed for 
DLTs through Cycle 2 (Day 56). Patients who discontinue treatment, do not receive the full course 
of protocol therapy, or have a delay in therapy will also be observed for DLTs through Day 56. 
Patients will be monitored through all cycles of protocol therapy for treatment-related toxicities.
DLT will be defined as any of the following events with onset during the DLT observation period 
that are considered by the investigator to be at least possibly related to therapy with brentuximab 
vedotin:

Any nonhematologic Grade ≥3 toxicity except for the following: Any nonhematologic toxicity 
Grade ≥3 that occurs in the absence of optimal supportive therapy (eg, antiemetic, 
antidiarrheal, etc) and lasting more than 5 consecutive days (such as vomiting, diarrhea, 
constipation, pyrexia, infection, or mucosal inflammation). Grade 3 or greater nonhematologic 
toxicity that is controllable to Grade 2 or less with appropriate treatment will not be considered 
dose-limiting DLT (excludes Grade 3 alopecia).

Treatment delay of more than 14 days.
Asymptomatic laboratory abnormalities should not be considered DLTs with the exclusion of 
Grade 2 pancreatitis (enzyme elevation only without clinical and/or radiographic findings).
8.3
Regimen De-Intensification Rules 
If more than 1 patient experience a DLT during the DLT observation period, a dose 
de-intensification schedule will be implemented in which brentuximab vedotin will be decreased 
by 25% to 36 mg/m2 (See Figure 6.a).
8.4
Dose Modification Guidelines
8.4.1
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity
Table 8.a details the recommended brentuximab vedotin dose modifications to be enacted in the 
event of treatment-associated toxicity.
In the case of brentuximab vedotin-specific toxicity (ie, severe neuropathy during or after 
brentuximab vedotin) or other unexpected severe AEs, the sponsor should be consulted to discuss 
therapeutic alternatives.
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Table 8.a
Recommended Brentuximab Vedotin Dose Modifications for 
Treatment-Associated Toxicity
Toxicity
Grade ≤2
Grade ≥3
Nonhematologic 
(excluding 
neuropathy)
Continue at same dose level.
Hold A+AVD dosing until toxicity has resolved to 
Grade ≤2 or has returned to baseline a, b, c.
Hematologic
Continue at same dose level.
For neutropenia, manage with growth factors (G-CSF 
or GM-CSF) per institutional guidelines.
G-CSF use is not permitted in the DLT observational 
period (Cycle 1+28 days in phase 1).
For thrombocytopenia, consider platelet transfusion 
and/or proceed according to institutional guidelines.
For anemia, manage per institutional guidelines.
Peripheral 
neuropathy
Grade 1
Continue at 
same dose 
level.
Grade 2
Reduce brentuximab 
vedotin dose by 25% 
and resume 
treatment; if already 
reduced by 25%, 
continue dosing at 
that level.
Grade 3
Withhold brentuximab 
vedotin until toxicity is 
Grade ≤2, then reduce dose 
by 25% and resume 
treatment. If already reduced 
by 25%, consult with 
sponsor.
(AVD may be continued or 
held concurrently at 
physician’s discretion.)
Grade 4
Discontinue 
brentuximab vedotin.
A+AVD: brentuximab vedotin, Adriamycin, vinblastine, and dacarbazine; AVD: Adriamycin (doxorubicin), vinblastine, 
and dacarbazine; DLT: dose-limiting toxicity; G-CSF: granulocyte colony stimulating factor; GM-CSF: granulocyte 
macrophage colony stimulating factor.
a Patients who develop clinically insignificant Grade 3 or 4 electrolyte laboratory abnormalities may continue study 
treatment without interruption.
b Dose modifications for nonhematologic toxicity may be considered after discussion with the medical monitor.
c In the case of dose delays >2 weeks, a discussion with the medical monitor should occur.
8.4.2
Reference Therapy Dose Modifications
AVD treatment should be modified or discontinued per applicable package insert instructions. 
8.4.3
Criteria for Dose Administration
Treatment with protocol therapy will occur on Days 1 and 15 of 28-day cycles. For a new cycle of 
treatment to begin or for study treatment to be administered on Day 15, the patient must meet the 
following criteria:

Recovery from treatment-related toxicity per Table 8.a.

General condition satisfactory.
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8.5
Excluded Concomitant Medications and Procedures
The following medications and procedures are prohibited during the study:

Any investigational agent other than A+AVD, including agents that are commercially 
available for indications other than HL that are under investigation for the treatment of HL.

Any anticancer treatment with activity against HL other than A+AVD.

Radiotherapy for disease under study before the EOT disease assessment.

The concomitant use of brentuximab vedotin and bleomycin has resulted in increased 
pulmonary toxicity versus bleomycin alone. Coadministration of brentuximab vedotin and 
bleomycin is contraindicated.

Any strong and listed moderate CYP3A4 inhibitors are prohibited, except moderate inhibitors 
when necessary for the medical management of a patient. Please refer to the Study Manual for 
an example list of prohibited CYP3A4 inhibitors. Patients will be closely monitored for the 
possibility of excess toxicity.
8.6
Permitted Concomitant Medications and Procedures 
The following medications and procedures are allowed during the study:

The use of local steroid treatments such as topical, inhalational, and ophthalmic steroids is 
permitted. Corticosteroids are permitted as part of a chemotherapy premedication regimen or 
for the treatment of HL symptoms per institutional standards. 

Radiotherapy for the emergency treatment of local HL-related symptoms (eg, spinal cord 
compression) is permitted, as long as such treatment does not interfere with staging/response 
assessment.

Radiotherapy is recommended following the EOT disease assessment for patients who have 
PET+ sites at Cycle 2 disease assessment.

Antiemetics are permitted per institutional standards. Due to its activity as a moderate 
CYP3A4 inhibitor, the use of aprepitant should be reserved for nausea/vomiting that is 
refractory to other agents.

Patients may receive concomitant hormonal therapy provided they have been on a stable 
dosage for at least 1 month before enrollment. No restrictions are placed upon the use of birth 
control.

The use of platelet and/or red blood cell supportive growth factors or transfusions when 
applicable is allowed.

The use of colony stimulating factors for the treatment or prevention of neutropenia per 
institutional practice is permitted during therapy. G-CSF use is not permitted in the DLT 
observational period (Cycle 1 + 28 days in phase 1).
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8.7
Precautions and Restrictions
8.7.1
Infusion-Related Reactions
All infusions should be administered at a site properly equipped and staffed for anaphylaxis should 
it occur. Medications for treatment of hypersensitivity reactions, such as epinephrine, 
antihistamines, and steroids, should be available for immediate use in the event of a reaction 
during administration and also during the observation period following brentuximab vedotin 
infusion.
8.7.2
Pregnancy
It is not known what effects brentuximab vedotin has on human pregnancy or development of the 
embryo or fetus. It is also not known how brentuximab vedotin affects mother’s milk or an unborn 
child. Therefore, patients who are breastfeeding and pregnant women are not allowed to take part 
in the study. Female patients participating in this study should avoid becoming pregnant, nursing a 
baby, or donating an egg or eggs (ova); and male patients should avoid impregnating a female 
partner or donating sperm during the study and for up to 6 months following the last dose of 
protocol therapy. Nonsterilized female patients of reproductive age and male patients should use 
effective methods of contraception through defined periods during and after study treatment as 
specified in the following:
Female patients must meet 1 of the following:

Surgically sterile, or

If they are of childbearing potential, agree to practice 1 highly effective method of 
contraception and 1 additional effective (barrier) method at the same time, from the time of 
signing of the informed consent form through 6 months after the last dose of protocol therapy, 
or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods], withdrawal, spermicides only, and lactational amenorrhea are not acceptable 
methods of contraception. Female and male condoms should not be used together.)
Male patients, even if surgically sterilized (ie, status postvasectomy) must agree to 1 of the 
following:

Practice effective barrier contraception during the entire study treatment period and through 
6 months after the last dose of protocol therapy, or

Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of 
the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, postovulation 
methods for the female partner], withdrawal, spermicides only, and lactational amenorrhea are 
not acceptable methods of contraception. Female and male condoms should not be used 
together.)
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8.8
Management of Clinical Events 
If dose alterations are necessary as a result of the events detailed in the following, please refer to 
Section 8.4.
8.8.1
Nausea and/or Vomiting
Although this study will not require prophylactic antiemetics, there is no prohibition against their 
use. Five-hydroxytryptamine 3 serotonin receptor antagonists and corticosteroids should be tried 
first. Due to its activity as a moderate CYP3A4 inhibitor, the use of aprepitant should be reserved 
for nausea/vomiting that is refractory to other agents.
8.8.2
Diarrhea
Prophylactic antidiarrheals will not be used in this protocol; however, patients will be instructed to 
take antidiarrheal medication(s) for the treatment of treatment-emergent diarrhea at the 
physician’s discretion until they are diarrhea-free for at least 12 hours. Fluid intake should be 
maintained to avoid dehydration.
8.8.3
Infusion-Related Reactions
Infusion-related reactions may occur during the infusion of brentuximab vedotin. The infusion 
should be administered at a site properly equipped and staffed to manage an infusion-related 
reaction, including anaphylaxis should it occur. The patient should be observed for approximately 
60 minutes following infusion of brentuximab vedotin. During this observation period, the IV line 
should remain open for at least 1 hour to allow administration of IV drugs if necessary. All 
supportive measures consistent with optimal patient care will be given throughout the study 
according to institution standards. Medications for infusion-related reactions, such as epinephrine 
and antihistamines, should be available for immediate use.
If anaphylaxis occurs, the administration of brentuximab vedotin should be immediately and 
permanently discontinued and appropriate medical therapy administered. If an infusion-related 
reaction occurs, the infusion should be interrupted and appropriate medical management 
instituted. Patients who have experienced a prior infusion-related reaction should be premedicated 
according to institutional guidelines for subsequent infusions. Premedication may include 
acetaminophen, an antihistamine, and a corticosteroid.
8.8.4
Peripheral Neuropathy
AEs of peripheral neuropathy will be monitored closely throughout the study. These events may 
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, will be followed for all changes in 
severity until 30 days after the last dose of protocol therapy, and recorded in the electronic case 
report form (eCRF). Thereafter, all ongoing events will be followed for improvement until the 
sooner of resolution to baseline or study closure, and recorded in the eCRF. Any ongoing events 
which worsen without initiation of subsequent anticancer therapy should also be recorded in the 
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eCRF. Events that are higher than Grade 1 will result in brentuximab vedotin dose modification 
described in Section 8.4. 
Study treatment–related peripheral neuropathy that is ongoing at the time of the first annual visit 
for the optional long-term follow-up will be assessed for improvement until the sooner of 
resolution to baseline or completion of the optional long-term follow-up (ie, at least 10 years after 
the patient’s enrollment) and recorded in the eCRF. Any ongoing events which worsen without 
initiation of subsequent anticancer therapy should also be recorded in the eCRF.
8.8.5
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. Seizures have also been reported in patients with PML (approximately 20%). The onset of 
neurological deficits may occur over weeks to months. See the IB for further details.
If PML is suspected, hold further brentuximab vedotin dosing and undertake a diagnostic workup 
that may include (but is not limited to):

Neurologic examinations, as warranted.

Brain magnetic resonance imaging (MRI): Features suggestive of PML include presence of 
unifocal or multifocal lesions, mainly of the white matter, which are typically non-enhancing 
and do not have mass effect.

Polymerase chain reaction analysis: John Cunningham virus (JCV) DNA detectable in 
cerebrospinal fluid or there is evidence of JCV in a brain biopsy.

Neurology consultation.
If PML is confirmed, permanently discontinue treatment with brentuximab vedotin.
8.9
Blinding and Unblinding
This is an open-label study. 
8.10
Description of Investigational Agents
8.10.1
Brentuximab Vedotin
Brentuximab vedotin will be supplied by the sponsor. Brentuximab vedotin for Injection is a 
sterile, preservative-free, white to off-white lyophilized cake for reconstitution for IV 
administration. Brentuximab vedotin for Injection is supplied in single-use, Type 1 borosilicate 
glass vials with FluroTec-coated butyl rubber stoppers and aluminum seals. Each vial of the 
product contains brentuximab vedotin, trehalose, sodium citrate, and polysorbate 80. The 
lyophilized product, after reconstitution with 10.5 mL sterile Water for Injection, United States 
Pharmacopeia or an equivalent standard, yields 11 mL of brentuximab vedotin solution 
(5 mg/mL).
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8.10.2
Doxorubicin
Doxorubicin will be supplied by the sponsor, depending on regional availability. Additional 
details are provided in the applicable package insert.
8.10.3
Vinblastine
Vinblastine will be supplied by the sponsor, depending on regional availability. Additional details 
are provided in the applicable package insert.
8.10.4
Dacarbazine
Dacarbazine will be supplied by the sponsor, depending on regional availability. Additional details 
are provided in the applicable package insert.
8.11
Preparation, Reconstitution, and Dispensation
Parenteral drug products should be inspected visually for particulate matter and discoloration 
before administration, whenever solution and container permit.
8.11.1
Brentuximab Vedotin
Brentuximab vedotin is an anticancer drug, and as with other potentially toxic compounds, caution 
should be exercised when handling brentuximab vedotin.
Recommended safety measures for handling and preparation include masks, protective clothing, 
gloves, and vertical laminar airflow safety cabinets.
Study treatment vials are single-use containers. Any partially used vials or diluted dosing solutions 
are to be discarded using appropriate institutional drug disposal procedures.
Study treatment must be reconstituted with the appropriate amount of sterile water for injection 
(see the Pharmacy Manual for details). GENTLY swirl the vial until the contents are completely 
dissolved. The vial must not be shaken or vigorously swirled; excess agitation may cause 
aggregate formation. Visually inspect the reconstituted drug product for any particulate matter and 
discoloration.
The appropriate amount of reconstituted study treatment will be withdrawn from the vial(s) and 
diluted in an infusion bag according to the instructions provided in the Pharmacy Manual. Refer to 
the Pharmacy Manual for more specific instructions on drug preparation.
8.11.2
Doxorubicin
Doxorubicin will be supplied by the sponsor, depending on regional availability. Additional 
details are provided in the applicable package insert.
8.11.3
Vinblastine
Vinblastine will be supplied by the sponsor, depending on regional availability. Additional details 
are provided in the applicable package insert.
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8.11.4
Dacarbazine
Dacarbazine will be supplied by the sponsor, depending on regional availability. Additional details 
are provided in the applicable package insert.
8.12
Packaging and Labeling
Vials of study treatment will be packaged in cardboard kits. Each kit will contain 1 vial of 
investigational product. Vials and kits will be labeled to meet country-specific regulatory 
requirements.
8.13
Storage, Handling, and Accountability
Drug accountability instructions are provided in the Pharmacy Manual.
8.13.1
Brentuximab Vedotin
Vials containing study treatment must be refrigerated at 2oC to 8oC in a secure location (eg, locked 
room) accessible only to the pharmacist, the investigator, or a duly designated person.
Study treatment does not contain preservatives; therefore, opened and reconstituted vials of study 
treatment must be used within 24 hours when stored under refrigeration at 2oC to 8oC. 
Reconstituted study treatment should not be stored at room temperature. It is recommended that 
study treatment vials and solutions be protected from direct sunlight until the time of use. 
Reconstituted vials must not be shaken.
8.13.2
Doxorubicin
Doxorubicin will be supplied by the sponsor, depending on regional availability. Additional 
details are provided in the applicable package insert.
8.13.3
Vinblastine
Vinblastine will be supplied by the sponsor, depending on regional availability. Additional details 
are provided in the applicable package insert.
8.13.4
Dacarbazine
Dacarbazine will be supplied by the sponsor, depending on regional availability. Additional details 
are provided in the applicable package insert.
9.0
STUDY CONDUCT
This trial will be conducted in compliance with the protocol, Good Clinical Practice (GCP), 
applicable regulatory requirements, and International Council on Harmonisation (ICH) guidelines.
9.1
Study Personnel and Organizations
The contact information for the medical monitor for this study, the central laboratory and any 
additional clinical laboratories, the coordinating investigator for each member state/country, and 
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the CRO team may be found in the Study Manual. A full list of investigators is available in the 
sponsor’s investigator database.
9.2
Arrangements for Recruitment of Patients
Recruitment and enrollment strategies for this study may include recruitment from the 
investigator’s local practice or referrals from other physicians. If advertisements become part of 
the recruitment strategy, they will be reviewed by the institutional review board (IRB)/ 
independent ethics committee (IEC). 
9.3
Treatment Group Assignments
This is a single-arm study with no reference therapy. Treatment group assignments are not 
applicable.
9.4
Study Procedures
Refer to the SOE (Appendix A) for timing of assessments. Additional details are provided as 
necessary in the sections that follow.
9.4.1
Informed Consent
Each patient’s parents (or patient’s legal guardian) must provide written informed consent, and 
each patient must provide written assent as appropriate for age, before any study-required 
procedures are conducted, unless those procedures are performed as part of the patient’s standard 
care.
Patients reaching an age that is not covered by their pediatric assent should provide re-assent for 
their appropriate age group to remain in the study. Patients who reach the age of consent must 
provide consent with a signed ICF to remain in the study.
All eligible patients, even those who discontinue early, are to be offered the option to participate in 
the optional long-term follow-up and acceptance or rejection is to be documented.
For participation in the optional long-term follow-up, each patient’s parent(s) (or patient’s legal 
guardian) must provide written informed consent, and each patient must provide written assent or 
consent, as appropriate for age.
9.4.2
Patient Demographics
The date of birth, race, ethnicity, and sex of the patient are to be recorded during Screening, as 
allowed. 
9.4.3
Medical History
During the Screening period, a complete medical history will be compiled for each patient. The 
history will emphasize the background and progress of the patient’s malignancy. Stage at initial 
diagnosis will be assessed per the Ann Arbor Staging System for Hodgkin Lymphoma (see 
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Appendix E). Evidence of bone marrow involvement and extranodal involvement at initial 
diagnosis will also be collected.
In addition, concomitant medications will be recorded as specified in Section 9.4.16.
9.4.4
Enrollment
A patient is considered to be enrolled in the study at the time of first dose of protocol therapy. 
Procedures for completion of the enrollment information are described in the Study Manual.
9.4.5
Patient Height, Weight and Body Surface Area
Height and weight will be measured at the times specific in the SOE (Appendix A) to support the 
development assessment (See Section 9.4.10) and dosing. 
BSA used for dosing calculations will be collected on each dosing day.
9.4.6
Physical Examination
A physical examination, including focused lymphoma assessment and peripheral neuropathy
assessment, will be completed per SOC at the times specified in the SOE (Appendix A).
9.4.7
Pregnancy Test
A serum or urine pregnancy test will be performed for female patients of childbearing potential as 
outlined in the SOE (Appendix A). 
9.4.8
Vital Signs
Vital sign measurements include seated (after 3-5 minutes in this position) measurements of 
diastolic and systolic blood pressure, heart rate, and temperature at the times specified in the SOE 
(Appendix A).
9.4.9
Lansky Play-Performance or Karnofsky Performance Status
Lansky Play-Performance or Karnofsky Performance Status are to be assessed as specified in the 
SOE (Appendix A). See Appendix F for Lansky Play-Performance. See Appendix G for 
Karnofsky Performance Status.
9.4.10
Development Assessment
Development assessment will be done as specified in the SOE (Appendix A) and will include 
weight-for-age and stature-for-age percentiles, and the Tanner Scale. 
Height and weight will be collected to determine the weight-for-age and stature-for-age 
percentiles. 
The Tanner Scale will be performed to assess physical developmental stage (See Appendix I).
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9.4.11
Clinical Chemistry and Hematology
Clinical chemistry and hematology evaluations will be performed locally. 
Blood samples for analysis of the clinical chemistry and hematology parameters shown in 
Table 9.a will be obtained at the time points specified in the SOE (Appendix A).
Table 9.a
Clinical Chemistry and Hematology Tests
Hematology
Serum Chemistry
Other
Hematocrit
Hemoglobin
Leukocytes with differential
Neutrophils (absolute 
neutrophil count; ANC)
Platelet (count)
Albumin
Alkaline phosphatase (ALP)
ALT 
AST 
Total bilirubin
Blood urea nitrogen (BUN)
Calcium
Carbon dioxide (CO2)
Creatinine (for age and gender)
Chloride
γ-glutamyl transferase (GGT)
Glucose
Lactate dehydrogenase (LDH)
Magnesium
Phosphate
Potassium
Sodium
Urate
Hemoglobin 
A1C
Troponin T a
ALT: alanine aminotransferase; AST: aspartate aminotransferase.
a Troponin T is the only test collected at the optional long-term follow-up visits.
9.4.12
Electrocardiogram
A 12-lead electrocardiogram (ECG) will be administered at the time points specified in the SOE 
(Appendix A).
9.4.13
Echocardiogram
Echocardiograms will be administered at the time points specified in the SOE (Appendix A). If
echocardiogram is not feasible, radionuclide angiogram (RNA or MUGA) will be performed at all 
time points specified in the SOE (Appendix A). The same modality should be used from screening 
and throughout the study.
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9.4.16
Concomitant Medications and Procedures
Medications used by the patient and therapeutic procedures completed by the patient will be 
recorded in the eCRF at the time points specified in the SOE (Appendix A). See Section 8.5 and 
Section 8.6 for a list of medications and therapies that are prohibited or allowed during the study.
9.4.17
Adverse Events
Monitoring of AEs, serious and nonserious, will be conducted throughout the study as specified in 
the SOE (Appendix A). Refer to Section 10.0 for details regarding definitions, documentation, and 
reporting of pretreatment events (PTEs), AEs, and SAEs. Changes in the severity of events relating 
to peripheral neuropathy will be recorded as described in Section 10.3.
9.4.18
Disease Assessment
9.4.18.1
Imaging, Restaging, and Radiation Therapy Guidance
Disease assessments will be performed as specified in the SOE (Appendix A) until PD is 
documented by the investigator, death occurs, or the study ends. If for any reason other than death 
or documented PD a patient discontinues protocol therapy after Cycle 2 Day 25 but before 
completion of EOT disease assessments, every effort must be made to obtain computed 
tomography (CT), MRI, and PET scans before initiation of subsequent therapy for HL. Additional 
assessments may be necessary when clinically indicated.
Patients will undergo CT with contrast as appropriate, MRI, and PET to monitor and assess PD 
according to the IWG Revised Response Criteria for Malignant Lymphoma [1]. CT scans will be 
used to evaluate the chest only; MRI will be used to evaluate the neck, abdomen, and pelvis. When 
possible, the same qualified physician will interpret results to reduce variability. Radiographic 
images will be maintained at the site, and test results and physician findings will be filed in patient
source documents. In addition, radiographic images will be provided to the IRF for assessment.
Restaging will be performed to assess the status of the patient’s underlying disease after 
completion of Cycle 2 treatment. ISRT should be employed at EOT in those patients who are 
PET+ at the end of Cycle 2 at the node sites that were PET+ at diagnosis. Radiotherapy should not 
be administered on the lung or spleen if those sites are PET- after the completion of Cycle 2, even 
if there is a persistence of PET activity in other sites. The target volume of irradiation should be 
based on initial nodal and extranodal involvement, as demonstrated by the baseline PET at the time 
of diagnosis [24-26].
Restaging will also be performed at the EOT disease assessment to determine if there is the need 
for radiotherapy in addition to any radiotherapy requirements identified at the end of Cycle 2.
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Only residual lymph nodes >1 cm that are still PET+ at EOT should be considered for 
radiotherapy. Extranodal lesions should require radiotherapy only if PET+ at the end of Cycle 2 or 
EOT. Whenever possible, pericardial and liver irradiation should be avoided. The use of 
radiotherapy is not permitted until patients have completed their EOT disease assessment.
For patients receiving radiation at EOT, the following guidance is provided: ISRT will consist of 
2100cGy in 14 fractions of 150cGy per day. Treatment should be given 5 days per week. All fields 
should be treated once per day. Treatment should begin no later than 4 weeks after completion of 
the last cycle of chemotherapy provided that the blood count recovery has occurred. Patients 
requiring radiation above and below the diaphragm should be treated with sequential rather than 
concurrent fields. The site of bulkiest involvement should be treated first and the second field 
should be treated with adequate hematologic recovery.
9.4.18.2
B Symptoms Assessments
B symptoms assessments, including fever, night sweats, and weight loss, will be evaluated at the 
time points indicated in the SOE (Appendix A).
9.4.18.3
Bone Marrow Assessments
Bone marrow biopsy will be collected as indicated in the SOE (Appendix A).
9.4.18.4
Biopsy Related to Disease Assessment
Biopsy specimens will not be collected for this study. However, the results of diagnostic biopsies 
must be recorded, documenting a diagnosis of CD30+ cHL. Additionally, the results of any 
biopsies related to disease assessment that are performed during the course of the study must be 
recorded.
9.4.19
PK Measurements
Blood samples for PK analysis will be collected as specified in the SOE (Appendix A). Samples 
will be analyzed for serum concentrations of brentuximab vedotin and TAb and plasma 
concentrations of MMAE (see Section 13.1.5). Population PK methodologies may be used to 
determine PK parameters.
Refer to the Laboratory Manual for information on collection, processing, storage, and shipment 
of samples to a central laboratory.
9.4.20
Immunogenicity
Blood samples will be collected as specified in the SOE (Appendix A) to evaluate serum ATA and 
nATA. On dosing days, the blood samples for ATA and nATA assessment must be collected 
before dosing. Neutralizing ATA assessment will be performed for ATA-positive samples only. 
The incidence of ATA and nATA to brentuximab vedotin will be assessed (see Section 9.4.20) and 
the impact of ATA and nATA on PK, efficacy, and safety will also be assessed.
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Refer to the Laboratory Manual for information on collection, processing, storage, and shipment 
of samples to a central laboratory.
9.4.21
Immune Reconstitution
The effects of protocol therapy on the pediatric peripheral immune system will be examined at the 
time points specified in the SOE (Appendix A) by measuring peripheral blood cell populations and 
the circulating Ig subclasses as follows:

IgG.

IgM.

IgA.

CD34+ cell count.

Tetanus antibodies.

HiB.

Polio serotypes.

Total Ig.

Lymphocyte count.

Lymphocyte subsets.
Peripheral cell populations will be examined using serum from the heparinized blood specimens 
collected. Cellular populations including T-cell subsets (T helper, cytotoxic, and memory cells), 
B cells, NK cells, granulocytes, and CD34+ cell count will be measured using flow cytometry. 
Immunoglobulin subclasses will be examined using standard clinical laboratory procedures. 
Refer to the Laboratory Manual for information on collection, processing, storage, and shipment 
of samples to a central laboratory.
9.5
Completion of Treatment
Patients will be considered to have completed treatment if they complete 6 cycles of treatment 
with protocol therapy, experience PD, or die before completing protocol therapy.
9.6
Completion of Study
Patients will be considered to have completed the study if they meet both of the following criteria:

Completed treatment (Section 9.5).

Have been followed for up to 2 years after enrollment of the last patient or have died.
9.7
Completion of Optional Long-term Follow-up
Patients will be considered to have completed the optional long-term follow-up if they have been 
followed for at least 10 years from their enrollment date in the main study or have died.
9.8
Discontinuation of Treatment With Protocol Therapy and Patient Replacement
Protocol therapy must be permanently discontinued for patients meeting any of the following 
criteria:

Completed 6 cycles of protocol therapy.
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
Investigator, patient, or patient’s legal guardian deems it is in the patient’s best interest to 
discontinue. (The reason justifying study treatment withdrawal must be documented in the 
eCRF.)

PD.
Treatment with protocol therapy may also be discontinued for any of the following reasons:

AE.

Protocol violation.

Unsatisfactory therapeutic response.

Study terminated by sponsor.

Withdrawal by patient or patient’s guardian.

Lost to follow-up.

Other.
Once protocol therapy has been discontinued, all study procedures outlined for the EOT visit will 
be completed as specified in the SOE (Appendix A). The primary reason for protocol therapy 
discontinuation will be recorded on the eCRF.
Patients who are withdrawn from study before the completion of the DLT observation period for 
reasons other than DLT will be replaced. Additional patients may be enrolled to ensure up to 
55 evaluable patients at the recommended dose.
9.9
Withdrawal of Patients From Study
Prior to completion of the treatment period and up to 2 year follow-up, a patient may be withdrawn 
from the study for any of the following reasons:

Death.

Lost to follow-up.

Study terminated by sponsor.

Withdrawal by patient or patient’s guardian.

Other.
The consequence of study withdrawal is that no new information will be collected from the 
withdrawn patient and added to the existing data or any database. 
9.10
Withdrawal of Patients from Optional Long-term Follow-up
Prior to completion of the optional long-term follow-up, a patient may be withdrawn for any of the 
following reasons:

Death.
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
Study terminated by sponsor.

Withdrawal by patient or patient’s guardian.

Other.
9.11
Study Compliance
Protocol therapy will be administered or dispensed only to eligible patients under the supervision 
of the investigator or identified subinvestigator(s). The appropriate study personnel will maintain 
records of study drug receipt, dispensing, and destruction/returns.
9.12
Posttreatment Follow-up Assessments (PFS and OS)
Patients will have an EOT assessment visit 30±7 days after receiving their final dose of protocol 
therapy. 
Patients who stop treatment for any reason other than PD as assessed by the investigator or the start 
of subsequent anticancer therapy will have progression-free survival follow-up (PFSFU) visits at 
the site every 12 weeks (±1 week) for 12 months and then every 24 weeks (±2 weeks) for up to 
2 years until the occurrence of PD, the start of subsequent anticancer therapy, the patient 
withdraws consent for further follow-up, or the study ends. During follow-up, all patients who start 
radiotherapy must be recorded. Patients who discontinue treatment for PD or the start of 
subsequent anticancer therapy will be followed for OS only.
After the occurrence of PD or the start of subsequent anticancer therapy, patients will continue to 
have overall survival follow-up (OSFU) visits every 24 weeks (±2 weeks) until the sooner of death 
or study closure or for up to 2 years from the date of the last patient enrolled. Survival and disease 
status information may be collected by methods that include, but are not limited to, telephone, 
email, or mail, or retrieved from online or other databases (eg, social security indexes). In addition, 
details of subsequent anticancer therapy will be collected. 
An End-of-Study eCRF is to be completed at the time the patient discontinues from the follow-up 
period of the main study. A separate End-of-Study eCRF is to be completed for all participating 
patients upon their completion of the optional long-term follow-up period (see Section 9.13).
NOTE: Related SAEs must be reported to the Global Pharmacovigilance department or designee. 
This includes deaths that the investigator considers related to protocol therapy that occur during 
the posttreatment follow-up. Refer to Section 10.0 for details regarding definitions, 
documentation, and reporting of SAEs.
9.13
Optional Long-term Follow-up
All study patients will be offered the opportunity to participate in an optional long-term follow-up 
to assess safety and survival annually. Patients participating in the optional long-term follow-up 
will commence their first optional long-term follow-up visit 2 years after the patient’s EOT visit 
and continue with annual visits until at least 10 years from the date of patient enrollment. 
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Regardless of the patient’s decision to participate in the optional long-term follow-up, patients are 
to continue with their posttreatment follow-up in the main study until the main study has 
completed, which is up to 2 years after the enrollment of the last patient to the study. For patients 
participating in the optional long-term follow-up, visits may initially overlap with the main study. 
The assessments to be performed at each annual visit are listed here and outlined in the SOE for the 
optional long-term follow-up (Appendix A):

Informed consent/assent.
–
To be obtained no later than at the first optional long-term follow-up annual visit.

Height, weight, and vital signs.

Lansky Play-Performance or Karnofsky Performance status, as appropriate for age (see 
Appendix F and Appendix G).

Targeted physical examination for medically relevant body systems with focus on:
–
Development assessment (see Appendix I).
–
Cardiac function abnormalities. 
–
Development of any secondary malignancy (NOTE: Reoccurrence of HL with the same 
histology as baseline should not be considered a secondary malignancy.)
–
Ongoing peripheral neuropathy assessment:
i.
Study treatment–related peripheral neuropathy that is ongoing at the time of the first 
annual visit for the optional long-term follow-up will be assessed for improvement 
until the sooner of resolution to baseline or completion of the optional long-term 
follow-up (ie, at least 10 years after the patient’s enrollment) and recorded in the 
eCRF. Any ongoing events which worsen without initiation of subsequent anticancer 
therapy should also be recorded in the eCRF.
–
Immune function abnormalities:
i.
For patients demonstrating or reporting any signs or symptoms of impaired immune 
function, appropriate blood tests (such as peripheral lymphocyte differentiation and 
activation, Ig levels, vaccine and antigen responses) are recommended, and results 
recorded in the eCRF.

Blood chemistry for troponin T (refer to Table 9.a).
–
Cardiac investigations, including such procedures as ECG, ECHO or MUGA, are 
recommended if troponin T levels are abnormal or there are other abnormal cardiac 
findings.

Treatment-related SAEs defined as investigator-assessed as related to brentuximab vedotin.

Pregnancy/partner pregnancy (refer to Section 10.4).
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
Recording of any anticancer therapy, including radiotherapy, and response since the last visit.
–
CT, MRI and PET scans are not required as part of the annual visits for the optional 
long-term follow-up. However, the investigator’s assessment of response determined from 
a scan performed either as SOC prior to initiation of any subsequent anticancer therapies 
for cHL is to be recorded in the eCRF. 
–
Treatment dates and regimens of any other anticancer therapy for the patient’s cHL and 
any investigator-assessed response before initiation of subsequent anticancer therapy for 
cHL, and investigator-assessed best response to subsequent therapies, will be recorded in 
the eCRF.

If a patient refuses to return to the clinic for annual study visits, information can be collected 
via telephone contact reports at the time of the regularly scheduled study visits; however, this 
is not preferred. If any concerns relating to study treatment are identified by the investigator 
during this telephone consultation with the patient, the investigator should request that the 
patient attend an in-person clinic visit to complete the assessments outlined above and in the 
SOE (Appendix A) for the optional long-term follow up visits, or alternatively, have the 
patient visit their personal physician / other consultant for appropriate follow-up. Any results 
generated outside of the investigative site must be obtained by the investigator and recorded in 
the eCRF.

Efforts will be made to avoid any patient being lost to follow-up during the conduct of the 
study. Before patients are considered lost to follow-up, a minimum of 2 documented telephone 
contact attempts must be made, and 1 certified letter must be sent within 6 weeks of the most 
recent planned study visit in an effort to contact patients.

If a patient has been documented as lost to follow-up or if the site staff becomes aware of a 
patient’s death between planned annual visits, then the following information must also be 
obtained and recorded in the eCRF:
–
Survival status or date of death. 

Survival information may be collected by methods that include, but are not limited to, 
telephone, email, mail, or retrieved from online or other databases (eg, social security indexes) 
as permitted by local regulations.

A separate End-of-Study eCRF will be completed for all participating patients upon their 
completion of the optional long-term follow-up period. 
9.14
COVID-19 Considerations
At the time of the COVID-19 outbreak, patient EOT visits were in progress. Delays to these visits 
were permitted as necessary based on site/regional restrictions. 
No restrictions are placed on patients receiving the COVID-19 vaccine. As of the time of the 
COVID-19 vaccine availability, all patients have completed the treatment period of the study and 
are participating in posttreatment follow-up and/or long-term follow-up. Administration of the 
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COVID-19 vaccine to patients therefore does not need to be reported on the concomitant 
medication log.
For patients who are unable to attend a protocol-required study visit either because the site has 
COVID-19 restrictions at the time of the visit or the patient is unable to attend due to COVID-19, 
telephone contact may be made to collect any data that are possible outside of the study visit. 
Thereafter, every effort should be made to have the visit rescheduled as soon as it is safe to have 
the patient come to the study site to complete the procedures. Procedures may be performed late 
and recorded as Unscheduled if they do not fall within the visit period. Subsequent 
protocol-required visits should be scheduled according to the original EOT date and not delayed 
visit dates. Delayed or missed protocol-required study visits will be documented as protocol 
deviations but specified as due to COVID-19.
Monitoring of study data may be delayed due to COVID-19 restrictions at a site or, where 
available, remote source data verification and monitoring may be implemented. However, if a 
study analysis is pending, every effort should be made by site staff to accommodate the study 
monitor in verifying data, including by remote means where applicable, or other acceptable 
methods. 
Should a study patient become infected with COVID-19 and have an outcome of death, the death 
should be reported as survival data.
10.0
ADVERSE EVENTS
10.1
Definitions
10.1.1
PTE Definition
A PTE is any untoward medical occurrence in a patient or subject who has signed informed 
consent/assent to participate in a study but before administration of any study medication; it does 
not necessarily have to have a causal relationship with study participation.
10.1.2
AE Definition
AE means any untoward medical occurrence in a patient or subject administered a pharmaceutical 
product; the untoward medical occurrence does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product whether or not it is related to the medicinal product. This includes any 
newly occurring event, or a previous condition that has increased in severity or frequency since the 
administration of protocol therapy.
An abnormal laboratory value will not be assessed as an AE unless that value leads to 
discontinuation or delay in treatment, dose modification, therapeutic intervention, or is considered
by the investigator to be a clinically significant change from baseline.
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10.1.3
SAE Definition
SAE means any untoward medical occurrence that at any dose:

Results in death.

Is life-threatening (refers to an AE in which the patient was at risk of death at the time of the 
event. It does not refer to an event which hypothetically might have caused death if it were 
more severe).

Requires inpatient hospitalization or prolongation of an existing hospitalization (see 
clarification in the paragraph in Section 10.2 on planned hospitalizations).

Results in persistent or significant disability or incapacity. (Disability is defined as a 
substantial disruption of a person’s ability to conduct normal life functions).

Is a congenital anomaly/birth defect.

Is a medically important event. This refers to an AE that may not result in death, be 
immediately life threatening, or require hospitalization, but may be considered serious when, 
based on appropriate medical judgment, may jeopardize the patient, require medical or 
surgical intervention to prevent 1 of the outcomes listed above, or involves suspected 
transmission via a medicinal product of an infectious agent. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at home, 
blood dyscrasias or convulsions that do not result in inpatient hospitalization, or the 
development of drug dependency or drug abuse; any organism, virus, or infectious particle 
(eg, prion protein transmitting transmissible spongiform encephalopathy), pathogenic or 
nonpathogenic, is considered an infectious agent.
In this study, intensity for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [23]. Clarification should be made 
between an SAE and an AE that is considered severe in intensity (Grade 3 or 4), because the terms 
serious and severe are NOT synonymous. The general term severe is often used to describe the 
intensity (severity) of a specific event; the event itself, however, may be of relatively minor 
medical significance (such as a Grade 3 headache). This is NOT the same as serious, which is 
based on patient/event outcome or action criteria described above, and is usually associated with 
events that pose a threat to a patient’s life or ability to function. A severe AE (Grade 3 or 4) does 
not necessarily need to be considered serious. For example, a white blood cell count of 1000/mm3
to less than 2000 is considered Grade 3 (severe) but may not be considered serious. Seriousness 
(not intensity) serves as a guide for defining regulatory reporting obligations.
10.2
Procedures for Recording and Reporting AEs and SAEs
All AEs spontaneously reported by the patient and/or in response to an open question from study 
personnel or revealed by observation, physical examination, or other diagnostic procedures will be 
recorded on the appropriate page of the eCRF (see Section 10.3 for the period of observation). Any 
clinically relevant deterioration in laboratory assessments or other clinical finding is considered an 
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AE. When possible, signs and symptoms indicating a common underlying pathology should be 
noted as 1 comprehensive event.
Regardless of causality, SAEs and serious PTEs (as defined in Section 10.1) must be reported (see 
Section 10.3 for the period of observation) by the investigator to the Takeda Global 
Pharmacovigilance department or designee (contact information provided below). This should be 
done by faxing the SAE Form within 24 hours after becoming aware of the event. The SAE Form, 
created specifically by Takeda, will be provided to each clinical study site. A sample of the SAE 
Form may be found in the Study Manual. Follow-up information on the SAE or serious PTE may
be requested by Takeda. SAE report information must be consistent with the data provided on the 
eCRF.
SAE Reporting Contact Information
Planned hospital admissions or surgical procedures for an illness or disease that existed before the 
patient was enrolled in the trial are not to be considered AEs unless the condition deteriorated in an 
unexpected manner during the trial (eg, surgery was performed earlier or later than planned).
For both serious and nonserious AEs, the investigator must determine both the severity (toxicity
grade) of the event and the relationship of the event to protocol therapy administration. For serious 
PTEs, the investigator must determine both the severity (toxicity grade) of the event and the 
causality of the event in relation to study procedures.
Severity (toxicity grade) for each AE, including any lab abnormality, will be determined using the 
NCI CTCAE, Version 4.03, effective date 14 June 2010 [23]. The criteria are provided in the 
Study Manual.
Relationship of the event to protocol therapy administration (ie, its causality) will be determined 
by the investigator responding yes (related) or no (unrelated) to this question: “Is there a 
reasonable possibility that the AE is associated with the protocol therapy?”
10.3
Monitoring of AEs and Period of Observation
AEs, both nonserious and serious, will be monitored throughout the study as follows: 
∀
AEs will be reported from the signing of the informed consent form (ICF)/assent form through 
30 days after administration of the last dose of protocol therapy and recorded in the eCRFs. All 
events relating to peripheral neuropathy, regardless of seriousness, will be followed for all
changes in severity until 30 days after the last dose of protocol therapy, and recorded in the 
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eCRF. Thereafter, all ongoing events will be followed for improvement until the sooner of 
resolution to baseline or study closure, and recorded in the eCRF. Any ongoing events which 
worsen without initiation of subsequent anticancer therapy should also be recorded in the 
eCRF. 

Study treatment–related peripheral neuropathy that is ongoing at the time of the first annual 
visit for the optional long-term follow-up will be assessed for improvement until the sooner of 
resolution to baseline or completion of the optional long-term follow-up (ie, at least 10 years 
after the patient’s enrollment) and recorded in the eCRF. Any ongoing events which worsen 
without initiation of subsequent anticancer therapy should also be recorded in the eCRF. 

SAEs
–
Serious PTEs will be reported to the Takeda Global Pharmacovigilance department or 
designee from the time of the signing of the ICF up to first dose of protocol therapy, and 
recorded in the eCRF.
–
Related and unrelated treatment-emergent SAEs will be reported to the Takeda Global 
Pharmacovigilance department or designee from the first dose of protocol therapy through 
30 days after administration of the last dose of protocol therapy and recorded in the eCRF. 
After this period, including during the optional long-term follow-up, only related SAEs 
must be reported to the Takeda Global Pharmacovigilance department or designee. SAEs 
should be monitored until they are resolved or are clearly determined to be due to a 
patient’s stable or chronic condition or intercurrent illness(es).
AEs or SAEs recorded due to COVID-19 should be prefaced by the term, “COVID-19” or 
“suspicion of COVID-19” to facilitate coding, as explained in the eCRF guidelines. 
10.4
Procedures for Reporting Drug Exposure During Pregnancy and Birth Events
If a woman becomes pregnant or suspects that she is pregnant while participating in this study, she 
must inform the investigator immediately and permanently discontinue protocol therapy. The 
sponsor must also be contacted immediately by faxing a completed Pregnancy Form to the Takeda 
Global Pharmacovigilance department or designee (see Section 10.2). The pregnancy must be 
followed for the final pregnancy outcome.
If a female partner of a male patient becomes pregnant during the male patient’s participation in 
this study, the sponsor must also be contacted immediately by faxing a completed Pregnancy Form 
to the Takeda Global Pharmacovigilance department or designee (see Section 10.2). Every effort 
should be made to follow the pregnancy for the final pregnancy outcome.
10.5
Procedures for Reporting Product Complaints or Medication Errors (Including 
Overdose)
A product complaint is a verbal, written, or electronic expression that implies dissatisfaction 
regarding the identity, strength, purity, quality, or stability of a drug product. Individuals who 
identify a potential product complaint situation should immediately report this via the phone 
numbers or email addresses below:
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A medication error is a preventable event that involves an identifiable patient and that leads to 
inappropriate medication use, which may result in patient harm. Whereas overdoses and 
underdoses constitute medication errors, doses missed inadvertently by a patient do not. 
Individuals who identify a potential medication error (including overdose) situation should 
immediately report this via the phone numbers or email addresses provided below.
Call center
Phone number
E-mail
Fax
Product complaints in and of themselves are not AEs. If a product complaint results in an SAE, an 
SAE form should be completed and sent to 
 (refer to Section 10.2)
10.6
Safety Reporting to Investigators, IRBs or IECs, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions 
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA, 
investigators, and IRBs or IECs, as applicable, in accordance with national regulations in the 
countries where the study is conducted. Relative to the first awareness of the event by/or further 
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory
authorities as an expedited report within 7 calendar days for fatal and life-threatening events and 
15 calendar days for other serious events, unless otherwise required by national regulations. The 
sponsor will also prepare an expedited report for other safety issues where these might materially 
alter the current benefit-risk assessment of an investigational medicinal product or that would be 
sufficient to consider changes in the investigational medicinal product’s administration or in the 
overall conduct of the trial. The investigational site also will forward a copy of all expedited 
reports to his or her IRB or IEC in accordance with national regulations.
11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, clinical endpoint committee, or 
adjudication committee will be used in this study.
12.0
DATA HANDLING AND RECORDKEEPING 
The full details of procedures for data handling will be documented in the Data Management Plan. 
If selected for coding, AEs, PTEs, medical history, and concurrent conditions will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). Drugs will be coded using the 
World Health Organization (WHO) Drug Dictionary.
12.1
eCRFs 
Completed eCRFs are required for each patient who receives protocol therapy.
The sponsor or its designee will supply investigative sites with access to eCRFs and will make 
arrangements to train appropriate site staff in the use of the eCRF. These forms are used to transmit
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the information collected in the performance of this study to the sponsor, CRO partners, and 
regulatory authorities. Investigative sites must complete eCRFs in English.
After completion of the entry process, computer logic checks will be run to identify items, such as 
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda 
personnel (or designees) and will be answered by the site. 
Any change of, modification of, or addition to the data on the eCRFs should be made by the 
investigator or appropriate site personnel. Corrections to eCRFs are recorded in an audit trail that 
captures the old information, the new information, identification of the person making the 
correction, the date the correction was made, and the reason for change.
The principal investigator must review the eCRFs for completeness and accuracy and must sign 
and date the appropriate eCRFs as indicated. Furthermore, the principal investigator must retain 
full responsibility for the accuracy and authenticity of all data entered on the eCRFs.
eCRFs will be reviewed for completeness and acceptability at the study site during periodic visits 
by study monitors. The sponsor or its designee will be permitted to review the subject’s medical 
and hospital records pertinent to the study to ensure accuracy of the eCRFs. The completed eCRFs 
are the sole property of the sponsor and should not be made available in any form to third parties, 
except for authorized representatives of appropriate governmental health or regulatory authorities, 
without written permission of the sponsor. 
During the COVID-19 pandemic, remote source data verification or review may be performed if 
permitted by regional regulations (see Section 9.14).
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that 
include (but are not limited to) the study-specific documents, the identification log of all 
participating subjects, medical records, temporary media such as thermal sensitive paper, source 
worksheets, all original signed and dated informed consent forms, subject authorization forms 
regarding the use of personal health information (if separate from the informed consent forms), 
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to 
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source 
documentation printed on degradable thermal sensitive paper should be photocopied by the site 
and filed with the original in the subject’s chart to ensure long-term legibility. Furthermore, ICH 
E6 Section 4.9.5 requires the investigator to retain essential documents specified in ICH E6 
(Section 8) until at least 2 years after the last approval of a marketing application for a specified 
drug indication being investigated or, if an application is not approved, until at least 2 years after 
the investigation is discontinued and regulatory authorities are notified. In addition, ICH E6 
Section 4.9.5 states that the study records should be retained until an amount of time specified by 
applicable regulatory requirements or for a time specified in the Clinical Study Site Agreement 
between the investigator and sponsor.
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Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The 
investigator should contact and receive written approval from the sponsor before disposing of any 
such documents.
13.0
STATISTICAL METHODS 
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before database lock. This 
document will provide further details regarding the definition of analysis variables and analysis 
methodology to address all study objectives.
13.1.1
Analysis Sets
The populations used for analysis will include the following:
Safety Population
The Safety Population will include patients who have received at least 1 dose of any drug in the 
A+AVD regimen.
PK Population
The PK Population will include patients with sufficient dosing and PK data to enable calculation of 
at least 1 PK parameter.
Immune Reconstitution Population
Patients with sufficient dosing and sufficient immune reconstitution blood sampling to allow for 
immune reconstitution evaluation will be included in the Immune Reconstitution Population.
Response-Evaluable Population
The Response-Evaluable Population will include patients who receive at least 1 dose of A+AVD, 
have measurable disease at baseline, and have 1 postbaseline disease assessment. The 
Response-Evaluable Population will be defined separately per IRF and per investigator.
DLT-Evaluable Population
The DLT-Evaluable Population will include both patients who receive at least 1 dose of protocol 
therapy and experience a DLT during the DLT observation period (Cycle 1+28 days [from first 
dose through Study Day 56]), and patients who receive all planned doses of protocol therapy in 
Cycle 1 and complete all relevant study procedures/assessments during the DLT observation 
period (Cycle 1+28 days [from first dose through Study Day 56]) without a DLT. Only patients 
used to determine the recommended dose will be included in the DLT-Evaluable Population
13.1.2
Analysis of Demographics and Other Baseline Characteristics
Demographic and baseline characteristics will be summarized, including gender, age, race, weight, 
height, BSA, disease stage, performance score, and other parameters as appropriate. No inferential 
statistics will be carried out.
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13.1.3
Efficacy Analysis
Analysis of efficacy measures will be descriptive. ORR, CR rate, and PR rate at EOT will be 
assessed by IRF and by investigators per IWG criteria [1]. The percentage of patients whose 
disease is PET- after 2 cycles of A+AVD chemotherapy and the percentage of patients whose 
disease is PET+ after 6 cycles will also be evaluated. Other efficacy endpoints, including PFS, 
EFS, OS, and DOR, will also be explored. The percentage of patients receiving irradiation for HL 
following study treatment will be summarized.
13.1.5
PK Analysis 
Descriptive statistics (eg, number of patients, arithmetic mean, geometric mean, standard 
deviation, median, percentage of coefficient of variation, minimum, and maximum) will be used to 
summarize brentuximab vedotin and TAb concentrations in serum, and concentrations of MMAE 
in plasma by dose group. Mean plasma concentration data will be plotted over time by dose group. 
PK parameters (Cmax, AUC0-15, Tmax) will be calculated from individual plasma (MMAE) or serum 
(brentuximab vedotin, TAb) concentration-time data using noncompartmental methods and 
summarized descriptively by analyte and dose group.
13.1.6
Immunogenicity Analysis
Immunogenicity parameters (ATA positive, ATA titer and nATA positive in serum) will be 
analyzed using the Safety Population - immunogenicity evaluable patients and descriptive 
statistics. The relationship of immunogenicity responses to PK, efficacy, and safety will be 
explored.
13.1.7
Immune Reconstitution Analysis
Descriptive statistics for the actual values (and/or the changes from baseline) of immune 
reconstitution (enumeration of the total lymphocyte count and lymphocyte subsets; total Ig and 
IgG, IgM, and IgA levels; levels of the antibodies to tetanus, HiB, and polio serotypes; and 
peripheral blood CD34+ cell count) will be presented for all scheduled measurements over time.
13.1.8
PK Modeling
PK modeling using population analysis may be additionally performed to describe pediatric PK 
and estimate individual PK parameters for brentuximab vedotin and MMAE in this study. This 
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analysis may additionally use data collected in other clinical studies of brentuximab vedotin. The 
analysis plan for such modeling and the results of these analyses will be reported separately.
13.1.9
Safety Analysis
Safety will be evaluated by the incidence of AEs, severity and type of AEs, and by changes from 
baseline in the patient’s vital signs, neuropathy assessment, and clinical laboratory results using 
the Safety Population. Exposure to protocol therapy, including the percentage of patients who are 
able to complete 6 cycles of treatment and reasons for discontinuation will be tabulated. TEAEs 
that occur after administration of the first dose of protocol therapy and through 30 days after the 
last dose of protocol therapy will be tabulated. AEs will be tabulated according to the MedDRA 
and will include the following categories:

TEAEs.

Drug-related TEAEs.

Grade 3 or higher TEAEs.

Grade 3 or higher drug-related TEAEs.

SAEs.
A listing of TEAEs resulting in protocol therapy discontinuation will be provided. The individual 
patient’s information on the DLTs will also be presented in a listing.
Descriptive statistics for the actual values of clinical laboratory parameters (and/or change from 
baseline in clinical laboratory parameters) will be presented for all scheduled measurements over 
time. Mean laboratory values over time will also be plotted for key laboratory parameters. Shift 
tables for laboratory parameters will be generated based on changes in NCI CTCAE grade from 
baseline to the worst postbaseline value. Graphical displays of key safety parameters, such as 
scatter plots of baseline versus worst postbaseline values, may be used to understand the 
brentuximab vedotin safety profile.
Descriptive statistics for the actual values (and/or the changes from baseline) of vital signs, weight, 
and development assessment results over time will be tabulated by scheduled time point. The 
results of lymphoma assessment and Lansky/Karnofsky scores over time will also be tabulated.
All concomitant medications collected from Screening through the study period will be classified 
to generic terms according to the WHO Drug Dictionary.
Additional safety analyses may be performed to most clearly enumerate rates of toxicities and to 
further define the safety profile of brentuximab vedotin.
13.2
Interim Analysis and Criteria for Early Termination
An interim futility analysis will be conducted after 25 patients have completed 6 cycles of study 
therapy and had their EOT response assessment. The study may be terminated early in the case of 
inferior efficacy.
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13.3
Time Points for Additional Analyses
As prespecified in the approved SAP, the primary analyses for reporting the results of the primary
endpoints in the CSR were performed after all enrolled patients had the opportunity to be followed 
for 15 months after enrollment of the last patient in the main study. Efficacy results are presented 
by study phase, and for all evaluable patients treated at the recommended dose. 
Patients will continue to be followed for survival and disease status every 12 weeks (1 week) for 
12 months, and then every 24 weeks (2 weeks) until death or study closure or for up to 2 years 
after enrollment of the last patient. An updated analysis of the time-to-event efficacy endpoints and 
other selected study endpoints will be performed after all enrolled patients have had the 
opportunity to be followed for up to 2 years after enrollment of the last patient, denoting the end of 
the main study. This updated analysis may include data from the long-term follow-up period. 
Results of the updated analysis at the end of the main study will be presented in an addendum to 
the CSR.
Data from the optional long-term follow-up will be analyzed after all participating patients have 
had the opportunity to complete 10 years of follow up from their date of enrollment in the main 
study and those results will be presented in a separate CSR addendum.
13.4
Determination of Sample Size
A total of approximately 55 evaluable patients treated at the recommended dose will be enrolled in 
this study. In phase 1, up to 12 DLT-evaluable patients will be enrolled into up to 2 planned dose 
cohorts (48 and 36 mg/m2, 3-6 patients per cohort) according to a modified 3+3 design. Once the 
recommended dose has been identified, additional patients will be enrolled into phase 2 so that the 
total number of evaluable patients will be at least 55, including the patients treated at the 
recommended dose in phase 1.
Assuming that the true ORR for the A+AVD regimen is 90%, with 55 evaluable patients and a 
2-sided type I error of α=0.2, the study would have approximately 78% power to state that the 
ORR is greater than 80%.
Analyses will be primarily descriptive in nature. No formal statistical tests will be performed. 
14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all 
aspects of the protocol are followed. Source documents will be reviewed for verification of data 
recorded on the eCRFs. Source documents are defined as original documents, data, and records. 
The investigator and institution guarantee access to source documents by the sponsor or its 
designee (CRO) and by the IRB or IEC.
All aspects of the study and its documentation will be subject to review by the sponsor or designee, 
including but not limited to the Investigator’s Binder, study medication, subject medical records, 
informed consent and assent documentation, documentation of subject authorization to use 
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personal health information (if separate from the informed consent and assent forms), and review 
of eCRFs and associated source documents. It is important that the investigator and other study 
personnel are available during the monitoring visits and that sufficient time is devoted to the 
process.
During the COVID-19 pandemic, remote source data verification or review may be performed if 
permitted by regional regulations (see Section 9.14).
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an 
immediate hazard to study subjects. Should other unexpected circumstances arise that will require 
deviation from protocol-specified procedures, the investigator should consult with the sponsor or 
designee (and IRB or IEC, as required) to determine the appropriate course of action. There will be 
no exemptions (a prospectively approved deviation).
The site should document all protocol deviations in the subject’s source documents. In the event of 
a significant deviation, the site should notify the sponsor or its designee (and IRB or EC, as 
required). Significant deviations include, but are not limited to, those that involve fraud or 
misconduct, increase the health risk to the subject, or confound interpretation of primary study 
assessment. A Protocol Deviation Form should be completed by the site and signed by the sponsor 
or designee for any significant deviation from the protocol. 
See Section 9.14 for deviations specific to COVID-19 or pandemic restrictions. 
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this 
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an 
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected, 
where the medication is stored and prepared, and any other facility used during the study. In 
addition, there is the possibility that this study may be inspected by regulatory agencies, including 
those of foreign governments. If the study site is contacted for an inspection by a regulatory body, 
the sponsor should be notified immediately. The investigator and institution guarantee access for 
quality assurance auditors to all study documents as described in Section 14.1.
15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects) 
according to the protocol, the ethical principles that have their origin in the Declaration of 
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct 
the study according to applicable local or regional regulatory requirements and align his or her 
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing 
requirements for informed consent and investigator responsibilities.
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15.1
IRB and/or IEC Approval
IRBs and IECs must be constituted according to the applicable local requirements of each 
participating region. The sponsor or designee will require documentation noting all names and 
titles of members who make up the respective IRB or IEC. If any member of the IRB or IEC has 
direct participation in this study, written notification regarding his or her abstinence from voting 
must also be obtained. Those American sites unwilling to provide names and titles of all members 
due to privacy and conflict of interest concerns should instead provide a Federal Wide Assurance 
Number or comparable number assigned by the Department of Health and Human Services.
The sponsor or designee will supply relevant documents for submission to the respective IRB or 
IEC for the protocol’s review and approval. This protocol, the IB, a copy of the informed consent 
and assent forms, and, if applicable, subject recruitment materials and/or advertisements and other 
documents required by all applicable laws and regulations, must be submitted to a central or local 
IRB or IEC for approval. The IRB’s or IEC’s written approval of the protocol and subject 
informed consent and assent must be obtained and submitted to the sponsor or designee before 
commencement of the study (ie, before shipment of the sponsor-supplied drug or study specific 
screening activity). The IRB or IEC approval must refer to the study by exact protocol title, 
number, and version date; identify versions of other documents (eg, informed consent form) 
reviewed; and state the approval date. The sponsor will notify the site once the sponsor has 
confirmed the adequacy of site regulatory documentation and, when applicable, the sponsor has 
received permission from competent authority to begin the trial. Until the site receives notification, 
no protocol activities, including screening may occur.
Sites must adhere to all requirements stipulated by their respective IRB or IEC. This may include 
notification to the IRB or IEC regarding protocol amendments, updates to the informed consent 
form, recruitment materials intended for viewing by subjects, local safety reporting requirements, 
reports and updates regarding the ongoing review of the study at intervals specified by the 
respective IRB or IEC, and submission of the investigator’s final status report to IRB or IEC. All 
IRB and IEC approvals and relevant documentation for these items must be provided to the 
sponsor or its designee.
Subject incentives should not exert undue influence for participation. Payments to subjects must 
be approved by the IRB or IEC and sponsor.
15.2
Subject Information, Informed Consent and Assent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the 
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all 
applicable laws and regulations. The informed consent and assent forms, subject authorization 
form (if applicable), and subject information sheet (if applicable) describe the planned and 
permitted uses, transfers, and disclosures of the subject’s personal and personal health information 
for purposes of conducting the study. The informed consent and assent forms and the subject 
information sheet (if applicable) further explain the nature of the study, its objectives, and 
potential risks and benefits, as well as the date informed consent and assent are given. The 
informed consent and assent forms will detail the requirements of the participant and the fact that 
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he or she is free to withdraw at any time without giving a reason and without prejudice to his or her 
further medical care.
The investigator is responsible for the preparation, content, and IRB or IEC approval of the 
informed consent and assent forms, and if applicable, the subject authorization form. The informed 
consent and assent forms, subject authorization form (if applicable), and subject information sheet 
(if applicable) must be approved by both the IRB or IEC and the sponsor prior to use.
The informed consent and assent forms, subject authorization form (if applicable), and subject 
information sheet (if applicable) must be written in a language fully comprehensible to the 
prospective subject or subject’s parent/legal guardian. It is the responsibility of the investigator to 
explain the detailed elements of the informed consent and assent forms, subject authorization form 
(if applicable), and subject information sheet (if applicable) to the subject or subject’s parent/legal 
guardian. Information should be given in both oral and written form whenever possible and in the 
manner deemed appropriate by the IRB or IEC. In the event the subject is not capable of rendering 
adequate written informed consent, then the subject’s legally acceptable representative may 
provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the 
subject, or the subject’s legally acceptable representative, determines he or she will participate in 
the study, then the informed consent and assent forms and subject authorization form (if 
applicable) must be signed and dated by the subject, or the subject’s legally acceptable 
representative, at the time of consent and assent and prior to the subject entering into the study. 
The subject or the subject’s legally acceptable representative should be instructed to sign using 
their legal names, not nicknames, using blue or black ballpoint ink. The investigator must also sign 
and date the informed consent and assent forms and subject authorization (if applicable) at the time 
of consent and assent and prior to subject entering into the study; however, the sponsor may allow 
a designee of the investigator to sign to the extent permitted by applicable law.
Once signed, the original informed consent and assent forms, subject authorization form (if 
applicable), and subject information sheet (if applicable) will be stored in the investigator’s site 
file. The investigator must document the date the subject signs the informed consent and assent in 
the subject’s medical record. Copies of the signed informed consent and assent forms, the signed 
subject authorization form (if applicable), and subject information sheet (if applicable) shall be 
given to the subject.
All revised informed consent and assent forms must be reviewed and signed by relevant subjects or 
the relevant subject’s legally acceptable representative in the same manner as the original 
informed consent and assent. The date the revised consent and assent were obtained should be 
recorded in the subject’s medical record, and the subject should receive a copy of the revised 
informed consent and assent forms. 
15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection 
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to 
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the sponsor’s clinical study database or documentation via a unique identification number. As 
permitted by all applicable laws and regulations, limited subject attributes, such as sex, age, or date 
of birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique 
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor 
requires the investigator to permit its monitor or designee’s monitor, representatives from any 
regulatory authority (eg, US FDA, Medicines and Healthcare products Regulatory Agency, 
Pharmaceuticals and Medical Devices Agency), the sponsor’s designated auditors, and the 
appropriate IRBs and IECs to review the subject’s original medical records (source data or 
documents), including, but not limited to, laboratory test result reports, ECG reports, admission 
and discharge summaries for hospital admissions occurring during a subject’s study participation, 
and autopsy reports. Access to a subject’s original medical records requires the specific 
authorization of the subject as part of the informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain 
personally identifiable information removed (ie, subject name, address, and other identifier fields 
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1
Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by 
the investigator from the study. During and after the study, only the sponsor may make study 
information available to other study investigators or to regulatory agencies, except as required by 
law or regulation. Except as otherwise allowable in the clinical study site agreement, any public 
disclosure (including publicly accessible websites) related to the protocol or study results, other 
than study recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information 
generated by the investigator) without the consent of the investigator. Manuscript authorship for 
any peer-reviewed publication will appropriately reflect contributions to the production and 
review of the document. All publications and presentations must be prepared in accordance with 
this section and the Clinical Study Site Agreement. In the event of any discrepancy between the 
protocol and the Clinical Study Site Agreement, the Clinical Study Site Agreement will prevail.
15.4.2
Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to 
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register 
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov or other 
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda 
contact information, along with investigator’s city, state (for Americas investigators), country, and 
recruiting status will be registered and available for public viewing. 
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For some registries, Takeda will assist callers in locating trial sites closest to their homes by 
providing the investigator name, address, and phone number to the callers requesting trial 
information. Once subjects receive investigator contact information, they may call the site 
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial 
inquiries according to their established subject screening process. If the caller asks additional 
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to Takeda providing this information to callers must provide Takeda 
with a written notice requesting that their information not be listed on the registry site. 
15.4.3
Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov or other publicly accessible 
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site 
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s 
designee will obtain clinical study insurance against the risk of injury to clinical study subjects. 
Refer to the Clinical Study Site Agreement regarding the sponsor’s policy on subject 
compensation and treatment for injury. If the investigator has questions regarding this policy, he or 
she should contact the sponsor or sponsor’s designee.
16.0
REFERENCES
1. Cheson BD, Pfistner B, Juweid ME, Gascoyne RD, Specht L, Horning SJ, et al. Revised 
response criteria for malignant lymphoma. J Clin Oncol 2007;25(5):579-86.
2. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin 2013.
3. Ferlay J, Shin H, Bray F, Forman D, Mathers C, Parkin D. GLOBOCAN 2008 v1.2, Cancer 
Incidence and Mortality Worldwide: IARC CancerBase No. 10 [Internet]. Published 2010. 
Accessed 25 February 2013.
4. Dinand V, Arya LS. Epidemiology of childhood Hodgkins disease: is it different in developing 
countries? Indian Pediatr 2006;43(2):141-7.
5. Hutchinson RJ, Fryer CJ, Davis PC, Nachman J, Krailo MD, O'Brien RT, et al. MOPP or 
radiation in addition to ABVD in the treatment of pathologically staged advanced Hodgkin's 
disease in children: results of the Children's Cancer Group Phase III Trial. J Clin Oncol 
1998;16(3):897-906.
6. Hunger SP, Link MP, Donaldson SS. ABVD/MOPP and low-dose involved-field radiotherapy 
in pediatric Hodgkin's disease: the Stanford experience. J Clin Oncol 1994;12(10):2160-6.
7. Thomson AB, Wallace WH. Treatment of paediatric Hodgkin's disease. a balance of risks. Eur 
J Cancer 2002;38(4):468-77.
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8. Smith RS, Chen Q, Hudson MM, Link MP, Kun L, Weinstein H, et al. Prognostic factors for 
children with Hodgkin's disease treated with combined-modality therapy. J Clin Oncol 
2003;21(10):2026-33.
9. Carroll W, Finlay J. Cancer in Children and Adolescents. Sudbury, MA: Jones and Bartlett 
Publishers; 2010.
10. Loge JH, Abrahamsen AF, Ekeberg O, Kaasa S. Reduced health-related quality of life among 
Hodgkin's disease survivors: a comparative study with general population norms. Ann Oncol 
1999;10(1):71-7.
11. Das P, Ng AK, Stevenson MA, Mauch PM. Clinical course of thoracic cancers in Hodgkin's 
disease survivors. Ann Oncol 2005;16(5):793-7.
12. van Leeuwen FE, Klokman WJ, Veer MB, Hagenbeek A, Krol AD, Vetter UA, et al. 
Long-term risk of second malignancy in survivors of Hodgkin's disease treated during 
adolescence or young adulthood. J Clin Oncol 2000;18(3):487-97.
13. Aleman BM, van den Belt-Dusebout AW, De Bruin ML, van 't Veer MB, Baaijens MH, de 
Boer JP, et al. Late cardiotoxicity after treatment for Hodgkin lymphoma. Blood 
2007;109(5):1878-86.
14. Capra M, Hewitt M, Radford M, Hayward J, Weston CL, Machin D, et al. Long-term outcome 
in children with Hodgkin's lymphoma: the United Kingdom Children's Cancer Study Group 
HD82 trial. Eur J Cancer 2007;43(7):1171-9.
15. Behringer K, Josting A, Schiller P, Eich HT, Bredenfeld H, Diehl V, et al. Solid tumors in 
patients treated for Hodgkin's disease: a report from the German Hodgkin Lymphoma Study 
Group. Ann Oncol 2004;15(7):1079-85.
16. Connors J, Ansell S, Park S, Fanale M, Younes A. Brentuximab Vedotin Combined with 
ABVD or AVD for Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma: 
Long Term Outcomes. 56th ASH Annual Meeting and Exposition; 6-9 December 2014; San 
Francisco, CA. Abstract 292.
17. Chiarle R, Podda A, Prolla G, Podack ER, Thorbecke GJ, Inghirami G. CD30 overexpression 
enhances negative selection in the thymus and mediates programmed cell death via a 
Bcl-2-sensitive pathway. J Immunol 1999;163(1):194-205.
18. DeYoung AL, Duramad O, Winoto A. The TNF receptor family member CD30 is not essential 
for negative selection. J Immunol 2000;165(11):6170-3.
19. Zengin E, Sarper N. Humoral immunity to diphtheria, tetanus, measles, and hemophilus 
influenzae type b in children with acute lymphoblastic leukemia and response to 
re-vaccination. Pediatr Blood Cancer 2009;53(6):967-72.
20. Foltz LM, Song KW, Connors JM. Hodgkin's lymphoma in adolescents. J Clin Oncol 
2006;24(16):2520-6.
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21. Yagoda A, Mukherji B, Young C, Etcubanas E, Lamonte C, Smith JR, et al. Bleomycin, an 
antitumor antibiotic. Clinical experience in 274 patients. Ann Intern Med 1972;77(6):861-70.
22. Common Terminology Criteria for Adverse Events (CTCAE), Version 4.03. U.S. Department 
of Health and Human Services National Cancer Institute. 14 June 2010.
23. Common Terminology Criteria for Adverse Events (CTCAE). National Cancer Institute, 
National Institutes of Health, U.S. Department of Health and Human Services Series v4.03. 
June 14, 2010. Publication No. 09-5410.
24. Zinzani PL, Tani M, Fanti S, Alinari L, Musuraca G, Marchi E, et al. Early positron emission 
tomography (PET) restaging: a predictive final response in Hodgkin's disease patients. Ann 
Oncol 2006;17(8):1296-300.
25. Hutchings M, Mikhaeel NG, Fields PA, Nunan T, Timothy AR. Prognostic value of interim 
FDG-PET after two or three cycles of chemotherapy in Hodgkin lymphoma. Ann Oncol 
2005;16(7):1160-8.
26. Aridgides P, Bogart J, Shapiro A, Gajra A. PET Response-Guided Treatment of Hodgkin's 
Lymphoma: A Review of the Evidence and Active Clinical Trials. Adv Hematol 
2011;2011:309237.
27. Meignan M, Gallamini A, Haioun C, Polliack A. Report on the Second International 
Workshop on interim positron emission tomography in lymphoma held in Menton, France, 8-9 
April 2010. Leuk Lymphoma 2010;51(12):2171-80.
28. Lansky SB, List MA, Lansky LL, Ritter-Sterr C, Miller DR. The measurement of performance 
in childhood cancer patients. Cancer 1987;60(7):1651-6.
29. Karnofsky D, Burchenal J. The Clinical Evaluation of Chemotherapeutic Agents in Cancer. In: 
MacLeod C, editor. Evaluation of Chemotherapeutic Agents: Symposium Held at the New 
York Academy of Medicine. New York: Columbia University Press; 1949, p. 191-205.
30. Peus D, Newcomb N, Hofer S. Appraisal of the Karnofsky Performance Status and proposal of 
a simple algorithmic system for its evaluation. BMC Med Inform Decis Mak 2013;13:72.
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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the applicable 
local laws and regulations. The responsibilities imposed on investigators by the FDA are 
summarized in the “Statement of Investigator” (Form FDA 1572), which must be completed and 
signed before the investigator may participate in this study.
The investigator agrees to assume the following responsibilities by signing a Form FDA 1572:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff who will assist in the protocol.
3. If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution should implement procedures to 
ensure the integrity of the trial-related duties and functions performed and any data generated.
4. Ensure that study related procedures, including study specific (non-routine/non-standard 
panel) screening assessments are NOT performed on potential subjects, prior to the receipt of 
written approval from relevant governing bodies/authorities.
5. Ensure that all colleagues and employees assisting in the conduct of the study are informed of 
these obligations.
6. Secure prior approval of the study and any changes by an appropriate IRB/IEC that conform to 
21 CFR Part 56, ICH, and local regulatory requirements.
7. Ensure that the IRB/IEC will be responsible for initial review, continuing review, and approval 
of the protocol. Promptly report to the IRB/IEC all changes in research activity and all 
anticipated risks to subjects. Make at least yearly reports on the progress of the study to the 
IRB/IEC, and issue a final report within 3 months of study completion.
8. Ensure that requirements for informed consent, as outlined in 21 CFR Part 50, ICH and local 
regulations, are met.
9. Obtain valid informed consent from each subject who participates in the study, and document 
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the IRB/IEC. Each informed consent form should contain a subject 
authorization section that describes the uses and disclosures of a subject’s personal 
information (including personal health information) that will take place in connection with the 
study. If an informed consent form does not include such a subject authorization, then the 
investigator must obtain a separate subject authorization form from each subject or the 
subject’s legally acceptable representative.
10. Prepare and maintain adequate case histories of all persons entered into the study, including 
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 
2 years following notification by the sponsor that all investigations have been discontinued or 
that the regulatory authority has approved the marketing application. The investigator should 
contact and receive written approval from the sponsor before disposing of any such 
documents.
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11. Allow possible inspection and copying by the regulatory authority of GCP-specified essential 
documents.
12. Maintain current records of the receipt, administration, and disposition of sponsor-supplied 
drugs, and return all unused sponsor-supplied drugs to the sponsor.
13. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor 
within 24 hours.
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Appendix C
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name, 
address, and other personally identifiable information. In addition, investigator’s personal 
information may be transferred to other parties located in countries throughout the world (eg, the 
United Kingdom, US, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

IRBs and IECs.
Investigator’s personal information may be retained, processed, and transferred by Takeda and 
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to 
regulatory agencies relating to other medications used in other clinical studies that may contain 
the same chemical compound present in the study medication.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible 
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data 
protection laws that offer the same level of protection as data protection laws in investigator’s own 
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda 
and other parties for the purposes described above.
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Appendix D
Deauville Criteria for PET
Score
1
no uptake
2*
uptake mediastinum
3*
uptake >mediastinum but liver
4
Uptake moderately increased compared to the liver at any site.
5
Uptake markedly increased compared to the liver at any site or/and new sites of disease.
Source: Meignan et al (2018). [27]
* If mediastinal blood pool activity is equal or greater than liver then the uptake within the lesion should be compared 
with liver (lesion uptake less than liver=score 2; lesion uptake equal to liver=score 3).
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Appendix E
Ann Arbor Staging System for Hodgkin Lymphoma
Stage
Definition
I
Involvement of a single lymph node region or lymphoid structure (eg, spleen, thymus, 
Waldeyer’s ring)
II
Involvement of 2 or more lymph node regions on the same side of the diaphragm (the 
mediastinum is a single site; hilar lymph nodes should be considered "lateralized" and, when 
involved on both sides, constitute Stage II disease)
III
Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm
III1
Subdiaphragmatic involvement limited to spleen, splenic hilar nodes, celiac nodes, or portal 
nodes
III2
Subdiaphragmatic involvement includes paraaortic, iliac, or mesenteric nodes plus structures in 
III1
IV
Involvement of extranodal site(s) beyond that designated as "E"
More than 1 extranodal deposit at any location
Any involvement of liver or bone marrow
A
No symptoms
B
Unexplained weight loss of >10% of the body weight during the 6 months before staging 
investigation
Unexplained, persistent, or recurrent fever with temperatures >38ºC during the previous month
Recurrent drenching night sweats during the previous month
E
Localized, solitary involvement of extralymphatic tissue, excluding liver and bone marrow
Source: Harrison’s Manual of Medicine, 17th Edition. 
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Appendix F
Lansky Play-Performance Scale for Children
The Play-Performance Scale for Children is designed to provide a standardized measure of the 
performance status of the child with cancer. Have the parent select the description that best 
describes the child’s play during the past week, averaging out good days and bad days.
Score
Performance
100
Fully active, normal
90
Minor restrictions in physically strenuous activity.
80
Active, but tires more quickly.
70
Both greater restriction of and less time spent in play activity.
60
Up and around, but minimal active play; keeps busy with quieter activities.
50
Gets dressed but lies around much of the day; no active play; able to participate in all quiet play and 
activities.
40
Mostly in bed; participates in quiet activities.
30
In bed; needs assistance even for quiet play
20
Often sleeping; play entirely limited to very passive activities.
10
No play; does not get out of bed.
0
Unresponsive.
Source: Lansky et al (1987). [28]
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Appendix G
Karnofsky Performance Status
Percent
Description 
100
Normal, no complaints, no evidence of disease.
90
Able to carry on normal activity, minor signs or symptoms of disease.
80
Normal activity with effort, some signs or symptoms of disease.
70
Cares for self. Unable to carry on normal activity or to do active work.
60
Requires occasional assistance, but is able to care for most of his needs.
50
Requires considerable assistance and frequent medical care.
40
Disabled, requires special care and assistance.
30
Severely disabled, hospitalization is indicated although death not imminent.
20
Hospitalization necessary, very sick, active supportive treatment necessary.
10
Moribund, fatal processes progressing rapidly.
0
Dead
Sources: Karnofsky et al (1949); [29] Péus et al (2013). [30]
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Appendix H
New York Heart Association Classification of Cardiac Disease
Class
Functional Capacity
Objective Assessment
I
Patients with cardiac disease but without resulting limitations of 
physical activity. Ordinary physical activity does not cause undue 
fatigue, palpitation, dyspnea, or anginal pain.
No objective evidence of 
cardiovascular disease.
II
Patients with cardiac disease resulting in slight limitation of 
physical activity. They are comfortable at rest. Ordinary physical 
activity results in fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of minimal 
cardiovascular disease.
III
Patients with cardiac disease resulting in marked limitation of 
physical activity. They are comfortable at rest. Less than ordinary 
activity causes fatigue, palpitation, dyspnea, or anginal pain.
Objective evidence of moderately 
severe cardiovascular disease.
IV
Patients with cardiac disease resulting in inability to carry on any 
physical activity without discomfort. Symptoms of heart failure or 
the anginal syndrome may be present even at rest. If any physical 
activity is undertaken, discomfort is increased.
Objective evidence of severe 
cardiovascular disease.
Source: The Criteria Committee of New York Heart Association. Nomenclature and Criteria for Diagnosis of Diseases 
of the Heart and Great Vessels. Ninth Ed. Boston, MA: Little, Brown & Co; 1994:253-256. 
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Appendix I
Tanner Scale
Criteria for Distinguishing Tanner Stages 1 to 5 During Female Pubertal Maturation
Stage
Breast
Pubic Hair
1 (prepubertal)
No palpable glandular tissue or pigmentation of areola; 
elevation of areola only
No pubic hair; short, fine vellus hair 
only
2
Glandular tissue palpable with elevation of breast and 
areola together as a small mound; areolar diameter 
increased
Sparse, long, pigmented terminal hair 
chiefly along the labia majora
3
Further enlargement without separation of breast and 
areola; although more darkly pigmented, areola still 
pale and immature; nipple generally at or above 
midplane of breast tissue when individual is seated 
upright
Dark, coarse, curly hair, extending 
sparsely over mons
4
Secondary mound of areola and papilla above breast
Adult-type hair, abundant but limited 
to mons and labia
5 (adult)
Recession of areola to contour of breast; development of 
Montgomery's glands and ducts on areola; further 
pigmentation of areola; nipple generally below 
midplane of breast tissue when individual is seated 
upright; maturation independent of breast size
Adult-type hair in quantity and 
distribution; spread to inner aspects 
of the thighs in most racial groups
Data from Ross GT: Disorders of the ovary and female reproductive tract. In Wilson JD, Foster DW (eds): Textbook 
of Endocrinology, 7th ed. Philadelphia, WB Saunders, 1985, p 206.
Pubertal Stages in Boys
Stage
Pubic Hair
Genital
1
Absence of pubic hair
Childlike penis, testes, and scrotum (testes 2 mL)
2
Sparse, lightly pigmented hair mainly at the 
base of the penis
Scrotum enlarged with early rugation and pigmentation; 
testes begin to enlarge (3–5 mL)
3
Hair becomes coarse, darker, and more curled 
and more extensive
Penis has grown in length and diameter; testes now 8–10 
mL; scrotum more rugated
4
Hair adult in quality, but distribution does not 
include medial aspect of thighs
Penis further enlarged with development of the glans; 
scrotum and testes (10–13 mL) further enlarged
5
Hair is adult and extends to thighs
Penis and scrotum fully adult; testes 15 mL and greater
Modified from Marshall WA, Tanner JM: Variation in pattern of pubertal changes in boys. Arch Dis Child 
1970;45:13–23.
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Appendix J
Detailed Description of Amendments to Text Changes

Detailed Description of Amendments to Text.

Strikethrough font indicates text that has been deleted from Protocol Amendment 3. Red, bold 
font denotes text that has been added. Typographical, punctuation, grammar, and formatting 
errors may also have been corrected but these are not listed individually.
The primary section(s) of the protocol affected by the changes in Amendment 04 are indicated. 
The corresponding text has been revised throughout the protocol. 
Change 1.: Update the sponsor’s name to Takeda Development Center (TDC) Americas, Inc.
The primary change occurs on the Title Page.
Revised Text: Takeda Development Center (TDC) Americas, Inc.
95 Hayden Avenue, Lexington, Massachusetts 02421 USA
Please note: TDC Americas, Inc. may be referred to in this protocol as “sponsor” or 
“Takeda”.
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda Pharmaceutical Company 
Limited
Please note: Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited, may be referred to in this protocol as “Millennium”, “Sponsor”, 
or “Takeda”.
Rationale for Change: Update the name of the legal entity responsible for the study.
The following sections also contain this change:
Section 2.0 STUDY SUMMARY; Name of Sponsor(s):
Revised text: Takeda Development Center (TDC) Americas, Inc. Millennium Pharmaceuticals, 
Inc.
Section 3.4 Corporate Identification
Revised text:
TDC Americas
Takeda Development Center Americas, Inc.
TDC Asia
Takeda Development Center Asia, Pte Ltd
TDC Europe Takeda Development Centre Europe Ltd
TDC Japan
Takeda Development Center Japan
Takeda
Millennium Pharmaceuticals, Inc, TDC Americas, TDC Asia, TDC Europe, 
TDC Japan
Millennium
Millennium Pharmaceuticals, Inc, a wholly owned subsidiary of Takeda 
Pharmaceutical Company Limited.
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Change 2.: Clarify definitions of the end of the main study and optional long-term follow-up. 
The primary change occurs in Section 2.0 STUDY SUMMARY.
Study Design:
Revised text: Survival will be assessed until the sooner of death, study closure, or up to 2 years 
after enrollment of the last patient. The main study will be considered to be complete when all 
patients have had the opportunity to be followed for up to 2 years after enrollment of the last 
patient. All patients will be offered the opportunity to participate in an optional long-term 
follow-up, for at least 10 years after patient their date of enrollment in the main study.
Rationale for Change: With the addition of an optional long-term follow-up period (Protocol 
Amendment 3), the revised text delineates the end of the main study from the end of long-term 
follow-up. 
The following sections also contain this change:
Period of Evaluation:
All patients will be offered the opportunity to participate in an optional long-term follow-up, for at 
least 10 years from patient their date of enrollment in the main study.
Section 9.7 Completion of Optional Long-term Follow-up
Revised text: Patients will be considered to have completed the optional long-term follow-up if 
they have been followed for at least 10 years after from their enrollment date in the main study or 
have died.
Change 3.: Clarify the time points for analysis and reporting of the study results.
The primary change occurs in Section 2.0 STUDY SUMMARY.
Added text: 
Planned Reporting: As prespecified in the approved SAP, the analyses for reporting the 
results of the study’s primary endpoints in the clinical study report (CSR) were performed 
after all enrolled patients had the opportunity to be followed for 15 months after enrollment 
of the last patient in the main study. Efficacy results are presented by study phase, and for all 
evaluable patients treated at the recommended dose. 
Patients will continue to be followed for survival and disease status every 12 weeks (1 week) 
for 12 months, and then every 24 weeks (2 weeks) until death or study closure or for up to 
2 years from the date of the last patient enrolled. An updated analysis of the time-to-event 
efficacy endpoints and other selected study endpoints will be performed after all enrolled 
patients have had the opportunity to be followed for up to 2 years after enrollment of the last 
patient, denoting the end of the main study. Results of the updated analysis will be presented 
in an addendum to the CSR.
Data from the optional long-term follow-up will be analyzed after all participating patients 
have had the opportunity to complete 10 years of follow up from their date of enrollment in 
the main study and those results will be presented in a separate CSR addendum.
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Rationale for Change: The decision to analyze the study data and report the results in the CSR at 
the time point of 15 months after enrollment of the last patient was made in consultation with and 
by agreement of the EMA PDCO. Based on the results from a similar study conducted in an adult 
patient population with advanced-stage cHL (ECHELON-1; NCT01712490), the sponsor
concluded that the event kinetics observed between 15 months and 24 months in ECHELON-1 are 
likely to be mirrored in this study (C25004), and that very few additional events would occur 
between 15 months and 2 years to make a clinically meaningful difference in the results of the 
time-to-event efficacy endpoints. Results of an updated analysis of time-to-event efficacy endpoints 
that is planned after all patients have had the opportunity to be followed for at least 2 years after last 
patient enrollment will be presented in an addendum to the CSR. A separate CSR addendum is 
planned to report the results from the optional long-term follow-up. 
The following sections also contain this change:
Section 6.3.2 End of Study/Study Completion Definition and Planned Reporting
Revised text: Primary Completion/Study Completion
As prespecified in the approved SAP, the analyses for reporting the results of the study’s 
primary endpoints in the CSR will be conducted a minimum of 8 weeks were performed after 
patients had the opportunity to be followed for 15 months after enrollment of the last patient
receives the last dose of protocol therapy.in the main study.
Patients will continue to be followed for survival and disease status every 12 weeks after the 
last patient receives the last dose of protocol therapy.(1 week) for 12 months, and then every 
24 weeks (2 weeks) until death or study closure or for up to 2 years from the date of the last 
patient enrolled. An updated analysis on of the time-to-event efficacy endpoints and other 
selected study endpoints will be conducted performed after all enrolled patients enrolled in the 
study have had the opportunity to be followed for up to 2 years after enrollment of the last patient, 
and will be included denoting the end of the main study. This updated analysis may include 
data from the long-term follow-up period. Results of this updated analysis will be presented
in an addendum to the clinical study report. CSR.
Data from the optional long-term follow-up will be considered complete when analyzed after 
all participating patients enrolled in the study have had the opportunity to be followed for up to 
2 complete 10 years after of follow-up from their date of enrollment of in the last patient. Data 
from the optional long-term follow-up main study and those results will be analyzed separately 
presented in a separate CSR addendum.
Section 13.3 Time Points for Additional Analyses
Added text: 13.3
Time Points for Additional Analyses
As prespecified in the approved SAP, the primary analyses for reporting the results of the 
primary endpoints in the CSR were performed after all enrolled patients had the opportunity 
to be followed for 15 months after enrollment of the last patient in the main study. Efficacy 
results are presented by study phase, and for all evaluable patients treated at the 
recommended dose. 
Patients will continue to be followed for survival and disease status every 12 weeks (±1 week) 
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for 12 months, and then every 24 weeks (±2 weeks) until death or study closure or for up to 
2 years after enrollment of the last patient. An updated analysis of the time-to-event efficacy 
endpoints and other selected study endpoints will be performed after all enrolled patients 
have had the opportunity to be followed for up to 2 years after enrollment of the last patient, 
denoting the end of the main study. This updated analysis may include data from the 
long-term follow-up period. Results of the updated analysis at the end of the main study will 
be presented in an addendum to the CSR.
Data from the optional long-term follow-up will be analyzed after all participating patients 
have had the opportunity to complete 10 years of follow-up from their date of enrollment in 
the main study and those results will be presented in a separate CSR addendum.
Change 4.: Provide additional drug accountability instructions.
The primary change occurs in Section 9.11 Study Compliance.
Revised text: The appropriate study personnel will maintain records of study drug receipt, and 
dispensing, and destruction/returns.
Rationale for Change: Include study drug destruction and return as an important component of the 
study drug accountability process. 
Change 5.: Clarify instructions for completion of the End-of-Study eCRFs for the main study and 
the optional long-term follow-up.
The primary change occurs in Section 9.12, Posttreatment Follow-up Assessments (PFS and OS).
Revised text: The An End-of-Study eCRF is to be completed at the time the patient discontinues 
from the follow-up period of the main study. A separate End-of-Study eCRF will be completed 
for all participating patients upon completion of the optional long-term follow-up period (see 
Section 9.13).
Rationale for Change: Clarify the requirement for completion of an End-of-Study eCRF for 
patients at the end of their participation in the main study and the optional long-term follow-up, if 
applicable.
Change 6.: Provide additional guidance for study conduct during the optional long-term follow-up.
The primary change occurs in Section 9.13 Optional Long-term Follow-up.
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Added text:

If a patient refuses to return to the clinic for annual study visits, information can be 
collected via telephone contact reports at the time of the regularly scheduled study visits; 
however, this is not preferred. If any concerns relating to study treatment are identified 
by the investigator during this telephone consultation with the patient, the investigator 
should request that the patient attend an in-person clinic visit to complete the assessments 
outlined above and in the SOE for the optional long-term follow-up visits, or 
alternatively, have the patient visit their personal physician / other consultant for 
appropriate follow-up. Any results generated outside of the investigative site must be 
obtained by the investigator and recorded in the eCRF.

Efforts will be made to avoid any patient being lost to follow-up during the conduct of the 
study. Before patients are considered lost to follow-up, a minimum of 2 documented 
telephone contact attempts must be made, and 1 certified letter must be sent within 
6 weeks of the most recent planned study visit in an effort to contact patients.

If a patient has been documented as lost to follow-up or if the site staff becomes aware of a 
patient’s death between planned annual visits, then the following information must also 
be obtained and recorded in the eCRF:

A separate End-of-Study eCRF will be completed for all participating patients upon 
completion of their optional long-term follow-up period.
Rationale for Change: Provide more specific instructions for study conduct during optional 
long-term follow-up.
Change 7.: Describe modifications in study conduct instituted because of the COVID-19 
pandemic.
The primary change occurs in Section 9.14 COVID-19 Considerations.
Added Text: Section 9.14 COVID-19 Considerations
At the time of the COVID-19 outbreak, patient EOT visits were in progress. Delays to these 
visits were permitted as necessary based on site/regional restrictions. 
No restrictions are placed on patients receiving the COVID-19 vaccine. As of the time of the 
COVID-19 vaccine availability, all study patients have completed the treatment period of the 
study and patients are participating in posttreatment follow-up and/or long-term follow-up.
Administration of the COVID-19 vaccine to study patients therefore does not need to be 
reported on the concomitant medication log.
For patients who are unable to attend a protocol-required study visit either because the site 
has COVID-19 restrictions at the time of the visit or the patient is unable to attend due to 
COVID-19, telephone contact may be made to collect any data that are possible outside of the 
study visit. Thereafter, every effort should be made to have the visit rescheduled as soon as it 
is safe to have the patient come to the study site to complete the procedures. Procedures may 
be performed late and recorded as Unscheduled if they do not fall within the visit period. 
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Subsequent protocol-required visits should be scheduled according to the original EOT date 
and not delayed visit dates. Delayed or missed protocol-required study visits will be 
documented as protocol deviations but specified as due to COVID-19.
Monitoring of study data may be delayed due to COVID-19 restrictions at a site or, where 
available, remote monitoring may be implemented. However, if a study analysis is pending, 
all effort should be made by site staff to accommodate the study monitor in verifying data, 
including by remote means where applicable, or other acceptable methods. 
Should a study patient become infected with COVID-19 and have an outcome of death, this 
event would be reported for survival data.
Rationale for Change: Describe the required modifications in study conduct because of the 
COVID-19 pandemic.
The following sections also contain this change:
Section 10.3 Monitoring of AEs and Period of Observation
Added text: AEs or SAEs recorded due to COVID-19 should be prefaced by the term, 
“COVID-19” or “suspicion of COVID-19” to facilitate coding, as explained in the eCRF 
guidelines.
Section 12.1 eCRFs
Added text: During the COVID-19 pandemic, remote source data verification or review may 
be performed if permitted by regional regulations (see Section 9.14).
Section 14.1 Study-Site Monitoring Visits
Added text: During the COVID-19 pandemic, remote source data verification or review may 
be performed if permitted by regional regulations (see Section 9.14).
Section 14.2 Protocol Deviations
Added text: See also Section 9.14 for deviations specific to COVID-19 restrictions.
Change 8.: Clarify the circumstances for collection of survival data. 
The primary change occurs in the Schedule of Events for Optional Long-term Follow-up.
Added text: Survival status or date of death: X (only for patients who are lost to follow-up or die 
between planned annual visits).
Rationale for Change: Provide more specific instructions pertaining to circumstances for 
collection of survival data during long-term follow-up. 
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Change 9.: Update the names and titles of the protocol signatories.
The primary change occurs in Section 1.2 Approval.
Revised text:
Rationale for Change: Provide the name and title of the current responsible Takeda medical 
officer and other protocol signatories.
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