Adcetris (Brentuximab Vedotin), Substituting Vincristine in the OEPA/COPDac Regimen [Treatment Group 3 (TG3) of Euro-Net C1] With Involved Node Radiation Therapy for High Risk Pediatric Hodgkin Lymphoma (HL)
Phase: PHASE2
Conditions: Stage II Childhood Hodgkin Lymphoma, Stage III Childhood Hodgkin Lymphoma, Stage IV Childhood Hodgkin Lymphoma
Sponsor: St. Jude Children's Research Hospital

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
St. Jude
HLHR13 - CTG# - NCT01920932
Initial version, dated:  03-21-2013.  Resubmitted to IRB 05-22-2013, (IRB approved: 05-23-2013) 
Revision 0.1, dated:  07-08-2013, IRB approved: 07-17-2013 Activation date: 08-08-2013 
Amendment 1.0, dated: 08-16-2013, IRB approved: 09-24-2013 Activation date:  10-02-2013 
Amendment 2.0, dated: 01-21-2014 IRB approved: 02-25-2014. Revision 2.1, dated: 02-26-2014 (IRB 
approved: 03-28-2014)
Amendment 3.0 dated: 09-11-2014 (IRB approved: 10-28-2014) Activation date: 12-17-2014 
Amendment 4.0, dated: 03-09-2015 (IRB approved: 04-14-2015) Activation date: 06-01-2015 
Amendment 5.0, dated 01-08-2016. Resubmitted to IRB 02-16-2016 (IRB approved: 02-23-2016) 
Activation date: April 12, 2016
Amendment 6.0, dated 12-14-2016. (IRB approved: 02-07-2017) Activation date: 03-20-2017
UNR (PI change), dated 08-11-2017 (IRB approved: 08-22-2017)  
Amendment 7.0, dated 01-30-2018 (IRB approved: 5-9-2018) Activation date: 5-14-2018
UNR (PI change), dated 07-25-2018 (IRB approved: 07-27-2018  )
Minor modification, dated 8-19-2019 (IRB approved: 09-06-2019  )
UNR (PI change), dated 05-10-2022 (IRB approved: 05/24/2022 )
UNR (PI change), dated 09-18-2023 (IRB approved:  )
ADCETRIS® (BRENTUXIMAB VEDOTIN) SUBSTITUTING VINCRISTINE IN THE 
OEPA/COPDAC REGIMEN [TREATMENT GROUP 3 (TG3) OF EURO-NET C1] 
WITH INVOLVED NODE RADIATION THERAPY FOR HIGH RISK PEDIATRIC 
HODGKIN LYMPHOMA (HL)
IND# 118603
Principal Investigator
 Matt Ehrhardt, MD
Department of Oncology
Leukemia/Lymphoma Division
Sub-Investigators
Jeffrey Rubnitz, MD, PhD
Melissa M. Hudson, MD
Department of Oncology
Leukemia/Lymphoma Division
Jun J. Yang, PhD
Department of Pharmaceutical Sciences
John K. Choi, MD, PhD
Department of Pathology
Belinda N.  Mandrell, PhD
Department of Pediatric Medicine
Nursing Research Division
Matthew J. Krasin, MD
Chia-ho Hua, PhD
Department of Radiological Sciences
Radiation Oncology Division
Sue C. Kaste, DO
Barry L. Shulkin, MD, MBA
Department of Radiological Sciences
Diagnostic Imaging Division
Hui Zhang, PhD
Department of Biostatistics
Coordinating center:
St. Jude Children's Research Hospital
262 Danny Thomas Place
Memphis, Tennessee  38105-3678
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
Telephone:  (901) 595-3300
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
Collaborating investigators/institutions contact information 
Amy Billett, MD / Karen Marcus, MD
Dana-Farber Cancer Institute
44 Binney St. SW360C
Boston, MA 02115
Eric Larsen, MD
Maine Children's Cancer Program
100 Campus Drive – Unit 107
Scarborough, ME 04074
Alison M. Friedmann, MD / Shannon 
McDonald, MD / Torunn Yock, MD
Massachusetts General Hospital
Pediatric Hematology/Oncology
Yawkey 8; 55 Fruit Street
Boston, MA 02114
Michael Link, MD/Sandra Luna-Fineman, 
MD/Sara Donaldson, MD
Stanford University Medical Center
1000 Welch Road, Suite 300
Palo Alto, CA 94304
Pedro de Alarcon, MD
St. Jude Midwest Affiliate Clinic
Children’s Hospital of Illinois 
530 N.E. Glen Oak Avenue
Peoria, IL 61637
Additional contact information for St. Jude principal investigator:
Contents of this document may not be extracted without permission from the Principal Investigator.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
Protocol summary
HLHR13, ADCETRIS® (BRENTUXIMAB VEDOTIN) SUBSTITUTING VINCRISTINE IN 
THE OEPA/COPDAC REGIMEN [TREATMENT GROUP 3 (TG3) OF EURO-NET C1] 
WITH INVOLVED NODE RADIATION THERAPY FOR HIGH RISK PEDIATRIC 
HODGKIN LYMPHOMA (HL)
Principal investigator: Matt Ehrhardt, MD 
IND holder: St. Jude Children’s Research Hospital, #118603
Brief overview: Targeted therapy in the OEPA/COPDac regimen for high risk patients with 
Hodgkin lymphoma will lead to an increased number of patients with HL to achieve CR at the 
end of 2 cycles and therefore reduce the number of patients requiring RT for cure.
Intervention: Substitution of vincristine with Adcetris® in each cycle of OEPA/COPDac (see 
GPOH-HD therapy as published in Mauz-Koerholz et al. JCO 2010) for patients with high risk 
Hodgkin lymphoma.
Brief outline of treatment plan: Adcetris® will substitute every vincristine in the 
OEPA/COPDac regimen according to the GPOH-HD2002 treatment group 3 (TG3) regimen. 
Involved node radiotherapy (25.5 Gy) will be given at the end of all chemotherapy to involved 
nodes that are not in CR after 8 weeks of therapy.  Radiotherapy will be administered after 
completion of all chemotherapy following recovery of counts.  
Objectives: 
Primary objectives
To evaluate the safety of AEPA/CAPDAC, as well as the efficacy (early complete 
response) after 2 cycles of AEPA chemotherapy in high risk patients with Hodgkin 
lymphoma (HL).  
To compare the event-free survival in high risk HL patients treated with AEPA/CAPDac to 
the historical control HOD99 unfavorable risk 2 arm (UR2).
Secondary objectives

To estimate the number of patients with adequate response according to the definitions in 
the Euro-Net C1 after 2 cycles of AEPA.

To evaluate the safety of Adcetris® in the AEPA/CAPDac regimen in children with high 
risk HL.
o To describe acute hematologic, neuropathic, and infectious toxicities as they relate to 
transfusion requirements, growth factor support, episodes of febrile neutropenia and 
hospitalizations, according to the NCI Common Terminology Criteria for Adverse 
Events (CTCAE), version 4.0.
o To study the association between local failure and original lymph node region and 
volume of radiation (patterns of treatment failure).

To assess patient-reported symptoms and health-related quality of life in children with high 
risk HL compared to those treated on the unfavorable HOD99 treatment arm.
Exploratory objectives
To compare the ratings of neuropathic toxicity according to the NCI Common Terminology 
Criteria for Adverse Events, version 4.0 to the Pain Quality Assessment Scale (PQAS©).
To describe the pharmacokinetics of Adcetris® when used as part of AEPA/CAPDac for 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
HLHR13, ADCETRIS® (BRENTUXIMAB VEDOTIN) SUBSTITUTING VINCRISTINE IN 
THE OEPA/COPDAC REGIMEN [TREATMENT GROUP 3 (TG3) OF EURO-NET C1] 
WITH INVOLVED NODE RADIATION THERAPY FOR HIGH RISK PEDIATRIC 
HODGKIN LYMPHOMA (HL)
pediatric HL patients. 
To describe the immunogenicity of Adcetris® and the relationship between early response 
and presence of anti-chimeric anti-body.
To explore the association between CD30 density in Reed Sternberg cells in paraffin 
embedded tumor tissue and early response and event-free survival.
To explore the association between soluble CD30 (in serum/plasma) and early response, 
event-free survival.
To identify pharmacogenetic predictors for treatment-related outcomes in the context of 
AEPA/CAPDac.
Study design: This is a single-arm phase II study. The endpoint of primary objective 1.1.1 is 
complete response (CR) rate after OEPA. The sample size is calculated based on a binomial 
distribution to test the hypothesis: H0: p=17% versus Ha: p>17%, where p is the true CR rate of 
patients after 2-cycles of AEPA. A total of 32 patients are needed to detect a 20% increase in CR 
rate (to 37% or higher) with 80% power and 5% type I error. If this primary objective is 
successful, we will proceed to evaluate primary objective 1.1.2 which is event-free survival. A 
historical control phase II design was utilized to compare the EFS of patients treated with 
AEPA/CAPDac to that of unfavorable arm of HOD99. A sample size of 77 patients is sufficient to 
detect a 12% increase of 3-year EFS (from 79% to 91%) with 80% power and 10% type I error.
Sample size:  A total of 32 are needed for the primary objective 1.1.1.  A total of 77 (including 32 
patients for the primary objective 1.1.1) patients are needed for primary objective 1.1.2.  Thus, a 
total of 77 patients are needed for the study.
Data management:  Provided by St. Jude Children’s Research Hospital, Comprehensive Cancer 
Center research personnel, Leukemia/Lymphoma Division.  
Human subjects:  The risks to participants will be related to the toxicity of multi-modality 
chemotherapy and radiation.  There is also the risk that reducing the number of patients who 
receive radiation therapy will increase the risk of relapse.  Participants will be informed of this and 
other potential side effects during informed consent.  Adverse events will be monitored and 
reported and treated appropriately.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
General overview of treatment
STUDY ENTRY
Chemotherapy with AEPA 
x 2 cycles
Chemotherapy with CAPDac x 4 cycles
(lasts 3-4 months)
Early response evaluation
Lymph node groups that show resolution of 
all signs of Hodgkin lymphoma after early 
response evaluation → no radiation
Lymph node groups that are still affected by 
Hodgkin lymphoma after early response 
evaluation → will get radiation treatment
 (RT lasts about 4 weeks)
No further treatment, enter 
follow-up phase
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
Table of Contents
1.0
OBJECTIVES..........................................................................................................1
1.1
Primary Objectives ..........................................................................................................1
1.2
Secondary Objectives ......................................................................................................1
1.3
Exploratory Objectives ....................................................................................................1
2.0
BACKGROUND AND RATIONALE....................................................................2
2.1
Combined Modality Therapy...........................................................................................2
2.2
Risk Adapted Therapy - Intermediate and Unfavorable Risk .........................................2
2.3
Results of Pediatric Hodgkin Group Collaborative Trials...............................................5
2.4
Proposed Study and Definition of Prognostic Groups.....................................................6
2.5
Patient Reported Outcomes and Health Related-Quality of Life ..................................10
2.6
Toxicity and Tumor Specific, Pharmacological and Pharmacogenetic Predictors of 
Outcome.....................................................................................................................................11
3.0
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT ................................13
3.1
Inclusion Criteria ...........................................................................................................13
3.2
Exclusion Criteria ..........................................................................................................13
3.3
Recruitment and Screening............................................................................................14
3.4
Enrollment at St. Jude....................................................................................................14
3.5
Enrollment Instructions for Collaborating Sites............................................................14
4.0
TREATMENT PLAN............................................................................................14
4.1
General Overview..........................................................................................................14
4.2
Chemotherapy Administration.......................................................................................15
4.3
Adcetris® Dose Modifications.......................................................................................18
4.4
Radiation Therapy .........................................................................................................19
4.5
Participation of St. Jude Affiliates in the Treatment Plan .............................................24
5.0
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION ....................................24
5.1
Brentuximab vedotin (SGN-35, ADCETRIS®).............................................................24
5.2
Etoposide (VP-16) (Vepesid®) .....................................................................................25
5.3
Prednisone, Prednisolone...............................................................................................25
5.4
Doxorubicin (Adriamycin) ..........................................................................................26
5.5
Cyclophosphamide (Cytoxan) .....................................................................................27
5.6
Dimethyl Triazeno Imidazole Carboximide (DTIC) (DACARBAZINE®)...................28
5.7
Filgrastim (Neupogen)................................................................................................29
6.0
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS......................30
6.1
Pre-treatment Evaluations..............................................................................................30
6.2
Evaluations during therapy............................................................................................30
6.3
Early Response and Off-Therapy Evaluations ..............................................................31
6.4
Suggested Long-Term Follow-Up Evaluations.............................................................32
6.5
Recommended Late Effects Evaluations.......................................................................33
6.6
Patient-Reported Symptoms and Health-Related Quality of Life .................................34
6.7
Expression of CD30 in Tumor Tissue (CD30 density) .................................................36
6.8
Soluble CD30 Assessments ...........................................................................................36
6.9
Pharmacogenetics ..........................................................................................................37
7.0
EVALUATION CRITERIA..................................................................................37
7.1
Early Response Criteria .................................................................................................37
7.2
Remission Evaluation after Completion of Therapy .....................................................38
7.3
Evaluation of Progressive Disease or Relapse...............................................................38
7.4
Response Criteria for Secondary Objective...................................................................38
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

HLHR13
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
7.5
Toxicity Evaluation Criteria ..........................................................................................38
7.6
Acceptable Percentage of Missed Doses for Study Drugs ............................................39
8.0
off therapy and off-study criteria...........................................................................39
8.1
Off-Study Criteria..........................................................................................................39
8.2
Off-Therapy Criteria......................................................................................................39
9.0
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS..............40
9.1
Reporting Adverse Experiences (AEs) and Deaths to St. Jude IRB..............................40
9.2
Reporting Requirements to the FDA .............................................................................42
9.3
Reporting to St. Jude Regulatory Affairs Office (RAO) ...............................................42
9.4
Reporting to Seattle Genetics by St. Jude......................................................................43
9.5
Reporting AEs to and from Collaborating Sites to St. Jude ..........................................44
9.6
Recording AEs and SAEs..............................................................................................45
10.0
DATA COLLECTION, STUDY MONITORING & CONFIDENTIALITY.......46
10.1
Data Collection ..............................................................................................................46
10.2
Data Collection Instructions for Collaborating Sites.....................................................47
10.3
Study Monitoring...........................................................................................................47
10.4
Confidentiality ...............................................................................................................48
11.0
STATISTICAL CONSIDERATIONS ..................................................................48
11.1
Safety Monitoring..........................................................................................................48
11.2
Primary Objectives ........................................................................................................49
11.3
Secondary Objectives ....................................................................................................52
11.4
Exploratory Objectives ..................................................................................................53
12.0
OBTAINING INFORMED CONSENT................................................................55
12.1
Consent/Assent at Enrollment .......................................................................................55
12.2
Consent at Age of Majority ...........................................................................................55
12.3
Consent When English is Not the Primary Language ...................................................55
12.4
Collection of Collaborating Institutions’ Consent Forms..............................................55
13.0
REFERENCES ......................................................................................................56
APPENDICES
Appendix I:
Ann Arbor Staging Classification for Hodgkin Lymphoma
Appendix II:
Response Criteria According to Euro-NET C1
Appendix III: Collection, Processing, Storage and Shipment of Biologic Samples
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
1.0
OBJECTIVES
1.1
Primary Objectives
1.1.1
To evaluate the safety of AEPA/CAPDAC, as well as the efficacy (early 
complete response) after 2 cycles of AEPA chemotherapy in high risk 
patients with Hodgkin lymphoma (HL).  
1.1.2
To compare the event-free survival in high risk HL patients treated with 
AEPA/CAPDac to the historical control HOD99 unfavorable risk 2 arm 
(UR2).
1.2
Secondary Objectives
1.2.1
To estimate the number of patients with adequate response according to 
the definitions in the Euro-Net C1 after 2 cycles of AEPA.
1.2.2
To evaluate the safety of Adcetris® in the AEPA/CAPDac regimen in 
children with high risk HL.
1.2.2.1 To describe acute hematologic, neuropathic, and infectious toxicities 
as they relate to transfusion requirements, growth factor support, episodes of 
febrile neutropenia and hospitalizations, according to the NCI Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.0.
1.2.2.2 To study the association between local failure and original lymph 
node region and volume of radiation (patterns of treatment failure).
1.2.3
To assess patient-reported symptoms and health-related quality of life in 
children with high risk HL compared to those treated on the unfavorable 
HOD99 treatment arm.
1.3
Exploratory Objectives
1.3.1
To compare the ratings of neuropathic toxicity according to the NCI 
Common Terminology Criteria for Adverse Events, version 4.0 to the Pain 
Quality Assessment Scale (PQAS©).
1.3.2
To describe the pharmacokinetics of Adcetris® when used as part of 
AEPA/CAPDac for pediatric HL patients. 
1.3.3
To describe the immunogenicity of Adcetris® and the relationship between 
early response and presence of anti-chimeric anti-body.
1.3.4
To explore the association between CD30 density in Reed Sternberg cells in 
paraffin embedded tumor tissue and early response and event-free survival.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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1.3.5
To explore the association between soluble CD30 (in serum/plasma) and 
early response, event-free survival.
1.3.6
To identify pharmacogenetic predictors for treatment-related outcomes in 
the context of AEPA/CAPDac.
1.3.7
Compare dosimetrically, the ability of PBRT to spare adjacent normal 
tissues compared to photon-based radiation therapy.
2.0
BACKGROUND AND RATIONALE
2.1
Combined Modality Therapy
Historically children and adults with Hodgkin lymphoma (HL) were treated with the 
same chemotherapy regimens, radiation therapy (RT) fields, and doses. However, 
irradiation techniques suitable for adults produced significant morbidities in children such 
as impaired musculoskeletal development, an increased risk for subsequent benign and 
malignant neoplasms, and cardiopulmonary toxicities. A desire to reduce these 
morbidities motivated the development of risk-adapted combined modality treatment 
strategies for pediatric HL.17;38
Chemotherapy with mechlorethamine, Oncovin (vincristine), procarbazine, and 
prednisolone (MOPP) was abandoned as frontline therapy due to its associated 
leukemogenesis and gonadal toxicity (azoospermia in more than 90% of males treated at 
any age; and age-related risk of ovarian failure in females).27 Subsequently, Adriamycin 
(doxorubicin), bleomycin, vinblastine, and dacarbazine (ABVD), which was not 
associated with secondary leukemia and sterility in adults, became the preferred 
chemotherapy regimen.37 The predominant adverse effects of ABVD are pulmonary 
toxicity related to bleomycin and cardiovascular toxicity secondary to Adriamycin. These 
side effects may be exacerbated by the addition of mediastinal or mantle irradiation.26 
Overtime, contemporary pediatric regimens have evolved to further limit exposure to 
agents in the MOPP and ABVD regimens in an effort to reduce the risk of sterility, 
leukemia and cardiopulmonary toxicity.
Because of differences in the age-related developmental status of children, and the 
gender-related sensitivity to gonadal chemotherapy toxicity, no single treatment is ideal 
for all children. The use of RT and chemotherapy can broaden the spectrum of potential 
toxicities but reduce the severity of individual toxicities. Most current approaches entail 
chemotherapy in conjunction with reduced RT doses. The volume of RT and the intensity 
and duration of chemotherapy are risk- and response-adapted and determined by 
prognostic factors at presentation.
2.2
Risk Adapted Therapy - Intermediate and Unfavorable Risk
In risk-adapted treatment regimens, patients with localized disease presenting with 
unfavorable features are often grouped into an intermediate risk category and includes 
those with localized (stage IA, IIA) disease with unfavorable features and those with 
stage IIIA disease. The criteria for unfavorable clinical presentations vary per 
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IRB APPROVAL DATE: 09/18/2023

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investigation, but typically include the presence of “B” symptoms, bulky 
lymphadenopathy, hilar lymphadenopathy, involvement of 3 or more nodal regions, 
extranodal extension to contiguous structures, or advanced stage (IIIB and IV). In our 
studies, the unfavorable or high risk group (both terms used interchangeable) comprises 
all patients with stage IIB, IIIB and any IV. The COG has been using an approach of dose 
density to support early-response adapted therapy. A dose dense regimen of doxorubicin, 
bleomycin, vincristine, etoposide, prednisone and cyclophosphamide (ABVE-PC) 
chemotherapy was used for both intermediate and high risk patients in the POG9425 
study which provided encouraging clinical outcomes using response based therapy (Table 
1).39 In the recently completed COG AHOD 0031 study, intermediate risk patients 
received 2 cycles of ABVE-PC followed by response assessment. Patients with RER 
received 2 additional cycles of ABVE-PC followed by a second response assessment; 
those with a CR were randomized to 21 Gy involved field RT (IFRT) or no further 
therapy. Patients with a RER who did not have a CR were all assigned to receive IFRT. 
SER patients were all randomized to either 2 additional cycles of ABVE-PC or 
dexamethasone, etoposide, cisplatin, and cytarabine (DECA) followed by an additional 2 
cycles of ABVE-PC. All SER patients received 21 Gy IFRT after chemotherapy. 3-year 
EFS was 87.1% for RER patients versus 77.8% for SER patients (P=0.0001). OS for 
RER patients was 98.7% versus 96.9% for SER patients (P=0.02). 3-year EFS was 87.9% 
for RER/CR patients randomized to receive IFRT versus 85.4% for those randomized to 
no IFRT (P=0.07). These results suggest that early response to chemotherapy defined by 
early reduction (60%) in tumor size by CT after 2 cycles can be a powerful predictor of 
outcome and inform optimization of subsequent treatment. A secondary analysis of PET 
response after 2 cycles of ABVE-PC demonstrated that PET may further inform 
treatment. Analyses of the AHOD0031 cohort are still ongoing, including an “as treated” 
analysis; we await further information on the influence of disease characteristics, such as 
bulk, and treatment-related factors on clinical outcome.13 
Patients with unfavorable and advanced disease presentations either receive a twice-
monthly chemotherapy schedule for 6–8 months or a weekly chemotherapy regimen 
condensed to enhance dose intensity and reduce the risk of developing resistant disease. 
COG investigators recently assessed results of a dose-intense, response-based regimen 
employing BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, 
vincristine, procarbazine and prednisone) in children with high-risk disease.23 Females 
with a rapid response, received 4 cycles of COPP/ABV following BEACOPP without 
IFRT and males received 2 cycles of ABVD and IFRT. All patients with a slow response 
received 4 additional cycles of BEACOPP and IFRT. A high 5-year EFS of 94% was 
achieved and OS was 97%.23 A summary of treatment results of published trials is 
provided in Table 1, which demonstrates EFS rates ranging from 70%-90%. 
The GPOH, building up on their original experience with the OPPA/COPP regimen, 
showed that 6 cycles OEPA/COPDAC together with 20-30 Gy IFRT also produced 
excellent results, with 5-year EFS of approximately 87%.28 
Risk adapted treatment regimens as described above have allowed patients with localized 
disease receive less intensive therapy compared to patients with advanced disease without 
compromising outcome. Furthermore, response adapted therapy has been incorporated to 
allow tailoring of radiotherapy in patients that achieve a complete response after a couple of 
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cycles or are considered rapid early responders according to predefined criteria. These 
strategies aim at balancing cure and acute and late effects of therapy.
Table 1: Treatment Results for Intermediate and High Risk Pediatric Hodgkin Lymphoma
Survival (%)
Group or 
Institution
Patients 
(n)
Stage
Chemotherapy
Radiation (Gy), 
Field
OS
DFS, 
EFS or 
RFS
F-up 
(year)
GPOH-HD 
200228
239
 IIBE, IIIAE, IIIB, 
IV
2 OEPA/OPPA + 
4 COPP/COPADC
20-35 IF
97
87
5
80
IIB, IIIA2, IIIB, 
IV
4 MOPP/4 ABVD
21 EF
87
80
5
POG 872543
81
IIB/IIIA2, IIIB, IV
4 MOPP/4 ABVD
None
96
79
5
POG 942539
216
IB, IIA/IIIA1 with 
bulky 
mediastinum or 
IIIA2,
IIB/IIIB/IVB
3 ABVE-PC for RER
5 ABVE-PC for SER
21 IF
21 IF
95
95
86
83
5
CCG 52120 
54
57
III/IV
6 ABVD
12 MOPP/ABVD
21 EF
None
90
84
87
77
4
109
33
IIB, III
IV
6 COPP/ABV
COPP/ABV + CHOP + 
Ara-C/VP-16
21 IF
21 IF
95
100
87
90
3
3
CCG 594232
110
34
IIB, III
IV
6 COPP/ABV
COPP/ABV + CHOP + 
Ara-C/VP-16
None
None
100
94
83
81
3
3
CCG 5970423
99
IIB or IIIB with 
bulky disease or 
IV
All: 4 BEACOPP then
(1) RER: Female: 
4 COPP/ABV
(2) RER: Male: 
2 ABVD
(3) SER:
 4 BEACOPP
(1) None
(2) 21 IF
(3) 21 IF
(<CR: boost 14 
Gy)
97
94
5
AHOD0031
1712
IA/IIA with bulk 
disease, IAE/IIAE, 
IB/IIB, IIIA/IVA 
All: 2 ABVE-PC then
1.
RER: 2 ABVE-
PC
2. SER: 
(2a) 2 DECA + 2 ABVE-
PC
(2b) 2 ABVE-PC
If CR: (1a) None
          (1b)  21 IF
(2) 21 IF
RER: 
99
SER: 
97
RER: 
87
SER: 78
3
HOD99
141
IIB, IIIB, IV
Stanford V
If CR: 15 IF
< CR: 25 IF
97
79
3
GPOH-HD, German Pediatric Oncology-Hematology Hodgkin Lymphoma Study Group; POG, Pediatric Oncology Group; CCG, Children’s Cancer Group; COG, 
Children’s Oncology Group; HOD, Studies by the Pediatric Hodgkin Consortium; 
OEPA, Oncovin, etoposide, prednisone, Adriamycin; OPA, Oncovin, prednisone, Adriamycin; OPPA, Oncovin, procarbazine, prednisolone and Adriamycin; COPDac, 
cyclophosphamide, Oncovin, prednisone and dacarbazine; COPP, cyclophosphamide, Oncovin, prednisone and procarbazine; MOPP, nitrogen mustard, Oncovin, 
procarbazine and prednisone; ABVD, Adriamycin, bleomycin, vinblastine and dacarbazine; ABVE-PC, Adriamycin, bleomycin, vincristine, etoposide, prednisone and 
cyclophosphamide; C/VP-16, cyclophosphamide and etoposide; BEACOPP, bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, 
prednisone; CHOP, cyclophosphamide, doxorubicin, Oncovin, prednisone; DECA, dexamethasone, etoposide, cyclophosphamide, Adriamycin; 
RER, rapid early response; SER, slow early response; IF, involved field; EF, extended field; CR, complete response; OS, overall survival; DFS, disease-free survival; 
EFS, event-free survival; RFS, relapse-free survival; F-up, follow up
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2.3
Results of Pediatric Hodgkin Group Collaborative Trials
In 1990, investigators from Stanford, Dana Farber, and St. Jude initiated studies with 
objectives of reducing cardiopulmonary, gonadal, and neoplastic treatment sequelae with 
the use of combination chemotherapy regimens that eliminated or reduced exposure to 
alkylating agents, anthracyclines and bleomycin. Patients with favorable (peripheral 
nodal disease < 6 cm or mediastinal mass to thoracic cavity ratio < 33% by chest 
radiograph) localized disease received 4 cycles of vinblastine, Adriamycin, methotrexate, 
and prednisone (VAMP) chemotherapy.10 At a median follow-up of 9.6 years, 5- and 10-
year EFS were 92.7% and 89.4%, respectively.10 Patients with localized, unfavorable 
bulky presentations and advanced disease received 6 cycles of vinblastine, etoposide, 
prednisone, and Adriamycin (VEPA) chemotherapy.14 All patients received involved-
field radiation with the prescribed dose based on disease response after 2 cycles of 
chemotherapy. Patients with a complete response received 15 Gy; those with a partial 
response or bulky disease at presentation received 25.5 Gy. Accrual to the VEPA plus 
radiotherapy regimen was closed in 1993 because of the inferior event-free survival 
experienced by advanced and unfavorable patients.14 Mature results of this trial suggest 
that disease control in patients with advanced stage HL is compromised when patients are 
treated with regimens that do not contain alkylating agent chemotherapy. The 5-year EFS 
for this cohort was 67.8%+6.3% and overall survival was 81.3%+5.2%, survival rates 
below the range typically observed for pediatric patients with advanced stage disease 
treated with combined modality therapy. The subsequent study for unfavorable and 
advanced disease prescribed alternating cycles of VAMP and COP chemotherapy with 
low-dose involved-field radiation therapy and started in 1993.19 The dose of radiation 
was the same as that given on the earlier study: 15 Gy for patients achieving a complete 
response after the first 2 cycles, and 25.5 Gy for patients with a partial response and to all 
sites of bulky lymphadenopathy. The 5-year EFS for the entire VAMP/COP + RT cohort 
(n=159) was 75.6%  4.1% and 5-year overall survival was 92.7%+2.5%. Event-free 
survival was somewhat higher for the 77 patients with localized unfavorable stage I/II 
disease than that of the 88 patients with advanced stage III/IV disease though the 
difference was not statistically significant (5-year estimates: 82.5%  5.0% versus 68.4% 
 6.5%, p=0.093).19 Overall, treatment outcomes following the VAMP/COP + RT 
regimen were inferior to other reports for unfavorable and advanced stage pediatric HL. 
Surviving patients are continuing with follow-up to determine if regimen-related long-
term toxicity will be significantly less than that observed after combined modality 
treatment protocols including higher doses of alkylating agents and radiation doses and 
volumes. Accrual to this study has been closed. Subsequent studies utilized more dose-
intensive therapy that may improve long-term outcomes (since 2002 for unfavorable 
patients and in 2004 for intermediate-risk patients).
The favorable risk arm of HOD99 closed in February 2009. In this arm favorable risk 
patients were treated with four cycles of VAMP. Patients who had a complete response 
after the first two cycles did not receive RT, whereas patients with a partial early 
response received low-dose (25.5 Gy) involved-field radiotherapy. Five-year OS and EFS 
for the whole cohort are 100% and 88% (SE=4.2%), respectively; the EFS for patients 
who achieved early CR and did not receive IFRT is 89% (SE=5.7%), compared with 87% 
(SE=6.4%) for those who did not achieve CR. All 5 relapsed non-irradiated patients were 
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retrieved with multi-agent chemotherapy and IFRT without an autologous stem cell 
transplant.30
In our closed intermediate risk study patients with stage IB, IIIA, plus IA/IIA patients 
with bulky mediastinal adenopathy, “E” lesions, or 3 or more nodal sites were treated 
with 12 weeks of Stanford V chemotherapy plus low-dose, involved node radiation 
therapy, with the radiotherapy dose based on response after 8 weeks (15 Gy if CR, 25.5 
Gy if PR) of chemotherapy. The unfavorable risk arm of HOD99 reached accrual in May 
of 2011. The 3–year EFS of HOD99 unfavorable risk patients is 79.4% (SE +/- 4%) with 
a total of 27 events among 142 patients (results unpublished).
2.4
Proposed Study and Definition of Prognostic Groups
The aim of this high risk (previously called unfavorable risk) study is to: 1) estimate  the 
number of patients (stages IIB, IIIB or IV) who achieve complete response to 8 weeks of 
chemotherapy with AEPA/CAPDac thereby reducing the number of patients requiring 
radiation therapy as well as the volume to the patients receiving radiation by inducing 
higher rates of early complete response and tailoring the volume of treatment only to sites 
that achieve less then CR after 2 cycles of AEPA (early response).
2.4.1
Adcetris® for the Treatment of Hodgkin Lymphoma
Adcetris® (generic name is Brentuximab vedotin, also previously known as SGN35) is an 
antibody-drug conjugate containing an anti-CD30 murine/human chimeric monoclonal 
antibody (cAC10; brentuximab) linked to monomethylauristatin E (MMAE; vedotin). 
CD30 is a transmembrane receptor highly expressed in both HL and anaplastic large cell 
lymphoma (ALCL). After binding CD30, brentuximab is internalized and is transported to 
lysosomes, where the peptide linker is selectively cleaved, releasing MMAE into the 
cytoplasm. Like vinorelbine, MMAE exerts its antineoplastic effect through inhibition of 
tubulin polymerization, leading to M-phase arrest and apoptosis.
The safety and efficacy of Adcetris® has been evaluated in adults with HL or ALCL, 
using the MTD of 1.8 mg/kg every three weeks. Among 102 patients with HL, the 
observed ORR was 76% (95% CI 65-83%), with a CR rate of 34% (95% CI 25-45%).6 
The ORR among patients with ALCL was 88% (95% CI: 75-94%), with a CR rate of 
53% (95% CI: 40-67%).40 Treatment related toxicity in these older heavily pretreated 
patients included peripheral sensory neuropathies (44%), fatigue (42%), nausea (41%), 
diarrhea (34%), pyrexia (31%), neutropenia (21%) and vomiting (20%). Based partly on 
these results, the FDA has approved Adcetris® for the treatment of patients with 
refractory HL or ALCL.
An adult phase I dose escalation study looking for the maximum tolerated dose (MTD) on a 
weekly schedule in 43 patients (38 HL and 5 ALCL) found it to be 1.2 mg/kg. The most 
common observed adverse events were peripheral sensory neuropathy, fatigue, nausea, 
diarrhea, arthralgia, and pyrexia; and the majority of events were mild to moderate in severity. 
Tumor regression occurred in 85% of patients and the overall objective response rate was 59% 
(n = 24), with 34% (n = 14) complete responses. The median duration of response was not 
reached at a median follow-up of 45 weeks on study.12 
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The pediatric experience to date is based on nine pediatric patients included in the Phase I 
or II trials of brentuximab vedotin (5 HL, 4 ALCL). Six were treated with 1.8 mg/kg 
every 3 weeks, for a median of 15 cycles.11 The most frequent treatment-related adverse 
events were fatigue, nausea, and peripheral neuropathy. Three of 9 patients experienced ≥ 
Grade 3 toxicity (hyperesthesia, leukopenia, and neutropenia). Six of 9 pediatric patients 
obtained a CR (2/5 HL patients and 4/4 ALCL patients). In this pediatric cohort, 
pharmacokinetic parameters for the antibody-drug conjugate, including volume of 
distribution and clearance, were within approximately 20% of the values measured 
among adults (Personal communication, Seattle Genetics, September, 2011). The 
Children’s Oncology Group has recently opened AHOD1221, a phase I/II trial for 
pediatric patients with relapsed Hodgkin lymphoma in which Adcetris® is given in 
combination with gemcitabine.
Combination trials with Adcetris® for adults with newly diagnosed advanced stage HL 
are ongoing.47 The objectives of these studies are to assess the safety profile of the 
combination of Adcetris® with ABVD or AVD as well as to determine the MTD and the 
antitumor activity of the combination. Forty-four patients were enrolled on one study and 
received biweekly 1.2 mg/kg brentuximab vedotin concurrent with the chemotherapy. 
The most common grade 3/4 adverse events were neutropenia and anemia with no report 
of grade 3 neuropathy. In the ABVD cohort 40% developed significant pulmonary 
toxicity, and none in the AVD cohort, this prompted the company to warn about the 
combination with bleomycin (black box warning). The results on 37 of the evaluable 
patients is 97% of the patients were PET negative after 2 cycles of therapy.47
2.4.2
Rationale for Testing a Modified OEPA/COPDac and Involved Node Radiation 
Therapy Incorporating Adcetris® Instead of Vincristine in High-Risk Pediatric HL
The OEPA/COPDac regimen is a well-established pediatric HL treatment regimen widely 
used in Europe, Latin America and at St Jude. The combination of vincristine, etoposide, 
prednisone and doxorubicin (OEPA) followed by cyclophosphamide, vincristine, 
prednisone and dacarbazine (COPDac) was first successfully implemented in the GPOH-
HD-2002 study for boys with omission of radiotherapy only in patients with favorable 
risk (stage IA, IB , and IIA without extranodal extension) features that achieved a 
complete response to chemotherapy.28 This regimen was further refined in the ongoing 
Euro-Net C1 study open in numerous European countries in which radiotherapy decision 
is based on early response assessment – after 2 cycles of OEPA (now given to all 
patients). For consolidation COPDac is given to all boys while girls are randomized 
between COPDac and COPP (procarbazine instead of dacarbazine). Preliminary results 
suggest excellent outcomes with this strategy with and without radiotherapy in patients 
achieving an early complete response; however only 33% of high risk patients (TG3) 
could be spared radiotherapy (personal communication Mauz-Körholz) altogether. Since 
the closure of our last high risk study (HOD99) and the unavailability of 
mechlorethamine that prompted us to substitute cyclophosphamide leading to inferior 
outcomes,29 we have been using the GPOH-HD 2002 approach in our intermediate and 
high risk patients successfully.  
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While we would have liked to continue building on our Stanford V backbone experience, 
addition of Adcetris® to this combination would not have been safe and feasible due to 
the interaction with bleomycin leading to unacceptable pulmonary toxicity and the risk of 
unacceptable neuropathic toxicity with the alternating weekly vincristine and vinblastine. 
Of all the agents included in the Stanford V regimen, bleomycin has the lowest single 
agent activity (approximately 40% response rate against HL as a single agent).45 While 
bleomycin-induced pulmonary toxicity is not very common in patients treated with 
Stanford V, it is significant in the ABVD regimen. In our previous HOD99 study with 
Stanford V we had no grade 3 pulmonary toxicity reported. In a recent study of Adcetris® 
along with ABVD, approximately 40% of patients experienced pulmonary toxicity, 
compared to a 10-25% historical incidence for patients receiving ABVD alone. As a 
result of the finding, the study protocol was amended to remove bleomycin. According to 
data presented at the American Society for Hematology (ASH) conference, patients 
treated with Adcetris® plus AVD has not been associated with pulmonary toxicity.2 The 
package insert has therefore been revised to indicate that Adcetris® shall not be combined 
with bleomycin. The other toxicity of concern is neuropathy. To date Adcetris® has not 
been combined with vincristine. In combination with AVD, which includes vinblastine, it 
appears to be tolerable; however, there is no combination data for vincristine and 
Adcetris®. In our previous Stanford V experience the incidence of grade 3 neuropathy 
(constipation, motor or sensory neuropathy, and pain) was reported in 9% of patients. 
According to the investigator brochure the neuropathy associated with single-agent 
Adcetris® is primarily sensory and in phase I clinical trials reaches 54% (any grade) 
which is mostly cumulative and observed after 10 weeks of therapy (for grade 2) and 36 
weeks of therapy (for grade 3). Most patients experiencing complete resolution after 
discontinuation of the drug. Therefore, in this protocol we have replaced the vincristine in 
the OEPA/COPDac regimen with Adcetris® leading to the new combination 
AEPA/CAPDac. The cumulative doses of anthracyclines are not significantly higher than 
in the Stanford V combination while below other American cooperative group regimens, 
so that no significant cardiotoxicity is expected. Furthermore, the use of dacarbazine 
instead of a classical alkylator promises to be less gonadotoxic then procarbazine, though 
no definitive data are of yet available to prove this. To date there is no report of 
secondary leukemias in patients treated with OEPA. (Please see Tables 2 and 3 for 
comparative drug intensities and cumulative doses of pediatric standard regimens).
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Table 2: Dose Intensities of Pediatric HL Regimens (mg/m2/week)
Table 3: Cumulative Doses Associated with Long-Term Sequelae in Pediatric HL Regimens (mg/m2)
Stanford 
V
DBVE-
PC
(POG 
9425)
DBVE-
PC
(POG 
9425)
COPP/ABV
(CCG5942)
GPOH-
HD 
2002
HLHR13
CCG 59704
RER
SER 
+RT
RER
+RT
SER 
+RT
Inter-
mediate risk
+ RT
OEPA/
COPDac
+RT
AEPA/
CAPDac
BOYS
BEACOPP+
ABVD + 
RT
GIRLS 
BEACOPP+
COPP/ABV
ALL
BEACOPP
+RT
Doxorubicin
150
180
300
210
160
160
340
280
280
Bleomycin 
30
45
75
60
120
80
80
Etoposide
360
1125
1875
1250
1250
2400
2400
4800
Cyclophosphamide
2400
4000
3600
2000
4000
4800
7600
9600
Procarbazine
4200
2800
4480
5600
Dacarbazine
3000
3000
1500
Mustargen
18
Adcetris® (mg/kg)
16.8
2.4.3
Response Adapted Involved Node Radiation
Traditional radiation therapy fields were delivered on the Hodgkin Collaborators’ trial up 
through HOD99. This involved treatment with anterior and posterior oriented radiation 
beams designed based on simulation radiographs or digitally reconstructed simulation 
radiographs. This approach contributed to the high disease control rates and low infield 
failure rates (10.9%) seen in our reported combined modality clinical trials.24 Despite the 
excellent results with radiation therapy, long-term toxicities are anticipated with a wide field 
anterior / posterior treatment approach.24 Starting with the HOD05 trial for intermediate risk 
patients we began to further tailor our radiation therapy volumes to individual lymph nodes 
with a safety margin. This included moving away from the concept of contiguous irradiation 
Stanford V
OEPA 
(GPOH 
HD-2002)
AEPA
COPDac 
(GPOH 
HD-2002)
CAPDac
COPP/
ABV 
(CCG5942)
DBVE+PC 
(POG9425)
BEACOPP
(CCG 59704)
Doxorubicin
12.5
20
20
8.75
20
11.7
Bleomycin
2.5
2.5
5
3.3
Vincristine
0.7
1.125
---
0.75
---
0.35
0.93
0.67
Vinblastine
3
1.5
Etoposide
30
156
156
125
200
Cyclophosphamide
250
250
150
267
400
Procarbazine
175
233
Dacarbazine
187.5
187.5
Mustargen
1.5
Adcetris® (mg/kg)
0.6
0.6
0.6
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of nodal regions. This approach was further refined in the on-going HOD08 trial with 
smaller safety margins. Though data is not yet released for these trials, no apparent efficacy 
concerns have been identified with this more limited volume approach. In this trial we build 
on this approach incorporating PET response, CT residual disease and conformal radiation 
treatment.
2.5
Patient Reported Outcomes and Health Related-Quality of Life
The standard reporting for adverse symptoms during a treatment trial has been through 
clinical reporting using terms from the National Cancer Institute (NCI) Common 
Terminology Criteria for Adverse Events (CTCAE). However, the CTCAE reporting 
does not describe symptoms from the perspective of the patient, with suggestions that the 
patient’s perspective is most relevant in informing clinicians of anticipated effects.3;4;15 
This has led to the establishment of Federal Drug Administration (FDA) guidelines on 
the incorporation of patient reported outcomes (PROs) into clinical trials and for labeling 
purposes (US Dept. of Health).1 Furthermore, the National Cancer Institute has begun 
development of a patient-reported version of the Common Terminology Criteria for 
Adverse Events.9;41 
Patient reported outcomes (PROs) are defined as self-report of disease and/or treatment 
effects during clinical research.8 Ultimately, the effect of treatment upon an individual is 
best described through self-report. The measurement of PROs is especially important 
when evaluating the efficacy and toxicity of newly prescribed therapy. Patient reported-
outcomes may also include Health-related quality of life (HR-QoL), defined as a multi-
domain concept that represents the patient’s perception and the impact of a given illness 
and treatment on their life.35  
Cancer therapy causes medical as well as psychosocial complications that may result in 
adverse effects on a patient's perception of health and quality of life. Roper et al (2009) 
identified 35 studies describing the health-related quality of life (HR-QoL) among 
survivors of HL.36 The review found adult HL survivors to have decreased HR-QoL, 
most specifically within the domain of physical function. Fatigue was the most common 
complaint within the physical HR-QoL domain. Among childhood cancer survivors, 
disrupted sleep and fatigue have been found to be common complaints. Mulrooney et al, 
using the Childhood Cancer Survivor Study cohort, reported the prevalence of cancer 
related fatigue and sleep disturbance among adult childhood cancer survivors to a sibling 
comparison group.31
The study found that 19% of the survivors were in the most fatigued range, with female 
gender, congestive heart failure, pulmonary fibrosis, depression and being unmarried 
significantly predicting fatigue. Disrupted sleep was reported by 17% of the survivors 
and 14% reported increased daytime sleepiness. Compared to other diagnostic groups, 
survivors of HL were found to score lower on the Functional Assessment of Chronic 
Illness Therapy-Fatigue FACIT-Fatigue and higher on the Pittsburg Sleep Quality Index 
(PSQI) and Epworth Sleepiness Scale (EES) suggesting increased fatigue, sleep 
disruption, and daytime sleepiness. Clanton et al further described the impact of fatigue 
and sleep on neurocognitive function among childhood cancer survivors. In the recent 
HOD99 protocol, we explored PROs and HR-QoL among patients treated with risk-
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adapted therapy for HL.7 Over the trajectory of treatment, patients treated on the 
favorable and intermediate arm had higher physical function than those treated on the 
unfavorable arm. Females reported an overall lower QoL when compared to males and 
also reported poorer emotional, physical and psychosocial functioning. Females also 
reported pain and nausea more often than males. The most common symptom reported on 
the symptom distress scale was feeling tired and trouble sleeping. Overall, QoL improved 
across treatment time points and PROs of symptoms improved. (Mandrell, unpublished)
Identifying patient reported outcomes of symptoms and QoL is of importance when 
introducing a new therapeutic drug in the treatment of HL. In the regimen of the current 
protocol, peripheral neuropathy is a dose limiting toxicity associated with brentuximab.   
Chemotherapy induced peripheral neuropathy is commonly evaluated using the National 
Cancer Institute’s Common Toxicity Criteria ™, version 4.0 (NCI-CTC). The NCI-CTC 
quantifies neuropathy signs and symptoms according to a 0-5 score. According to the 
NCI-CTC neuropathy is graded according to cranial nerve function, as well as sensory 
and motor function. Neuropathic pain is graded as pain. The 0-5 scales is as follows: 0= 
no signs or symptoms, 1= neuropathy that does not interfere with activities of daily 
living; 2 = neuropathy that interferes with instrumental activities of daily living; 3= 
neuropathy that interferes with self-care, 4= disabling neuropathy, and 5= death. While 
the NCI-CTC toxicity criteria are widely used, published evidence of validity is limited.5 
Descriptive study of PROs and HR-QoL is important during the introduction of new 
therapeutic agents. Therefore, patient reported symptoms and quality of life will be 
evaluated during the trajectory of therapy and compared to those treated on the HOD 99 
unfavorable arm. In addition we will compare the ratings of the CTC toxicity criteria with 
the Pain Quality Assessment Scale. This scale measures pain quality and perceived depth 
of neuropathic pain. The use of this scale may be found to be more useful in detecting 
neuropathic pain and pain management assessment.22
2.6
Toxicity and Tumor Specific, Pharmacological and Pharmacogenetic 
Predictors of Outcome
Intra-patient variability in clinical response has been observed in previous trials of 
Adcetris®,12;46 although the underlying causes for such variations are largely unknown. More 
recently, central nervous system and pulmonary toxicities have been reported in a small 
fraction of patients receiving Adcetris®, prompting the FDA to add a boxed warning to the 
Adcetris® drug label. Again, the source of inter-patient variability in toxicities is unclear. In 
this trial pulmonary toxicity is unlikely, as there is no combination with other known 
pulmonary toxic therapies like bleomycin or gemcitabine, but neurotoxicity may occur.
2.6.1
Progressive Multifocal Leukoencephalopathy (PML)
In January 2012, the US Food and Drug Administration (FDA) issued a warning to health 
care professionals noting that three cases of PML have been described among patients 
treated with Adcetris®, including two diagnosed with PML after the FDA approval of 
Adcetris® for patients with relapsed/refractory lymphoma. A mechanism by which 
Adcetris® causes PML is not known. Due to the serious nature of PML, a new Boxed 
Warning highlighting this risk has been added to the drug label. The FDA recommends 
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that healthcare professionals suspend Adcetris® dosing if PML is suspected, and 
discontinue the drug therapy if a diagnosis of PML is confirmed.
2.6.2
Predictors of Adcetris® Response and Toxicities
We propose to evaluate the following pharmacological and genetic variables as potential 
predictors of Adcetris® clinical response/toxicities: 
Adcetris® plasma clearance: To characterize pharmacokinetics of Adcetris® in pediatric 
patients, we will determine serum concentration of Adcetris® at baseline, and at 
predetermined time points of the first cycle, using ELISA assay by an independent vendor.
Immunogenicity of Adcetris®: In a recent Phase I study of Adcetris® in CD30 positive 
hematologic malignancies, anti-therapeutic antibodies were observed during treatment in 
5% of patients. However, it was unclear whether immunogenicity adversely affected 
tumor response due to the small sample size.12 To address this question, we propose to 
prospectively examine serum concentration/titer of anti – Adcetris® antibody at 
predetermined time points. This assay is ELISA-based and will be performed by an 
independent vendor.
Soluble CD30: Soluble CD30 is known to be expressed in patients with Hodgkin 
lymphoma and represent a poor prognostic factor. Evaluation of this marker at diagnosis 
and prior to therapy, after 2 cycles of AEPA, and at the end of therapy in the context of 
targeted therapy may show an association with response and outcome. This assay will be 
performed at St Jude Molecular Clinical Trial Core.
Tumor cell CD30: Because CD30-mediated endocytosis is required for Adcetris® 
activation33 it is speculated that tumor CD30 density might be related to efficacy, 
although this has not been definitively observed in clinical studies. We plan to perform a 
semi-quantitative immunohistochemical scoring (scale 1 – 5) of the CD30 density of 
individual Hodgkin Reed-Sternberg cells as well as the microenvironment. This assay 
will be performed at St. Jude Molecular Clinical Trial Core.
Germline genetic polymorphisms: Pharmacogenetic variants have long been recognized 
as important predictors for drug response in various hematologic malignancies.34 For 
example, tumor response to gentuzumab ozogamicin, another antibody-targeted cytotoxic 
agent, has been linked to germline genetic variation in CD33 in children with AML, 
plausibly via regulating CD33 internalization.25 As an explorative aim, we plan to 
interrogate a small panel of inherited genetic variations (coding variants in the CD30 
gene) for possible associations with Adcetris® response and toxicities (e.g. peripheral 
neuropathy). 
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3.0
ELIGIBILITY CRITERIA AND STUDY ENROLLMENT 
According to institutional and NIH policy, the study will accession research participants 
regardless of gender and ethnic background. Institutional experience confirms broad 
representation in this regard.
3.1
Inclusion Criteria
3.1.1
Histologically confirmed, previously untreated CD30+ classical HL.
(Participants receiving limited emergent RT or steroid therapy - maximum 
of 7 days - because of cardiopulmonary decompensation or spinal cord 
compression will be eligible for protocol enrollment). 
3.1.2
Age < 18 years at the time of diagnosis (i.e., participants are eligible until 
their 19th birthday). 
3.1.3
Ann Arbor stage IIB, IIIB, IVA, or IVB.
3.1.4
Adequate renal function based on GFR ≥ 70 ml/min/1.73m2 or serum 
creatinine adjusted for age and gender as follows: 
Age
Maximum Serum Creatinine (mg/dL)
Male
Female
1 to < 2 years
0.6
0.6
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
3.1.5
Adequate hepatic function (total bilirubin < 1.5 x ULN for age, and 
SGOT/SGPT < 2.5 x ULN for age).
3.1.6
Female participant who is post-menarchal must have a negative urine or 
serum pregnancy test.
3.1.7
Female or male participant of reproductive potential must agree to use an 
effective contraceptive method throughout duration of study treatment.
3.2
Exclusion Criteria
3.2.1
CD30 negative HL.
3.2.2
Has received prior therapy for Hodgkin lymphoma, except as noted above.
3.2.3
Inadequate organ function as described above in 3.1.4 and 3.1.5.
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3.2.4
Inability or unwillingness of research participant or legal guardian / 
representative to give written informed consent.
3.3
Recruitment and Screening
Six institutions will participate in the protocol:  St. Jude Children’s Research Hospital 
(coordinating center and sponsor) and collaborating sites Dana-Farber Cancer Institute, 
Maine Children's Cancer Program, Massachusetts General Hospital, Stanford University 
Medical Center, and Children’s Hospital of Illinois in Peoria.
3.4
Enrollment at St. Jude
A member of the study team will confirm potential participant eligibility as defined in 
Section 3.1-3.2, complete and sign the ‘Participant Eligibility Checklist’. The study team 
will enter the eligibility checklist information into the St. Jude Clinical Trials 
Management System (CTMS). Eligibility will be reviewed, and a research participant-
specific consent form and assent document (where applicable) will be generated. The 
complete signed consent / assent form(s) must be faxed or emailed to the CPDMO at 
595-6265 to complete the enrollment process. 
The CPDMO is staffed 7:30 am-5:00 pm CST, Monday through Friday. A staff member 
from the St. Jude Cerner Millennium (MILLI) helpline is on call Saturday, Sunday, and 
holidays from 8:00 am to 6:00 pm. If you have a prospective research enrollment and 
need assistance releasing your consent, please call the MILLI helpline 
 on 
call number.
3.5
Enrollment Instructions for Collaborating Sites 
Collaborating Site research participants should be registered at St. Jude within 24 hours 
of enrollment at the site.  The completed Eligibility Checklist and entire signed Informed 
Consent should be faxed to 
. Please call 
 if confirmation of 
the enrollment information is needed. The Protocol Eligibility Coordinator will then 
register the research participant in the St. Jude CTMS.  
4.0
TREATMENT PLAN
4.1
General Overview
One dose of Adcetris® will replace each vincristine in the OEPA/COPDac regimen (2 
cycles of AEPA and 4 cycles of CAPDac) according to GPOH-HD2002 treatment group 
3 (TG3). Involved node radiotherapy (25.5 Gy) will be given at the end of all 
chemotherapy to involved nodes that are not in CR after 8 weeks of therapy.  
Radiotherapy will be administered after completion of all chemotherapy following 
recovery of counts.  
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4.2
Chemotherapy Administration
Table 4:  Chemotherapy Administration
Agent*
Dosage and 
route
Route
Schedule (days)
Max. Dose
AEPA x 2 (cycle length 28 days)
(A)dcetris®
1.2 mg/kg
IV over 30 min
1, 8, and 15
120 mg
(E)toposide
125 mg/m2 
IV over 1 to 2 hrs.
1 to 5
(P)rednisone
60 mg/m2/day
PO
1 to 15 (divided TID)
30 mg TID
(D)oxorubicin 
(Adriamycin)
40 mg/m2
IV over 1 to 6 hrs.
1 and 15
CAPDac x 4 (cycle length 21 days)
(C)yclophosphamide
500 mg/m2
IV over 60 min**
1 and 8
(A)dcetris®
1.2 mg/kg
IV over 30 min
1 and 8
120 mg
(P)rednisone
40 mg/m2/day
PO
1 to 15 (divided TID)
20 mg TID
(Dac)arbazine
250 mg/m2
IV over 15 to 30 
min
1 to 3
Filgrastim
5 mcg/kg
SC
as clinically indicated
*All agents should be given according to institutional guidelines or as recommended herein
**Post hydration with intravenous glucose or saline solution according to institutional guidelines
4.2.1
Adcetris® Administration Guidelines:
Adcetris® will be administered on days 1, 8 and 15 during the first 2 cycles (AEPA) and 
days 1 and 8 of the following 4 cycles (CAPDac). The dose of Adcetris® is 1.2 mg/kg 
(120 mg max.) and should be rounded to the nearest whole number of milligrams. It is 
administered by outpatient IV infusion given over approximately 30 minutes. In the 
absence of infusion toxicities, the infusion rate for all patients must be calculated in order 
to achieve a 30-minute infusion period. Adcetris® must not be administered as an IV push 
or bolus. 
Adcetris® cannot be mixed with other medications.
4.2.1.1 Required Pre-medication and Post-medication
Routine premedication should not be administered prior to the first dose of Adcetris®. 
However, participants who experience a Grade 1 or Grade 2 infusion-related reaction 
may receive subsequent Adcetris® infusions with premedication as described below. 
Patients who experience a Grade 3 or Grade 4 infusion-related reaction may potentially 
receive additional treatment with Adcetris® at the discretion of the treating investigator, 
after discussion with the principal investigator.
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4.2.1.2 Management of Adcetris® Infusion Reactions
Infusion-related reactions may occur during the infusion of Adcetris®. The infusion 
should be administered at a site properly equipped and staffed to manage anaphylaxis 
should it occur. The patient should be observed for 60 minutes following the first 
infusion of Adcetris®.
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 institutional standards. 
Medications for infusion-related reactions, such as epinephrine, antihistamines, and 
corticosteroids, should be available for immediate use.  Patients who experience a Grade 
1 or Grade 2 infusion-related reaction may receive subsequent Adcetris® infusions with 
premedication consisting of acetaminophen (15 mg/kg orally; max. 650 mg) and 
diphenhydramine (1-2 mg/kg orally max. 50 mg; or max. 25 mg IV) or according to 
institutional standards, administered 30–60 minutes prior to each 30-minute Adcetris® 
infusion. 
The routine use of steroids as premedication is discouraged.
4.2.2
Management of Etoposide Infusion Reactions
Cardiovascular effects
Transient hypotension has occurred in about 1 to 2 % of patients following rapid IV 
administration of etoposide during clinical trials. However, hypotension has not been 
associated with cardiac toxicity or electrocardiogram changes. Blood pressure usually 
normalizes within a few hours after discontinuation of the infusion. To avoid this 
complication, etoposide should be infused over 60 – 120 minutes. If hypotension should 
occur, stop the infusion, and if necessary, give 10 mL/kg NS bolus over 15 minutes. 
Repeat as necessary. Once symptoms resolve, resume infusion at ½ previous infusion rate 
until full dose administered. If hypotension recurs, stop infusion and administer 10 mL/kg 
NS bolus as indicated. Once hypotension resolves, resume infusion at ½ previous 
infusion rate until complete. Consider infusing NS at 1 – 1.5 x maintenance during 
remainder of infusion. For all subsequent doses, infuse over 2 hours.
Sensitivity reactions
Anaphylactoid reactions consisting principally of chills, rigors, diaphoresis, pruritis, loss 
of consciousness, nausea, vomiting, fever, bronchospasm, dyspnea, tachycardia, 
hypertension, and/or hypotension have occurred in 0.7 – 3% of patients receiving 
etoposide. Other manifestations include flushing, rash, substernal chest pain, 
lacrimations, sneezing, coryza, throat pain, back pain, abdominal cramps, and auditory 
impairment. Facial/lingual swelling, coughing, diaphoresis, cyanosis, tightness in the 
throat, and laryngospasm have also occurred.
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If an anaphylactoid reaction should occur: 

Stop the infusion immediately and notify prescriber 

Administer the following as indicated: 
o
diphenhydramine 1mg/kg IV (max dose 50 mg) 
o
hydrocortisone 50 – 100 mg/m2 IV 
o
epinephrine 0.01 mg/kg of a 1:1000 concentration for SQ administration 
o
fluid bolus 10 mL/kg NS infused over 15 minutes 

Once symptoms have resolved, resume infusion at ½ previous rate until infusion 
complete. Consider infusing NS at 1 – 1.5 x maintenance during remainder of 
infusion. 

If anaphylaxis recurs, stop the infusion and re-treat as above. Do not administer 
remainder of dose. Consider substituting etoposide with etoposide phosphate 
(Etopophos®) for all subsequent doses. 

If anaphylaxis does not recur, pre-medicate all subsequent doses with 
diphenhydramine 1mg/kg (max 50 mg) and hydrocortisone 50 – 100 mg/m2. 
Consider slowing the loading dose to be administered over 2 hours. 

Have at bedside all of the following for all subsequent infusions: 
o
Diphenhydramine 1mg/kg IV (max 50 mg) 
o
Hydrocortisone 50 – 100 mg/m2 IV 
o
Epinephrine 0.01 mg/kg of a 1:1000 concentration for SQ administration 
Note: anaphylactoid reactions are still possible with etoposide phosphate. If the patient 
cannot tolerate the substitution, drug is contraindicated and must be discontinued.
4.2.3
Dose Rounding
Dose rounding for chemotherapeutic agents will be allowed according to each 
institution’s policy (For St. Jude see Policy # 20.109, Institutional Policy and Procedure 
Manual). Dose rounding for standard of care medications may follow each institution’s 
written policy.
4.2.4
Chemotherapy Administration Guidelines and Supportive Medical Care:

The first cycle of AEPA starts immediately after completion of staging.

Start subsequent cycles when ANC > 500/mm3, and platelets > 
80,000/mm3. (28 days between AEPA and 21 days between CAPDac)

Chemotherapy should only be interrupted in case of severe inter-current 
infections or other severe complications. 

Treatment is not interrupted for cytopenias during each cycle.

Delay cycle if necessary, to give full dose of standard chemotherapy. For 
dose modifications on Adcetris® see 4.3.

Filgrastim (5 mcg/kg) should be used if needed to shorten treatment delays 
due to myelosuppression (likely no need to give longer than 2-3 days).  It 
should be discontinued if the ANC is > 2,000/mm3 on any one 
measurement or > 1000/mm3 two days in a row. Filgrastim should not be 
given within 24 hours of chemotherapy administration.

Drugs with a maximum dose are: Adcetris® at 120 mg.
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
Administer Pneumocystis juroveci prophylaxis as follows or as 
recommended by institutional guidelines: Trimethoprim-sulfamethoxazole 
150 mg TMP/m2: 750 mg SMX/m2 for 3 consecutive days per week at the 
onset of therapy and continue for 6 weeks after chemotherapy or 
radiotherapy is completed.

If the treating physician feels that trimethoprim-sulfamethoxazole is 
contributing to significant neutropenia, an alternative prophylaxis, such as 
atovaquone or pentamidine (IV or inhaled) may be substituted.
4.2.5
Guidance During Times of Drug Shortages and Unavailability
Treating investigators are urged to consult with the PI and use their best clinical judgment 
in optimizing therapeutic intent and ensuring patient safety in managing the protocol-
specified therapy. Although these decisions may constitute “protocol violations,” they are 
unavoidable and made in consideration of the best interest of an individual patient. These 
will not be considered monitoring/audit findings if appropriately documented. All 
protocol deviations must be documented in the clinic note and noted in the research 
database so that the alterations in therapy due to the agent shortage can be captured. This 
should be accomplished by entering “dose modified” and details noted in the comments 
field. These deviations will also be noted in the Deviation Log with the notation “Drug 
substitution/reduction due to unavoidable drug shortage/ unavailability”.
4.3
Adcetris® Dose Modifications
4.3.1
Non-Hematologic Toxicities (except neuropathy)
Toxicity
Grade 1
Grade 2
Grade 3
Grade 4
Non-hematologic 
(except 
neuropathy)
Continue at 
same dose level
Continue at 
same dose level
Withhold dose 
until toxicity is 
Grade < 2 or 
has returned to 
baseline, then 
resume 
treatment at the 
same dose level
Withhold until 
toxicity if 
Grade < 2, then 
reduce dose to 
1.2 mg/kg and 
resume 
treatment, or 
discontinue at 
the discretion 
of the treating 
investigator
4.3.2
Sensory and Motor Peripheral Neuropathy
According to the NCI CTCAE 4.0 grading criteria, neuropathy characterized by loss of 
deep tendon reflexes or paresthesias (for sensory) or weakness on exam or testing (for 
motor) that does not interfere with activities of daily living is assigned Grade 1; 
neuropathy that interferes with instrumental activities of daily living, is assigned Grade 2; 
neuropathy that interferes with self-care is assigned Grade 3, and neuropathy that is 
disabling is assigned Grade 4.
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Grade 1 toxicities will be managed clinically as indicated with pain control. For new or 
worsening Grade 2 neuropathy reduce the dose to 0.9 mg/kg. For new or worsening 
Grade 3 neuropathy dosing should be held until neuropathy improves to Grade 1 or 
baseline and then restarted at the 0.9 mg/kg dose level. For Grade 4 peripheral 
neuropathy, Adcetris® should be discontinued.
4.3.3
Pulmonary Toxicity
The incidence of Adcetris®-related pulmonary toxicity will be monitored in all patients 
treated with at least one dose of Adcetris®. Unacceptable pulmonary toxicity will be 
defined according to the NCI CTCAE 4.0 grading criteria: Grade 3 dyspnea (shortness of 
breath limiting self-care), pneumonitis (severe respiratory symptoms requiring oxygen 
and limiting self-care), and/or hypoxia (oxygen saturation <88% on pulse oximetry) that 
persist for at least three days; any Grade 4 toxicity characterized by life threatening 
airway compromise requiring urgent intervention. There must be no evidence of other 
etiologies, including left atrial hypertension, congestive heart failure, infection, metabolic 
abnormalities, or cancer related causes (e.g., malignant pericarditis). 
4.3.4
Hematologic Toxicity
At first occurrence of severe neutropenia (ANC < 500/mm3) consider starting filgrastim 
24 hours after chemotherapy administration for 2-3 consecutive days or until count 
recovery and repeat after each subsequent week of chemotherapy in order to avoid 
administration delays and dose modifications.
4.3.5
Progressive Multifocal Leukoencephalopathy
The incidence of Adcetris® related progressive multifocal leukencephalopathy will be 
monitored in all patients treated with at least one dose of Adcetris®. The FDA 
recommends that healthcare professionals suspend Adcetris® dosing if PML is suspected, 
and discontinue the drug therapy if a diagnosis of PML is confirmed. The clinical 
manifestation is of an encephalopathy that limits instrumental activities of daily living 
and is characterized on MRI by focal T2/FLAIR hyperintensities, involving 
periventricular white matter extending into centrum semiovale or involving 1/3 to 2/3 of 
susceptible areas of cerebrum +/- moderate increase in SAS and/or moderate 
ventriculomegaly
4.4
Radiation Therapy
Involved node radiation therapy is delivered on this trial. Doses and volumes of treatment 
are based on the response obtained after 2 cycles of AEPA (early response evaluation) 
measured by PET scan and diagnostic CT. Radiation doses will be selected for each 
individual lymph node, though this will be limited at times due to nodal conglomerates 
and shifting of nodal masses that have responded.  ICRU style target volumes are 
required on this study. The intent of this radiotherapy approach is to reduce both the 
radiation dose and volume, treating residual lymph node disease that responded slowly or 
incompletely at 8 weeks of therapy.
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4.4.1
Timing of Initiation of Involved Node Radiation Therapy:
Radiation therapy will be initiated approximately 2-3 weeks after completion of the last 
chemotherapy week or as soon as counts have recovered to ANC > 1000/mm3, and 
platelets > 100,000/mm3 and radiation treatment planning is complete.
4.4.2
Application of Response for Radiation Volume and Dose Selection
Response criteria are applied to each individual node as opposed to nodal regions based 
on the clinical and imaging response at early response evaluation. A lymph node is 
classified in CR if it meets BOTH the PET and CT criteria for complete response (both 
PET – CR and CT – CR).
PET criteria:
PET - CR – no evidence of residual disease in the lymph node, spleen 
(either focally or diffusely), extra-nodal site or metastatic site at early 
response evaluation.  PET activity consistent with brown fat, normal 
background activity or a non-cancer related finding will still be considered 
a “PET CR” as long as disease PET activity is not present.
PET - PR – 
Residual PET activity, above background, in an initially involved site of 
disease, felt to be consistent with HL.
PET - PD - 
New activity or an enlarging area of activity consistent with HL. 
CT criteria:
CT - CR – > 75% reduction (as measured by the product of 2 
perpendicular diameters of lesions by CT or MR imaging) in the original 
lymph node, spleen, extra nodal site or metastatic site at the early response 
evaluation will be considered a complete response.  Response to bony 
metastatic lesions will not be based on CT criteria but by PET alone. Any 
residual lymph node that measures <4 cm2 (e.g. < 2 cm x 2 cm) as 
measured by the product of 2 perpendicular diameters will also be 
considered in CT - CR, regardless of the percent reduction from baseline.  
Any metastatic lesion (e.g. lung, liver) that is <1 cm in maximal 
dimension at the 8 week response time point will be considered to be in 
CT-CR.
CT - PR – Reduction of > 50% (but ≤ 75%) in the original tumor product 
of 2 perpendicular diameters by CT (or MRI) scan.
CT - PD - An increase in the product of 2 perpendicular diameters of any 
measured lesion by >25% over the size present at entry on study or the 
appearance of new areas of disease consistent with HL.
4.4.3
Volume Definition
The selection of the lymphatics requiring radiation occurs at the early response time 
point, yet the planning and delivery of radiation therapy occurs ~ 2 weeks after 
completion of all chemotherapy.  This may result in continued shifting of nodal volumes 
and further shrinkage of individual lymph nodes or lymph node conglomerates.  It may 
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be helpful to co-register (image fusion) the early response diagnostic CT, early response 
PET-CT or obtain the early response imaging in the radiation treatment position. The 
objective in this trial is reduction of the volume of radiation treatment only to those 
lymph nodes with a less than complete response. Even with these aids in planning it is 
anticipated that the radiation oncologist will have to use some judgment in defining the 
location of the residual lymph nodes assigned a mixed or inadequate response.  
Lymphatics – involved nodal irradiation
CR (both a PET – CR and CT – CR) – these sites will not receive radiation therapy and 
will not be contoured.
PR (a PR in any lymph node by EITHER PET or CT criteria):

GTV - Individual lymph nodes that are classified as PR will be contoured as the 
GTV based on their residual shape after completion of all chemotherapy (at the 
time of simulation).  This may include one node in a larger group of nodes or may 
include the entire nodal conglomerate if it had residual PET avidity at early 
response evaluation point or continues to meet the CT criteria for PR (CT – PR).  
If there is significant uncertainty about delineation of the PET residual, the entire 
lymph node mass may be contoured.  These volumes do not need to be contiguous.  

CTV - The GTV will be surrounded by a 1 cm CTV that is anatomically 
constrained to lymphatic regions of tissue at risk for invasion by HL.

The CTV will be surrounded by an institution specific margin accounting for 
positional uncertainty and target motion (an ITV may be contoured)
Spleen
CR (both a PET – CR and CT – CR) – If the spleen has no residual focal activity and any 
lesion meets CT – CR response criteria, the spleen will not be contoured or irradiated.  
PR (a PR in the spleen by EITHER PET or CT criteria):

GTV - Regardless of whether the spleen was focally or diffusely involved, the 
entire spleen will be contoured as a GTV.

CTV - For the spleen the CTV = GTV and no margin is added.  If there are 
splenic hilar lymph nodes that required radiation, these will be targeted as noted 
above in the guidelines for lymphatics.  

PTV - The CTV will be surrounded by an institution specific margin accounting 
for positional uncertainty and target motion (an ITV may be contoured).
“E” lesions and metastatic sites
CR (both a PET – CR and CT – CR) – these sites will not receive radiation therapy and 
will not be contoured.
PR (a PR in any metastatic site or “E” lesion by EITHER PET or CT criteria with the 
exception of bone which will be assessed only by PET) – Metastatic sites or “E” lesions 
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with either residual PET activity or dimension that do not meet CT – CR criteria will be 
radiated.

GTV - Individual metastatic sites and “E” lesions that are classified as PR at early 
response evaluation will be contoured as the GTV based on its residual shape 
after completion of all chemotherapy (at the time of simulation). This may include 
bone (not bone marrow involvement), lung (individual lesions, not the entire 
lung), or liver lesions (not the entire liver) as examples.  

CTV - For metastatic and “E” lesions the CTV = GTV and no margin is added.

PTV - The CTV will be surrounded by an institution specific margin accounting for 
positional uncertainty and target motion (an ITV may be contoured).
Whole lung radiation therapy is not used in this trial.  If individual lung nodules felt to be 
residual Hodgkin’s lymphoma remain and meet size criteria, they will be treated according 
to the guidelines above.  If the metastatic sites are too numerous to target safely, or if at the 
end of chemotherapy the metastatic sites have resolved and cannot be targeted (previously 
present at the 8 week response time point), no radiation may be given to those sites.
Normal tissue volumes
The following normal tissues should be delineated based on the location of the 
lymphatics requiring radiation.  Delineation of other normal tissues is at the discretion of 
the radiation oncologist:
Neck
Thyroid
Abdomen 
Liver
Kidneys
Chest Heart 
Lungs
Pelvis 
Bladder
Ovaries
Testes
4.4.4
Dose: PTV - 25.5 Gy at 1.5 Gy per in 17 fractions
4.4.5
Treatment technique: All forms of conformal radiation therapy are allowed on this 
trial including proton beam radiation, intensity modulated radiation (IMRT), and conformal 
photon radiation, including tomotherapy and arc therapy.  
Prescription point – The prescription point is to a point within the PTV with the goal of 
coverage of 95% PTV with the 95% isodose volume.  This allows for the anticipated under-
dosing of the PTV at superficial nodal sites, not a risk for invasion by HL.  
Proton beam radiation is prescribed using Cobalt-Gray-Equivalents (CGE).  Planning will 
additionally incorporate a distal target margin for each beam in place of the PTV to 
determine the distal range of each beam (described below).
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Proton distal target margin - This is the distal edge of the CTV + Range Uncertainty + 
Internal Margin + Set-up Margin

Range uncertainty = 1.5% of the water-equivalent range of the CTV at max 
depth (> 1mm)

Set-up margin = set-up, mechanical, dosimetric and registration uncertainties 
(> 1mm)

Internal margin = compensates for all variations in site, size and shape of the 
tissues contained in or adjacent to the CTV (> 1mm)
Tissue heterogeneity - Dose corrections are required for tissue heterogeneity.
Dose heterogeneity - Treatment plans must have no more than 10% of the combined 
GTV, CTV and PTV volume exceed 110% of the prescribed dose.
4.4.6
Dose Limitations and Treatment Interruptions.
Normal tissues should be maximally shielded as allowed by the target volume.  Portions 
of the target volume may be partially shielded if necessitated by normal tissue tolerance.  
The following are recommended guidelines for normal tissue tolerances but individual 
patient and tumor circumstances may require deviation from these normal tissue limits.

Heart:  The whole heart may not receive more than 20 Gy and 50% of the heart 
may not receive more than 25 Gy.

Lung: The volume of the total lung receiving more than 24 Gy should be limited 
to less than 30% (V24Gy<30%)18

Liver: The entire liver should not receive more than 15 Gy. 

Kidney: Maximum of 15 Gy to the entire kidney volume bilaterally.

Oophoropexy should be offered prior to pelvic radiotherapy in all females who 
require pelvic radiotherapy. A testicular shield should be used for male patients 
requiring radiation therapy to the pelvic region during that course of therapy when 
feasible.
Treatment interruptions – Treatment interruptions should be kept to a minimum, but may 
be necessary for significant events such as infection, neutropenia or thrombocytopenia.
4.4.7
Position Verification 
Some method of patient localization should be used at a minimum of weekly, but is 
allowed more frequently based on institutional standard.  This may include (but is not 
limited to) implanted fiducials, cone beam CT, in-room CT, EPIDs, or port films.
4.4.8
Urgent Radiotherapy 
Urgent radiotherapy at the time of presentation and prior to chemotherapy will be given 
for those presenting with life threatening conditions such as airway compromise, spinal 
cord compression, or disease interfering with optimal and timely work-up of the patient.
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4.4.9
Collection of Volumetric Radiation Therapy Data 
The composite volumetric radiation therapy treatment plan will be submitted in a 
DICOM format to the Radiation Oncology PI (Matthew Krasin) in a manner determined 
appropriate for each participating institution.  This information will include:

DICOM RT dataset (structures, targets, dose, CT simulation study)

Copy of the total dose record (treatment chart)

The 8 week PET-CT in DICOM format
This information should be submitted within 6 weeks of completion of radiation therapy.
4.5
Participation of St. Jude Affiliates in the Treatment Plan
St Jude participants may receive standard chemotherapy, as well as laboratory/tests to 
monitor for toxicity at St. Jude affiliates and local physicians’ offices, as recommended 
by treating investigator.  Adcetris® must be administered at St. Jude unless special 
permission is granted to the affiliate site. 
Radiotherapy for St. Jude patients and all protocol required response assessments will be 
done at St. Jude or a site approved by the PI.
5.0
DRUG/DEVICE/BIOLOGIC AGENT INFORMATION 
5.1
Brentuximab vedotin (SGN-35, ADCETRIS®)
Description:  Brentuximab is a sterile, preservative-free, white to off-white lyophilized 
cake for reconstitution for IV administration. Brentuximab is supplied by Seattle Genetics 
in single-use, Type 1 borosilicate glass vials with FluroTec®-coated butyl rubber stoppers 
and aluminum seals. Each vial of the product contains brentuximab, trehalose, sodium 
citrate, and polysorbate 80. See the Pharmacy Manual and Investigator’s brochures for 
further information.
Storage and handling:  Vials containing brentuximab must be refrigerated at 2–8oC in an 
appropriate locked room accessible only to the pharmacist, the investigator, or a duly 
designated person.  Reconstituted brentuximab should not be stored at room temperature. 
The effect of light on brentuximab has not been assessed; therefore, it is recommended 
that brentuximab vials and solutions be stored in the dark until the time of use. 
Reconstituted vials must not be shaken.  Drug accountability instructions are provided in 
the Pharmacy Manual.
Packaging and labeling:  Refer to the Pharmacy Manual for information regarding 
packaging and labeling.
Preparation:  Please refer to the Pharmacy Manual, Sections 3.5 – 3.8.
Toxicity: The most commonly reported side effects are tiredness, fever, diarrhea, nausea, 
abnormal nerve function in arms or legs, low white blood cells, muscle pain, vomiting, 
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back pain, rash, constipation, cough, shortness of breath, chills, upper respiratory tract 
infection, dizziness, joint pain, itching, low platelets, alopecia, high blood sugar, low red 
blood cells, stomach pain, and weight loss.
See investigator’s brochure for complete safety information.
Dosage and route of administration:  See section 4.2.
5.2
Etoposide (VP-16) (Vepesid®)
Source and pharmacology: Etoposide is an epipodophyllotoxin derived from
Podophyllum pelatatum. It is thought to act mainly by inhibiting topoisomerase II, 
causing double and single strand DNA breaks. Etoposide is cell cycle, phase-specific, 
with activity in the G2 and S phases. Absorption of etoposide is approximately 30-40% 
and is highly variable and somewhat dose-dependent. It is extensively bound to serum 
proteins and is metabolized in the liver, including cytochrome P450 3A metabolism to 
several moieties that include a reactive oxidized species. Etoposide and its metabolites 
are excreted mainly in the urine with a smaller amount excreted in the feces. Dosage 
adjustments should be considered in patients with liver dysfunction, kidney dysfunction 
or hypoalbuminemia.
Formulation and stability: Etoposide is available in multi-dose vials containing
100mg, 150mg, 500mg and 1000mg of etoposide as a 20mg/ml solution and 30% 
alcohol. Etoposide is also available as a 50 mg capsule. The intact vials of etoposide 
solution should be stored at room temperature. The capsules should be stored under 
refrigeration. Etoposide solution should be diluted in D5W or 0.9% NaCl prior to 
administration. Solutions with a final concentration of 0.2 and 0.4 mg/ml are stable at 
room temperature for 96 hours and 24 hours respectively.
Supplier: Commercially available.
Toxicity: Dose limiting toxicity is myelosuppression. Nausea and vomiting (usually of 
low to moderate severity), diarrhea, mucositis (particularly with high doses), alopecia and 
anorexia are fairly common. Hypotension can occur with rapid infusions. Other side 
effects reported less commonly include hepatitis, fever and chills, anaphylaxis and 
peripheral neuropathy. Secondary leukemia has been reported.
Dosage and route of administration:  See section 4.2.
5.3
Prednisone, Prednisolone
Source and pharmacology: Prednisone is a synthetic congener of hydrocortisone, the 
natural adrenal hormone.  Prednisone is a white or yellowish crystalline powder.  It binds 
with steroid receptors on nuclear membranes, impairs cellular mitosis and inhibits protein 
synthesis.  Prednisone also has potent anti-inflammatory effects and suppresses the 
immune system. Prednisone is well absorbed orally.  It is converted to prednisolone, the 
pharmacologically active metabolite, in the liver.  Prednisolone is further metabolized to 
inactive compounds in the liver.  The metabolites are excreted mainly in the urine.  
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Formulation and stability: Prednisone is available as various strength tablets and oral 
solution from multiple manufacturers. All dosage forms can be stored at room 
temperature. Prednisolone oral solution may be substituted for prednisone liquid at equal 
doses due to its superior palatability. 
Supplier: commercially available
Toxicity: Side effects of prednisone vary depending on the duration of its use.  Side 
effects that can occur with short term use include sodium and water retention with 
associated hypertension, peptic ulcer with possible perforation and hemorrhage, increased 
susceptibility to infections, emotional instability, insomnia, increased appetite, weight 
gain, acne and hyperglycemia. Side effects more commonly associated with prolonged 
use include cataracts, increased intraocular pressure and associated glaucoma, 
development of a “cushingoid” state, compression fractures, menstrual irregularities, 
suppression of growth in children, secondary adrenocortical and pituitary 
unresponsiveness particularly in times of stress as in trauma, surgery or illness, 
osteoporosis and muscle wasting.
Dosage and route of administration:  See section 4.2
5.4
Doxorubicin (Adriamycin)
Source and pharmacology: Doxorubicin is an anthracycline antibiotic produced by 
Streptomyces peucetius. Doxorubicin exerts its anti-tumor effects in several different 
ways. Doxorubicin intercalates between base pairs of DNA causing steric obstruction, 
disruption of DNA function and inhibition of RNA synthesis. In addition, doxorubicin 
inhibits topoisomerase II, an enzyme responsible for allowing strands of DNA to pass 
through one another as they unwind.  Lastly, doxorubicin undergoes enzymatic electron 
reduction to generate highly reactive species, including the hydroxyl free radical, which 
is thought to be responsible for the drug’s cardiac toxicity, but may play a role in its anti-
tumor activity as well. Doxorubicin is cell-cycle, phase non-specific.  Doxorubicin is 
widely distributed in the tissues and plasma, but does not cross the blood brain barrier to 
an appreciable extent. It is metabolized to doxorubicinol, which is thought to be the major 
active metabolite, and aglycones. Doxorubicin and its metabolites are excreted mainly in 
the bile and feces (80%). The remainder is excreted in the urine. Dosage should be 
reduced in patients with liver dysfunction (bilirubin > 1.2 mg/dl) or renal dysfunction 
(creatinine > 3 mg/dl). 
Formulation and stability:  Doxorubicin is available in vials containing 10 mg, 20 mg, 50 
mg and 200 mg as a 2mg/ml red-orange solution. It is also available in vials containing 
10 mg, 20 mg, 50 mg, 100 mg and 150 mg of doxorubicin as a red-orange lyophilized 
powder. Intact vials of doxorubicin solution should be stored under refrigeration while 
the lyophilized product should be stored at room temperature. Both products should be 
protected from light. Lyophilized doxorubicin can be reconstituted by adding 5, 10, 25, 
50 or 75 ml of 0.9% NaCl respectively to the 10, 20, 50, 100 and 150 mg vials to produce 
a final concentration of 2 mg/ml. Bacteriostatic diluents are not recommended. After 
reconstitution, the resultant solution should be protected from light and is stable for 7 
days at room temperature and 15 days if refrigerated.
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Supplier:  Commercially available.
Toxicity: Dose-limiting toxicities include myelosuppression and cardiotoxicity. Two 
forms of cardiac toxicity can occur.  Acute toxicity may take the form of arrhythmias, 
heart block or pericarditis and may be fatal.  The chronic form of   cardiotoxicity is 
related to total cumulative dose and is characterized by heart failure. Mediastinal 
radiotherapy and/or other cardiotoxic drugs may increase the risk of cardiotoxicity.  In 
general, total lifetime dosages of 450-550 mg/m2 should not be exceeded.  Other 
toxicities include nausea and vomiting, mucositis, alopecia, diarrhea and red 
discoloration of the urine and other body fluids. Severe tissue damage and necrosis can 
occur upon extravasation.  Radiation recall reactions can occur and can be severe.  
Rarely, allergic reactions have occurred.  Typhilitis can occur when combined with 
cytarabine.
Dosage and route of administration:  See section 4.2
5.5
Cyclophosphamide (Cytoxan)
Source and pharmacology: Cyclophosphamide is a nitrogen mustard derivative. It acts as 
an alkylating agent that causes cross-linking of DNA strands by binding with nucleic acids 
and other intracellular structures, thus interfering with the normal function of DNA. 
Cyclophosphamide is cell-cycle, phase non-specific. Cyclophosphamide is well absorbed 
from the GI tract with a bioavailability of > 75%. Cyclophosphamide is a prodrug that 
requires activation. It is metabolized by mixed-function oxidases in the liver to 4-
hydroxycyclophosphamide, which is in equilibrium with aldofosfamide. Aldofosfamide 
spontaneously splits into cyclophosphamide mustard, which is considered to be the major 
active metabolite, and acrolein. In addition, 4-hydroxycyclophosphamide may be 
enzymatically metabolized to 4-ketocyclophosphamide and aldofosfamide may be 
enzymatically metabolized to carboxyphosphamide which are generally considered to be 
inactive. Cyclophosphamide and its metabolites are excreted mainly in the urine.  Dosage 
adjustments should be made in patients with a creatinine clearance of < 50 mL/min/1.73m2.
Formulation and stability: Cyclophosphamide is available in 25 and 50 mg tablets. 
Cyclophosphamide is also available in vials containing 100, 200, 500, 1000 and 2000 mg 
of lyophilized drug and 75 mg mannitol per 100 mg of cyclophosphamide. Both forms of 
the drug can be stored at room temperature. The vials are reconstituted with 5, 10, 25, 50 
or 100 ml of sterile water for injection respectively to yield a final concentration of 20 
mg/ml. Reconstituted solutions may be further diluted in either 5% dextrose or 0.9% 
NaCl containing solutions. Diluted solutions are physically stable for 24 hours at room 
temperature and 6 days if refrigerated, but contain no preservative, so it is recommended 
that they be used within 24 hours of preparation.
Supplier:  Commercially available.
Toxicity: Dose-limiting toxicities of cyclophosphamide are bone marrow suppression and 
cardiac toxicity. Cardiac toxicity is typically manifested as congestive heart failure, 
cardiac necrosis or hemorrhagic myocarditis and can be fatal. Hemorrhagic cystitis may 
occur and necessitates withholding therapy. The incidence of hemorrhagic cystitis is 
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related to cyclophosphamide dose and duration of therapy. Forced fluid intake and/or the 
administration of MESNA decrease the incidence and severity of hemorrhagic cystitis. 
Other toxicities reported commonly include nausea and vomiting (may be mild to severe 
depending on dosage), diarrhea, anorexia, alopecia, immunosuppression and sterility. 
Pulmonary fibrosis, SIADH, anaphylaxis and secondary neoplasms have been reported 
rarely.
Dosage and route of administration:  See section 4.2.
5.6
Dimethyl Triazeno Imidazole Carboximide (DTIC) (DACARBAZINE®)
Description:  The chemical structure of DTIC is 5-(3,3-dimethyl-1-triazeno)-imidazole-4-
carboxamide. Three hypotheses have been offered as the mechanism(s) ofaction of DTIC: 
inhibition of DNA synthesis by acting as a purine analog, action as an alkylating agent, 
and/or interaction with SH groups.
Source and pharmacology:  Kinetics: After IV administration, plasma disappearance is 
biphasic with the initial half-life of 19 minutes and terminal half-life of 5 hours. In 
patients with renal and hepatic dysfunction half-life is lengthened to 55 minutes and 7.2 
hours. 40% of unchanged DTIC is excreted in the urine in 6 hours. The drug is not 
apparently bound to plasma proteins. Formulation: 100 and 200 mg ampules containing a 
white powder. 
Formulation and stability:  Dacarbazine 100 mg/vial and 200 mg/vial are reconstituted 
with 9.9 ml and 19.7 ml, respectively, of Sterile Water for Injection, USP. The resulting 
solution contains 10 mg/ml of dacarbazine. The reconstituted drug may be given as a 
rapid intravenous injection (although this may be quite painful) or more preferable as an 
infusion in 150-200 cc of diluent over a 15 - 30 minute period. This latter form of 
administration is rarely associated with any pain along the infusion site.  The drug must 
be stored in a refrigerator 2° to 8°C (36° - 46°F) at a temperature of 4°C or less and 
protected from the light while stored. Once reconstitution occurs, the drug should be 
utilized within an 8-hour period.
Supplier: DTIC is commercially available.
Toxicity: Myelosuppression is the dose-limiting toxicity. The predominant side effect 
observed in humans has been anorexia, nausea and vomiting. This occurs with maximal 
intensity on the first day of a five-day course, and in many patients, it is less with each 
subsequent day. Myelosuppression consisting of thrombocytopenia and leukopenia 
occurs in approximately one quarter of patients after a five-day course of 250 mg/m2. The 
time course for this myelosuppression is generally maximal approximately three weeks 
after administration with the period of recovery variable. Other side effects reported 
included infrequent flu-like syndrome associated with fever and myalgia, phlebitis, tissue 
necrosis, hepatic toxicity, anaphylaxis, photosensitivity, alopecia, and facial flushing. 
Rarely, DTIC has caused diarrhea.
Dosage and route of administration:  See section 4.2.
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5.7
Filgrastim (Neupogen)
Source and pharmacology:  Filgrastim (granulocytic colony stimulating factor) is a 
biosynthetic hematopoietic agent that is made using recombinant DNA technology in 
cultures of Escherichia coli. Filgrastim stimulates production, maturation and activation 
of neutrophils. In addition, endogenous filgrastim enhances certain functions of mature 
neutrophils, including phagocytosis, chemotaxis and antibody--dependent cellular 
cytotoxicity.
Formulation and stability:  Filgrastim is supplied in vials containing 300 mcg and 480 
mcg of filgrastim at a concentration of 300 mcg/ml.  The intact vials should be stored 
under refrigeration.   The vials can be left out of refrigeration for 24 hours, but should be 
discarded if left at room temperature for longer periods of time. Filgrastim can be drawn 
up into tuberculin syringes for administration and stored under refrigeration for up to 7 
days prior to usage.  Filgrastim can be further diluted for IV infusion in 5% dextrose.  Do 
not dilute in saline---precipitate may form.  If the final concentration of this product is < 
15 mcg/ml, it is recommended that albumin be added to a final concentration of 2mg/ml 
(0.2%) to minimize adsorption of the drug to infusion containers and equipment.  
Supplier:  Commercially available.
Toxicity: Filgrastim causes marked leukocytosis.  Adverse reactions reported commonly 
include bone pain, thrombocytopenia, diarrhea, nausea, rash, alopecia, fever, anorexia 
and pain or bruising at the injection site.  Allergic reactions, MI, atrial fibrillation, and 
splenomegaly have been reported rarely.  Filgrastim is contraindicated in participants 
with allergy to E. coli derived products.
Dosage and route of administration:  See section 4.2
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6.0
REQUIRED EVALUATIONS, TESTS, AND OBSERVATIONS
6.1
Pre-treatment Evaluations
See Table 5 below.   All entry/eligibility studies should be performed within 4 weeks 
prior to entry onto the trial.  
6.1.1
Required Clinical Staging Evaluations:

History and physical exam

Complete blood count with differential

Complete metabolic profile (including electrolytes, BUN, creatinine, bilirubin, 
SGOT and SGPT)

C-Reactive Protein (CRP) or  erythrocyte sedimentation rate (ESR)

LDH, alkaline phosphatase and albumin

Chest x-ray* (mediastinal adenopathy must be expressed as equal to, greater 
than or less than 33% of the maximum intra-thoracic diameter or no 
mediastinal involvement)

CT scan or MRI of the neck and chest with contrast

CT scan or MRI of the abdomen and pelvis with contrast

PET scan 

Blood or urine pregnancy test for female patients more than 10 years old or 
post-pubertal, regardless of age.

Echocardiogram and EKG
Surgical staging:  Staging laparotomy with splenectomy is not recommended; however, 
untreated patients who have been surgically staged are eligible.
Initial staging:  Initial staging will be based on the primary physician’s interpretation of 
physical examination, laboratory and diagnostic imaging evaluations.
6.1.2
Other pre-therapy evaluations recommended but not required for good clinical 
care or as clinically indicated may include the following:

Urinalysis

Pulmonary function studies

Referral for sperm cryopreservation for male patients when appropriate

Introductory visit with radiation oncology

Bone marrow biopsies
6.2
Evaluations during therapy
See Table 5 below.  History and physical examinations as well as CBCs are 
recommended for good patient care or as clinically indicated prior to chemotherapy 
administration as deemed necessary by the treating physicians.
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Table 5: Evaluations before, during, and at the end of therapy
Pre-
treatment
Before each 
chemotherapy/
Adcetris®
Early response  
Evaluation 
(after 2 AEPA)
Off therapy 
evaluation*
History & physical
X
X
X
X
CBC with diff
X
X
O
X
ESR or CRP
X
O
X
Bone marrow biopsy
O
Chest X-ray
X
O
O
Pregnancy test
X
X**
LDH, alkaline phosphatase, albumin
X
O
O
Urinalysis
O
O
O
Complete metabolic profile 
(including renal and liver function)
X
O
O
O
Pulmonary function tests
O
O
ECHO/EKG 
X
X
O
CT or MRI neck/chest
X
Areas positive 
at diagnosis
Areas positive at 
diagnosis
CT or MRI abdomen/pelvis
X
Areas positive 
at diagnosis
Areas positive at 
diagnosis
PET scan
X
If positive at 
diagnosis
If positive at early 
response evaluation 
and no subsequent 
negative scan
Radiation oncology consultation
O
X
O
* For patients with complete response at all sites after 2 AEPA, end of therapy evaluation will be performed 4-6 weeks 
after 4th cycle of CAPDac 
* For patients not with complete response at all sites after 2 AEPA end of therapy evaluation will be performed 4-6 
weeks after finishing all prescribed radiotherapy 
**Pregnancy testing required at a minimum of every 4 weeks in females of childbearing potential during chemotherapy
X = Required study evaluations     O = Evaluations recommended for good patient care or as clinically indicated.
6.3
Early Response and Off-Therapy Evaluations
All participants will be evaluated for chemotherapy response after 2 cycles of AEPA to 
determine fields and volumes of radiotherapy. It is required to perform history and 
physical exam at the time, laboratory tests are recommended for good clinical practice. 
PET scan is required for everybody, as is CT or MRI of sites involved at diagnosis. For 
patients with complete response at all sites that will not require radiotherapy, off therapy 
evaluation is performed 4-6 weeks after the end of the 4th cycle of CAPDac, while 
patients requiring radiotherapy will have their off therapy evaluation performed 4 to 6 
weeks after the end of all prescribed radiotherapy. Required evaluations at this point will 
comprise history and physical exam, CBC with differential, and ESR or CRP. CT or MRI 
of areas positive at diagnosis need to be repeated, PET scans will only be repeated if 
previous scan positive.
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6.4
Suggested Long-Term Follow-Up Evaluations
See Table 6 below.  After confirmation of disease status at the first off therapy 
evaluation, participants should have regular follow-up with a recommended schedule of 
every 3 months for 1 year, every 4 months for the next 2 years, every 6 months for the 
4th year, and annually thereafter. Follow-up studies are recommended as clinically 
indicated for patients with abnormal values at baseline and to monitor for organ 
dysfunction related to the toxic effects of chemotherapy and include a physical 
examination, CBC with differential and ESR/CRP. Chest radiograph is recommended for 
good patient care and as clinically indicated during follow-up for patients with 
mediastinal disease.
CT or MRI of initially involved sites of disease is required at 1 year off therapy 
evaluation. Follow-up PET is only recommended if CT or MRI shows suspicious lesions 
requiring further characterization. 
Table 6: Recommended schedules for off-therapy evaluation for disease status
Time since end of therapy
H&P
CBC
ESR/CRP
CXR
CT or MRI 
neck/chest
CT or MRI
abd/pelvis
PET
scan
3 months
X
O
O
6 months
X
O
O
O
9 months
X
O
O
1 year
X
X
X
O
X1
X1
X2
16 months
X
O
O
20 months
X
O
O
2 years
X
X
X
O
X1
X1
X2
28 months
X
O
O
32 months
X
O
O
3 years
X
X
X
O
3 ½ years
X
O
O
4 years
X
X
X
O
4 ½ years
X
O
O
5 years and yearly thereafter
X
X
X
O
11 year off therapy CT or MRI, only re-image sites that were positive at diagnosis.
2 PET scan only necessary if CT or MRI shows suspicious lesions requiring further 
characterization.
X = Required study evaluations     O = Evaluations recommended for good patient care or as 
clinically indicated.
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6.5
Recommended Late Effects Evaluations
See Table 7 below.  Participants will be followed for at least 10 years after completion of 
therapy and follow up captured at least yearly.  Specific late effects’ testing should follow 
the Children’s Oncology Group Long-Term Follow-up Guidelines for Survivors of 
Childhood, Adolescent, and Young Adult Cancers http://www.survivorshipguidelines.org 
or institutional guidelines.
Table 7: Recommended Late Effects Evaluations
Off therapy follow-up for 
late organ toxicity
Physical exam
(includes growth and 
fertility information)
ECHO/
EKG
T4/TSH
PFT
Annually
O
O
1-year evaluation
O
O
2-year evaluation
O
O
5-year evaluation
O
O
10 -year evaluation
O
O
O = Evaluations recommended for good patient care or as clinically indicated

Heart:  echocardiogram, electrocardiogram at 1, 2, 5 and 10 years.

Lung: pulmonary function studies at 1, 2, 5 and 10 years for patients with 
respiratory symptoms or that have received significant pulmonary radiation

Growth:  physical examination with attention to growth abnormalities 
of soft tissues and bones with every physical exam.

Thyroid: Free T4 and TSH yearly if patient received radiation possibly 
encompassing the thyroid, but should be captured only at 1, 2, 5, and 10 years 
when available.

Document initiation date for thyroid hormone replacement therapy, if 
applicable.

Fertility:  Record menstrual cycle and pregnancy information.  Referral of 
men for semen analysis or measurement of testosterone levels is optional and 
should be performed when appropriate.

Obtain pathology of second tumors for histological review.
Late effects follow-up evaluations for patients in first remission should be captured at 
years 1, 2, 5 and 10.
Evaluations at 1, 2, 5, and 10 years should be performed within 6 months of the Off-
Therapy anniversary date. We recognize, however, that patients may be monitored more 
frequently and that off therapy evaluations and diagnosis of treatment-related toxicity 
may not adhere exactly to 1, 2, 5, or 10 years after completion of therapy. For patients in 
first remission, whose off therapy evaluations are performed beyond the 6 month 
anniversary date, a HLHR13 Late Organ Function Screening Form for Patients in First 
Remission and a HLHR13 Late Effects Follow-Up Form can be submitted as part of good 
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clinical practice.  Follow-up after relapse or progressive disease should be captured on an 
annual basis for as long as the study is open for follow-up.
6.6
Patient-Reported Symptoms and Health-Related Quality of Life 
The described instruments will be administered in conjunction with the scheduled clinic 
visit (± 7 days) (Table 8), then at 4-6 weeks after the completion of chemotherapy for 
those that had CR after 8 weeks of therapy and 4-6 weeks after completion of radiation 
for those that did not have a CR after 8 weeks of chemotherapy, 1 year, 2 years and 5 
years scheduled off therapy visit (Table 9). It should take no more than 15-20 minutes to 
complete all instruments. Participation in the Quality of Life part of the trial is voluntary 
for participating institutions and voluntary by patient.  
6.6.1
The Symptom Distress Scale (SDS)
The SDS is a 10-item, self-report, Likert type scale developed to measure the patient’s 
degree of discomfort from specific treatment-related symptoms i.e., nausea, sleep 
disturbances, appetite, etc. In our previous work using the SDS with adolescents 
receiving treatment for cancer, the scale achieved coefficient alphas of 0.81 to 0.82. The 
SDS also was noted to have construct validity, as hypotheses predicting negative 
relationships with measures of hopefulness, self-esteem, and self-efficacy were all 
supported. The SDS may be completed in 3 to 5 minutes.16
6.6.2
The Peds QL Multidimensional Fatigue Scale (MFS)
The Peds QL MFS is an 18-item Likert type scale with three subscales which include 
general fatigue, sleep/rest fatigue and cognitive fatigue. The patient and parent proxy 
forms are for three different age groups (5- to 7-year-olds, 8- to 12-year-olds, and 13- to 
21- year- olds). There is a parent form only for age group 2-4 year olds. Internal 
consistency and reliability have been reported (α = 0.89 child, α = 0.92 parent) and 
validity demonstrated using the known groups method.42
6.6.3
Peds QL V4.0 Module 
The Peds QL v4.0 Module is a 23-item Likert scale with four subscales measuring 
physical, emotional, social and school function. . The patient and parent proxy forms are 
for three different age groups (5- to 7-year-olds, 8- to 12-year-olds, and 13- to 21- year- 
olds). There is a parent form only for age group 2-4 year olds. Both patient and parent 
forms have been found to be internally consistent with α = 0.91 to 0.92, respectively.42
6.6.4
Peds QL Cancer Module
The Peds QL Cancer Module is a 27-item Likert scale with eight subscales which include 
pain and hurt, nausea, procedural anxiety treatment anxiety, worry, cognitive problems, 
physical appearance, and communication. The patient forms are for three different age 
groups (5- to 7-year-olds, 8- to 12-year-olds, and 13- to 21- year- olds). There is a parent 
form only for age group 2-4 year olds.42
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6.6.5
The Short-Form 36 (SF-36)
The Short Form 36 health survey questionnaire (SF-36) is a generic measurement of 
QOL and is a 36-item Likert-type scale measuring physical functioning, role physical 
function, bodily pain, general health perception, mental health, role emotional function, 
energy, and social functioning. The SF-36 will be administered to adolescents ages 13-21 
and is reported to have high validity and internal consistency.21 
6.6.6
Pain Quality Assessment Scale (PQAS©) 
The PQAS© is a 20-item scale for assessment of neuropathic pain with additional pain 
assessment qualities associated with non-neuropathic pain. This scale was developed 
from modification of the Neuropathy Pain Scale, with additional pain descriptors to 
ascertain non-neuropathic pain. This assessment scale will help in better describing the 
pain that patients at risk for neuropathy might experience.22
Table 8: Schedule for Symptom and Quality of Life Measurements during Therapy
Symptom/QoL
Entry
Course 1 
Day 8
Course 1 
Day 15
Course 2 
Day 1
Course 2 
Day 15
Course 3 
Day 1
Course 3 
Day 8
Course 6 
Day 1
Course 6 
Day 8
PedsQL 4.0 
Generic Patient 
(5-21) 
Parent (2-21)
X
X
X
X
Cancer QL 
Generic                  
Patient (5-21)        
Parent (2-21)
X
X
X
X
Multidimensional 
Fatigue Acute
Patient (5-21)        
Parent (2-21)
X
X
X
X
X
X
X
X
X
Pain Quality 
Assessment
Scale ≥ 8 years
X
X
X
X
X
X
X
X
X
Symptom 
Distress Scale 
Patient only ≥ 8 
years 
X
X
X
X
X
X
X
X
X
SF-36 
≥ 13 years
X
X
X
X
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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Table 9: Schedule for Symptom and Quality of Life measurements off Therapy
6.7
Expression of CD30 in Tumor Tissue (CD30 density)
Archival formalin-fixed, paraffin embedded tumor sections will be assessed by 
immunohistochemistry for CD30 expression in Reed Sternberg cells.  
Immunohistochemistry will be performed on formalin-fixed, paraffin embedded tissue 
specimens using commercially available antibodies to CD30, evaluated and graded semi-
quantitatively for the percentage of RS cells stained and the intensity (0, +, ++, +++) of 
staining.  The density of CD30 expression in RS cells and potential correlation with PR 
or CR will be explored via descriptive methods.  See Appendix III for details on 
collection, processing and shipment of samples.
6.8
Soluble CD30 Assessments
Table 10: Soluble CD30 (all sites) Sampling Time points
Cycle
Day
Time 
Relative Time
sCD30
C1
1
Pre-dose
Prior to Adcetris
X
C3
1
Pre-dose
Prior to Adcetris
X
EOTb
X
bEOT, End of Therapy – at off therapy evaluation 
Symptom/QoL
Evaluation 4-6 
weeks after 
chemotherapy
(participants who do 
not receive radiation)
Evaluation 4-6 
weeks after
radiation
1 year
2 year
5 year
PedsQL 4.0 
Generic Patient (5-21) 
Parent (2-21)
X
X
X
X
X
Cancer QL Generic
Patient (5-21)
Parent (2-21)
X
X
Multidimensional 
Fatigue Generic
 Patient (5-21)
 Parent (2-21)
X
X
X
X
X
Pain Quality Assessment
Scale ≥ 8 years
X
X
X
X
X
Symptom Distress Scale 
Patient only ≥ 8 years 
X
X
X
X
X
SF-36
 ≥ 13 years
X
X
X
X
X
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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6.9
Pharmacogenetics
All research participants at St. Jude Children’s Research Hospital will be asked to enroll 
on the institutional protocol PGEN5, while patients from external sites will be consented 
for pharmacogenetics research as part of this therapeutic protocol. Participation on this 
part of the protocol is voluntary.
7.0
EVALUATION CRITERIA
7.1
Early Response Criteria
Early response at the end of 2 cycles of AEPA will be determined for each individual 
nodal group. The response evaluation will be based on the multidisciplinary (oncologist, 
radiotherapist, and radiologist) interpretation of physical examination, laboratory and 
diagnostic imaging as described below (see Appendix II for response evaluation for the 
secondary objective 1.2.1). 
7.1.1
Complete Response (CR):
Disappearance of all measurable or evaluable disease, signs, symptoms and biochemical 
changes related to the tumor.  Biopsy confirmation is not mandatory.  Residual PET-
negative CT scan abnormalities representing > 75% reduction (as measured by the 
product of 2 perpendicular diameters of lesions by CT or MR imaging) in the original 
tumor volume will be considered scar tissue without active tumor.
7.1.2
Complete Response Unconfirmed (CRu):
Persistent radiographic abnormalities (PET negative) at a site of previous disease not 
thought to represent active disease as long as residual abnormalities are stable or 
improved when compared to previous evaluations.  Biopsy is not required to confirm a 
complete remission status.
7.1.3
Partial Response (PR):
Reduction of 50% to 75% in the original tumor volume of any measurable lesion by CT 
scan regardless of PET avidity. Persistence of PET avidity in residual nodal masses that 
shrunk ≥ 75% (as measured by the product of 2 perpendicular diameters of lesions by CT 
or MR imaging) from original tumor volume.
7.1.4
Stable Disease (SD):
Neither sufficient shrinkage (<50%) to qualify for partial response, nor sufficient increase 
(<25%) or appearance of new lesions to qualify for progressive disease. 
7.1.5
Progressive Disease (PD):
An increase in the product of two perpendicular diameters of any measured lesion by 
>25% over the size present at entry on study or the appearance of new areas of biopsy 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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proven disease. Recurrence within 3 months from the end of therapy is also considered 
progressive disease.
7.2
Remission Evaluation after Completion of Therapy
All patients will undergo a complete disease evaluation 4 to 6 weeks after completing all 
prescribed therapy. For patients that achieved a complete response after 2 cycles of 
AEPA and will not undergo radiotherapy, this will be performed 4 to 6 weeks after 
finishing the 4th cycle of CAPDac, while for patients that did not achieve a complete 
response after 2 cycles of AEPA and went on to receive radiotherapy, this will be done 4 
to 6 weeks after completing all prescribed radiotherapy. 
7.2.1
Complete Remission:
Patients will be designated to be in complete remission after the completion of all of the 
protocol-prescribed chemotherapy and radiotherapy as long as off therapy evaluations do 
not reveal new abnormalities suggestive of disease progression. This definition allows for 
persistent radiographic abnormalities (PET negative) at a site of previous disease not 
thought to represent active disease as long as residual abnormalities are stable or 
improved when compared to previous evaluations.  Biopsy is not required to confirm a 
complete remission status.
7.3
Evaluation of Progressive Disease or Relapse
Biopsy is required for confirmation of progression during planned therapy, or for relapse 
following completion of therapy.
Participants with progressive disease on therapy will be taken off treatment, but will 
remain on study and followed for survival. Participants who relapse off therapy will 
continue on study and followed for survival. Participants will receive salvage therapy 
according to investigator preference. When progression or relapse occurs, a protocol 
outcomes event form and off-treatment date will be entered into CRIS. 
7.4
Response Criteria for Secondary Objective
See Appendix II for detailed response definition according to Euro-Net C1. This objective 
will not be evaluated in real time, but will be centrally reviewed retrospectively.
7.5
Toxicity Evaluation Criteria
Common Terminology Criteria for Adverse Events v4.0 (CTCAE): This study will utilize 
the CTCAE of the National Cancer Institute (NCI) for toxicity and performance 
reporting. A copy of the current version of the CTCAE can be downloaded from the 
Cancer Therapy Evaluation Program (CTEP) home page (http://ctep.info.nih.gov). 
Additionally, toxicities are to be reported on the appropriate data collection screens.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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7.6
Acceptable Percentage of Missed Doses for Study Drugs
It is understood that deviations from the protocol should be avoided, except when 
necessary to eliminate an immediate hazard to a research participant. In such case, the 
deviation must be reported to the IRB. However, it is expected that participants will 
occasionally miss some doses or receive the wrong dose of oral chemotherapy. 
Compliance with oral medication will be captured in the CRIS database and appropriately 
documented in the participants’ medical records. Appropriately documented doses of 
missed or wrong doses of chemotherapy will not constitute a deviation unless the amount 
in question is over 10% of the expected total dose due in the respective protocol cycles 
(these are specified in the CRIS HLHR13 database). Missed doses do not include doses 
held or reduced for medical reasons (toxicity, illness) and will not be considered protocol 
deviations or violations.
8.0
OFF THERAPY AND OFF-STUDY CRITERIA
8.1
Off-Study Criteria

Death

Withdrawal of consent

Found to be ineligible (e.g., incorrect diagnosis)

Completion of protocol-required interventions and follow-up period (10 years)

Lost to follow-up
8.2
Off-Therapy Criteria

Progressive disease or relapse 

Second malignancy

Completion of all protocol prescribed treatment

Development of unacceptable toxicity during treatment (with concurrence of 
the PI)

Participant/family decision to withdraw from protocol treatment at any time 
for any reason

Discretion of the study PI or co-PI, such as the following:
o
The researcher decides that continuing in the study would be harmful
o
A treatment is needed that is not allowed on this study
o
The participant misses so many appointments that the data cannot be 
used in the study – Lost to follow up
o
The participant’s condition gets worse
o
New information is learned that a better treatment is available, or that 
the study is not in the participant’s best interest
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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9.0
SAFETY AND ADVERSE EVENT REPORTING REQUIREMENTS
9.1
Reporting Adverse Experiences (AEs) and Deaths to St. Jude IRB
Only “unanticipated problems involving risks to participants or others” referred to 
hereafter as “unanticipated problems” are required to be reported to the St. Jude 
IRB promptly, but in no event later than 10 working days after the investigator 
first learns of the unanticipated problem. Regardless of whether the event is 
internal or external (for example, an IND safety report by the sponsor pursuant to 
21 CFR 312.32), only adverse events that constitute unanticipated problems are 
reportable to the St. Jude IRB.  As further described in the definition of 
unanticipated problem, this includes any event that in the PI’s opinion was:

Unexpected (in terms of nature, severity, or frequency) given (1) the 
research procedures that are described in the protocol-related documents, 
such as the IRB-approved research protocol and informed consent 
document, as well as other relevant information available about the 
research; (2) the observed rate of occurrence (compared to a credible 
baseline for comparison); and (3) the characteristics of the subject 
population being studied; and

Related or possibly related to participation in the research; and

Serious; or if not serious suggests that the research places subjects or 
others at a greater risk of harm (including physical, psychological, 
economic, or social harm) than was previously known or recognized. 
Unrelated, expected deaths do not require reporting to the IRB.  Though death is 
“serious”, the event must meet the other two requirements of “related or possibly 
related” and “unexpected/unanticipated” to be considered reportable.
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of 
the death. 
The following definitions apply with respect to reporting adverse experiences: 
Serious Adverse Event: Any adverse event temporally associated with the 
subject’s participation in research that meets any of the following criteria:

results in death;

is life-threatening (places the subject at immediate risk of death from the 
event as it occurred);

requires inpatient hospitalization or prolongation of existing 
hospitalization;

results in a persistent or significant disability/incapacity;

results in a congenital anomaly/birth defect; or

any other adverse event that, based upon appropriate medical judgment, 
may jeopardize the subject’s health and may require medical or surgical 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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intervention to prevent one of the other outcomes listed in this definition 
(examples of such events include:  any substantial disruption of the ability 
to conduct normal life functions, allergic bronchospasm requiring 
intensive treatment in the 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), a congenital 
anomaly/birth defect, secondary or concurrent cancer, medication 
overdose, or is any medical event which requires treatment to prevent any 
of the medical outcomes previously listed.  
Unexpected Adverse Event: 
Any adverse event for which the specificity or severity is not consistent 
with the protocol-related documents, including the applicable investigator 
brochure, IRB approved consent form, Investigational New Drug (IND) or 
Investigational Device Exemption (IDE) application, or other relevant 
sources of information, such as product labeling and package inserts; or if it 
does appear in such documents, an event in which the specificity, severity 
or duration is not consistent with the risk information included therein; or 
The observed rate of occurrence is a clinically significant increase in the 
expected rate (based on a credible baseline rate for comparison); or 
The occurrence is not consistent with the expected natural progression of 
any underlying disease, disorder, or condition of the subject(s) 
experiencing the adverse event and the subject’s predisposing risk factor 
profile for the adverse event. 
Internal Events: Events experienced by a research participant enrolled at a site 
under the jurisdiction of St. Jude IRB for either multicenter or single-center 
research projects.
External Events: Events experienced by participants enrolled at a site external to 
the jurisdiction of the St. Jude Institutional Review Board (IRB) or in a study for 
which St. Jude is not the coordinating center or the IRB of record.
Unanticipated Problem Involving Risks to Subjects or Others: An 
unanticipated problem involving risks to subjects or others is an event which was 
not expected to occur and which increases the degree of risk posed to research 
participants.  Such events, in general, meet all of the following criteria: 

unexpected; 

related or possibly related to participation in the research; and 

suggests that the research places subjects or others at a greater risk of 
harm (including physical, psychological, economic, or social harm) than 
was previously known or recognized.  An unanticipated problem involving 
risk to subjects or others may exist even when actual harm does not occur 
to any participant. 
Consistent with FDA and OHRP guidance on reporting unanticipated problems 
and adverse events to IRBs, the St. Jude IRB does not require the submission of 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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external events, for example IND safety reports, nor is a summary of such 
events/reports required; however, if an event giving rise to an IND safety or other 
external event report constitutes an “unanticipated problem involving risks to 
subjects or others” it must be reported in accordance with this policy.  In general, 
to be reportable external events need to have implications for the conduct of the 
study (for example, requiring a significant and usually safety-related change in the 
protocol and/or informed consent form).
Although some adverse events will qualify as unanticipated problems involving 
risks to subjects or others, some will not; and there may be other unanticipated 
problems that go beyond the definitions of serious and/or unexpected adverse 
events.  Examples of unanticipated problems involving risks to subjects or others 
include:

Improperly staging a participant’s tumor resulting in the participant being 
assigned to an incorrect arm of the research study;

The theft of a research computer containing confidential subject 
information (breach of confidentiality); and 

The contamination of a study drug.  Unanticipated problems generally will 
warrant consideration of substantive changes in the research protocol or 
informed consent process/document or other corrective actions in order to 
protect the safety, welfare, or rights of subjects or others. 
9.2
Reporting Requirements to the FDA
Any unexpected fatal or unexpected life-threatening event (e.g. progressive multifocal 
leukoencephalopathy or pulmonary toxicity as described on page 47) judged by the PI to 
possibly be due to the investigational agent, will be reported to the FDA by telephone or 
fax as soon as possible but no later than seven calendar days after notification of the 
event and followed by a written safety report as complete as possible within eight 
additional calendar days (i.e. full report 15 calendar days total after notification of event).
Unexpected, non-fatal and non-life-threatening SAEs, which occur in on-study 
participants during the time periods specified in Section 9.1 that are considered due to or 
possibly due to the investigational agent, will be reported to the FDA by written safety 
report as soon as possible but no later than 15 calendar days of the notification of the 
occurrence of the event. Expected SAEs, even unexpected fatal SAEs, considered by the 
PI to be not related to the study, will be reported to the FDA in the Annual Review 
Report along with non-serious AEs.  All FDA correspondence and reporting will be 
conducted through the St. Jude Office of Regulatory Affairs.
9.3
Reporting to St. Jude Regulatory Affairs Office (RAO)
Copies of all correspondence to the St. Jude IRB, including SAE reports, are provided to 
the St. Jude Regulatory Affairs office by the St. Jude study team.  FDA-related 
correspondence and reporting will be conducted through the Regulatory Affairs office.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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9.4
Reporting to Seattle Genetics by St. Jude
Safety Reporting Requirements:
Reporting Timeframe:  The Principal Investigator will report all Serious Adverse Event 
(SAE)s that occur in a study subject within the following timeframe:
Individual expedited SAE reports 
required by competent health authority 
(i.e. FDA, Health Canada)
At time of submission to competent 
authority:
Seattle Genetics Drug Safety by: 
Facsimile 
 (USA only toll free)
Email: 
Aggregate listing of all SAEs 
Monthly:
or portal
Reporting Forms for individual expedited submissions: The Principal Investigator 
will report such SAEs on the approved local regulatory form (i.e. FDA MedWatch form 
or CIOMS) to include an assessment of causality to the Product. 
Reporting format for monthly SAEs:  St. Jude will provide a study-specific cumulative 
SAE line listing of all SAEs including an assessment of causality to the Product.
Reporting Period: The reportable events that are subject to this provision are those that 
occur from the start of administration of the first dose of the Product through thirty (30) 
days after discontinuation of the Product.  SAEs occurring more than thirty (30) days 
after discontinuation of the Product that are assessed by the Investigator as related to the 
Product should also be reported.
Follow-up Information: The IST Sponsor-Investigator will assist Seattle Genetics in 
investigating any SAE and will provide any follow-up information reasonably requested 
by Seattle Genetics.
Regulatory Reporting: Reporting an SAE to Seattle Genetics does not relieve the IST 
Sponsor-Investigator conducting the study of the responsibility for reporting it to the 
FDA, local regulatory authority, or IRB/IEC as required.
St. Jude Investigator Responsibilities
The Sponsor-Investigator of the study, and/or Institution must ensure that the study is 
conducted in accordance with the provisions of the ICH GCP Guidelines and all 
applicable local and regulatory requirements.  The Sponsor-Investigator must assume all 
regulatory responsibilities including, but not limited to, IRB/IEC approvals, regulatory 
approvals, monitoring responsibilities and any and all reporting obligations to local 
Regulatory Authorities.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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Seattle Genetics Requirements for IST Collaboration
Study initiation
The Sponsor-Investigator and/or Institution must provide the following to Seattle Genetics 
prior to initiation of Seattle Genetics support (provision of Product and/or  funding):

Final study protocolFully executed IST Agreement

Regulatory Response Documentation (IND or CTA documentation if applicable)

IRB/IEC approval
Study maintenance
Throughout the study, Seattle Genetics requires the following:

For studies administering study drug:  At least one safety study status update per 
year, to include information on enrollment and study completion dates.  

Notification of any amendment to the original protocol after the research has 
begun; and immediate notification of any amendments made due to safety 
reasons. 
Study closure
Any Sponsor-Investigator and/or Institution conducting an IST is contractually required 
to provide Seattle Genetics a copy of the IND Annual Report (or equivalent in rest of 
world regions).  Upon study closure, the Sponsor-Investigator and/or Institution will be 
required to certify that all safety reporting obligations were met.
9.5
Reporting AEs to and from Collaborating Sites to St. Jude
Adverse events from collaborating sites will also be reviewed by the PI and discussed in 
study team meetings as described above.  SAE report from collaborating sites for AEs that 
are serious, unexpected, and at least possibly related to protocol treatment or interventions 
will be reported to site IRB and the St. Jude IRB within the reporting requirements 
described above.  The PI will determine if this is an event that will need to be reported 
expeditiously to all participating sites, considering the following criteria:

Is the AE serious, unexpected, and related or possibly related to participation 
in the research?

Is the AE expected, but occurring at a significantly higher frequency or 
severity than expected?

Is this an AE that is unexpected (regardless of severity that may alter the 
IRB’s analysis of the risk versus potential benefit of the research and, as a 
result, warrant consideration of substantive changes in the research protocol or 
informed consent process/document?
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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With the submission of the “Reportable Event” in St. Jude TRACKS application, the PI 
will indicate if all sites should be notified to report to their IRBs, and if the protocol 
and/or consent should be amended (consent will be amended if event is information that 
should be communicated to currently enrolled subjects).  Generally, only events that 
warrant an amendment to the protocol and/or consent will be reported expeditiously to all 
sites.  However, any event may be reported expeditiously to all sites at the discretion of 
the PI. 
A cumulative summary of Grade 1-5 AEs and expected/unrelated deaths that occur more 
than 30 days off last protocol treatment will be reported to all sites with study progress 
report at the time of continuing review.
Contact information for SAEs meeting reporting requirements:
Collaborating sites should send SAE reports to St. Jude IRB promptly, but in no event 
later than 10 working days after the investigator first learns of the unanticipated 
problem.  
Deaths meeting reporting requirements are to be reported immediately to the St. 
Jude IRB, but in no event later than 48 hours after the investigator first learns of 
the death. 
E-mail reports to the HLHR13 study team:
9.6
Recording AEs and SAEs
Adverse events (AEs) will be evaluated and documented by the clinical staff and 
investigators throughout inpatient hospitalizations and each outpatient visit.  CRAs are 
responsible for reviewing documentation related to AEs and entering directly into CRIS 
protocol-specific database.  The data to be recorded are:

The event description

The NCI CTCAE v4.0 code and grade

The onset date, 4) the resolution date (or ongoing)

Action taken for event

Participant outcome

Relationship of AE to protocol treatment/interventions

If AE was expected or unexpected (see investigator’s brochure, package 
inserts, informed consent document)

Comments, if applicable.  
AEs that are classified as serious, unexpected, and at least possibly related will be 
notated as such in the database as “SAEs”.  These events will be reported expeditiously to 
the St. Jude IRB within the timeframes as described above.  
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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Cumulative summary of all adverse events (Grades 1-5) during treatment and for 30 days 
after the last therapeutic intervention will be recorded and reported as part of the progress 
reports to IRB at the time of continuing review.  Specific data entry instructions for AEs 
and other protocol-related data will be documented in protocol-specific data entry 
guidelines, which will be developed and maintained by study team and clinical research 
informatics.
The study team will meet regularly to discuss AEs (and other study progress as required 
by institutional DSMP).  The PI will review Adverse Event reports generated from the 
research database, and corrections will be made if applicable. Once the information is 
final the PI will sign and date reports, to acknowledge his/her review and approval of the 
AE as entered in the research database.
Any unexpected fatal or unexpected life-threatening event judged by the PI to possibly be 
due to the investigational agent, will be reported to the FDA by telephone or fax as soon 
as possible but no later than seven calendar days after notification of the event and 
followed by a written safety report as complete as possible within eight additional 
calendar days (i.e. full report 15 calendar days total after notification of event).
Unexpected, non-fatal and non-life-threatening SAEs, which occur in on-study 
participants during the time periods specified in Section 9.1 that are considered due to or 
possibly due to the investigational agent, will be reported to the FDA by written safety 
report as soon as possible but no later than 15 calendar days of the notification of the 
occurrence of the event. Expected SAEs, even unexpected fatal SAEs, considered by the 
PI to be not related to the study, will be reported to the FDA in the Annual Review 
Report along with non-serious AEs. All FDA correspondence and reporting will be 
conducted through the St. Jude Office of Regulatory Affairs.
10.0
DATA COLLECTION, STUDY MONITORING & CONFIDENTIALITY
10.1
Data Collection
Electronic case report forms (e-CRFs) will be completed by the SJCRH 
Leukemia/Lymphoma CRAs. Data will be entered from record directly into a secure 
CRIS database, developed and maintained by St. Jude Clinical Research Informatics. 
Data management will be supervised by the Director of Clinical Trials Management, and 
Manager of Clinical Research Operations for the Leukemia/ Lymphoma Division, 
working with Dr. Ehrhardt or his designee. All protocol-specific data and all grade 1-5 
adverse events will be recorded by the clinical research associates into the CRIS 
database, ideally within 2-4 weeks of completion of study phase. All questions will be 
directed to the attending physician and/or PI and reviewed at regularly-scheduled 
working meetings. The attending physicians (or their designees) are responsible for 
keeping up-to-date roadmaps in the patient’s primary SJCRH medical chart.
Regular (at least monthly) summaries of toxicity and protocol events will be generated 
for the PI and the department of Biostatistics to review.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
IRB APPROVAL DATE: 09/18/2023

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10.2
Data Collection Instructions for Collaborating Sites
Collaborating sites will collect data by using e-CRFs via remote electronic data entry.  
All protocol-specific data and all grade 1-5 adverse events during treatment and for 30 
days post last dose of protocol therapy will be recorded by the clinical research associates 
into the CRIS database, ideally within 2-4 weeks of completion of study phase.
10.3
Study Monitoring
This study is considered high risk (HR-3) for monitoring purposes. Protocol and 
regulatory compliance, including essential regulatory documentation, will be assessed as 
well as the accuracy and completeness of all data points relating to the primary and 
secondary objectives semi-annually. If the study design has strata, accrual will be tracked 
continuously. The first two enrollees will be monitored and 15 % of the study enrollees 
thereafter, semi-annually. 
The PI and study team are responsible for protocol and regulatory compliance, and for data 
accuracy and completeness.  The study team will meet at appropriate intervals to review 
case histories or quality summaries on participants and retain copies of the minutes which 
are signed by the PI.
The Eligibility Coordinators in the Central Protocol and Data Monitoring Office 
(CPDMO) will verify informed consent documentation and eligibility status on 100% of 
St. Jude participants within 5 working days of enrollment completion.
The Clinical Research Monitor (CRM) will verify informed consent documentation and 
eligibility status of all non-St. Jude participants and perform a quality verification of 
select St. Jude participants during routine monitoring intervals (every 6 months). 
Overall study conduct, compliance with primary and secondary objectives, age of majority 
consenting, safety assessments and reporting, and the timeliness and accuracy of database 
entries are monitored routinely.  
Study documents routinely monitored on selected participants include medical records, 
database entries, study worksheets, and case report forms.  Study documents are 
monitored for participant status, demographics, staging, subgroup assignment, treatments, 
investigational drug accountability, evaluations, responses, participant protocol status, 
off-study and off-therapy criteria, and for all other specifics as detailed in a separate 
study-specific monitoring plan. The study-specific monitoring plan may be revised over 
time, to adapt monitoring frequency and/ or intensity to a changing environment when 
appropriate (for example:  new safety signals; positive history of compliance; all 
participants are in long term follow-up; or the enrollment period has ended).
The recording and reporting of Adverse Events, Serious Adverse Events (SAEs), and 
Unanticipated Problems (UPs) to include type, grade, attribution, duration, timeliness and 
appropriateness will be reviewed by the Monitor/ CRM. The CRM will generate a formal 
report which is shared with the Principal Investigator (PI), study team and the Internal 
Monitoring Committee (IMC).
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Continuing reviews by the Internal Review Board (IRB) and Clinical Trials- Scientific 
Review Committee (CT-SRC) will occur at least annually.  In addition, unanticipated 
problems are reviewed in a timely manner by the IRB.
St. Jude affiliates and domestic collaborating study sites will be monitored on-site by a 
representative of St. Jude as needed.  International collaborators will be monitored by a 
Contract Research Organization (CRO), or other mechanism according to the study 
specific monitoring plan.
10.4
Confidentiality
Study numbers will be used in place of an identifier such as a medical record number. No 
research participant names will be recorded on the data collection forms. The list 
containing the study number and the medical record number will be maintained in a 
locked file and will be destroyed after all data have been analyzed. 
The medical records of study participants may be reviewed by the St. Jude IRB, FDA, 
and St. Jude clinical research monitors.
11.0
STATISTICAL CONSIDERATIONS
The objective of this pilot phase II study is to study the safety and efficacy of the 
incorporation of Adcetris® into frontline therapy as AEPA/CAPDac in pediatric patients 
with high risk HL. The first 32 patients will be used to answer the first primary objective 
as described below; the total of 77 patients will contribute to answer the second primary 
objective relating to EFS. The trial is written to allow publication of the first primary 
objective as soon as the results are available.
It is foreseeable to have a successful primary objective of increasing the proportion of 
patients that achieve a complete response to 8 weeks of chemotherapy that will not 
translate into increased EFS if omission of radiotherapy proves to be unsafe in this patient 
population under these given circumstances.
On the other hand if the first primary objective is not successful, then the second primary 
objective no longer is of interest, as the paradigm in pediatric HL, to improve survival 
without radiation therapy, could not be achieved.
11.1
Safety Monitoring
The thresholds for safety monitoring were chosen after careful consideration of the 
potential risk/benefit ratio for the trial. All eligible patients who receive any 
AEPA/CAPDAC therapy will be included in safety monitoring described below from the 
initiation to the end of all chemotherapy. 
Critical for the timely safety monitoring described in this section is up-to-date and 
accurate data for analysis. Each of the monitoring analyses will be conducted as follows: 
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
The triggering event will be confirmed by the attending physician and the protocol PI. 
Upon confirmation, all associated information for the event (dates, grade, etc.) will be 
locked (frozen) in the HLHR13 database. 
o
If the safety stopping threshold is not reached, the trial continues unabated and 
this will conclude the analysis for this event. 
o
If the safety stopping threshold is exceeded, the analysis is repeated by assuming 
that patients who do not have data in the HLHR13 database current to the date of 
the triggering event are “safe” on that date.

If the analysis of these data still exceeds the stopping threshold, then the 
appropriate action described below is executed. 

If the analysis of these data does not result in the stopping threshold being 
exceeded, then the relevant data in the HLHR13 database is immediately 
(within several days) updated and the analysis repeated. This will constitute 
the final analysis triggered by the event and appropriate action will be taken 
pending on whether the stopping threshold is or is not exceeded. 
o
Safety monitoring rules provide a statistical framework in which to consider 
whether observed toxicities are excessive. Upon completion of an interim 
analysis, the findings will be reported to the St. Jude DSMB that will make 
recommendations to the protocol PI and advise the St. Jude leadership on 
continuing, stopping or amending the trial. 

For monitoring purposes we will count the first episode of a monitored toxicity 
should the same toxicity occur multiple times on a single patient. The monitored 
toxicities will be pulmonary toxicity (see Section 4.3.2) and progressive multifocal 
leukoencephalopathy (see Section 4.3.4) as these are the only life threatening 
toxicities or toxicities possibly associated with long term morbidity. Both toxicities 
will be monitored independently.
o
Given the drug combinations, no pulmonary toxicity is expected; however in the 
rare event of having any grade ≥3 pulmonary toxicity, the trial shall be closed if 
this happens in 2 out of the first 32 patients, or is greater than 5% in subsequent 
cohort with additional 10 more cumulative patients than the previous cohort if the 
trial is extended to a cohort of 77 patients for the event-free survival evaluation.
o
Progressive multifocal leukoencephalopathy is a rare but serious adverse event. A 
single event could be tolerated and considered to have happened by chance alone; 
however, in the event of a second patient presenting with this toxicity, the 
stopping criteria will be reached.
11.2
Primary Objectives
11.2.1 To evaluate the safety of AEPA/CAPDac, as well as the efficacy (early complete 
response) after 2 cycles of AEPA chemotherapy in high-risk patients with HL.
Responsible investigator:  Matt Ehrhardt, M.D.
Responsible statistician:  Hui Zhang, Ph.D.
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Study design:  The proportion of historical control of HOD99 unfavorable risk patients 
had CR at week 8 of 17% (24/141).  The sample size for this primary objective is 
calculated based on a binomial distribution to test following hypothesis: H0: p=17% vs. 
Ha: p>17%, where p is the true CR rate of high risk patients treated on this protocol after 
2 cycles of AEPA chemotherapy. A total of 32 patients are needed to detect 20% increase 
CR rate with 80% power and 5% type I error. After 32 evaluable patients had CR 
assessment, the CR rate will be estimated and exact 90% and 95% confidence intervals of 
the CR rate will be provided. After the first 32 patients had response assessment, an 
analysis will be conducted to determine the efficacy of 2 cycles of AEPA chemotherapy. 
If it shows efficacy, the response results will be reported in a national/international 
meeting and the study will continue to enroll for a total of 77 patients (see primary 
objective 11.2.2) to assess response and event-free survival. If it shows futility, the study 
accrual will be closed and the study will be amended or closed. 
11.2.2 To compare the event-free survival in high-risk HL patients treated with 
AEPA/CAPDac to the historical control HOD99 unfavorable risk 2 arm (UR2).
Responsible investigator:  Matt Ehrhardt, M.D.
Responsible statistician: Hui Zhang, Ph.D.
Study design: In this protocol, an event is defined as a relapse, disease progression, 
second malignance (except basal cell carcinoma) or death. The EFS is defined as the time 
interval from on study to the first event or last follow-up if a patient without an event. 
Based on the current HOD99 follow-up data (cut-off date is 9/19/2011, data are frozen 
for future interim analysis and final analysis. The follow-up of the historical data will 
also be updated for the final analysis.), the 3–year EFS of historical control HOD99 
unfavorable risk 2 arm (UR2) patients is 79.4% (se=4%) with a total of 27 events among 
142 patients (see Table 11 and Figure 1). Sample size for this objective is then 
determined to detect 12% increase of 3-year EFS (from 79% to 91% of 3-year EFS or 
equivalently to detect a hazard ratio 0.4).  Under the proportional hazard model 
assumption, using a two-sample log-rank test comparing with historical control of 
HOD99 unfavorable risk 2 arm (UR2) patients, a total of 77 patients (or 7 events, 
relapse/progression or death) are needed to detect a 11% increasing 3-year EFS with 
study power of 80% and 10% type I error, assumed a 2-year follow-up period for current 
study45. 
Table 11: Event-free Survival of HOD99 UR2 Patients
Unfavorable risk 2 Arm
Years from Study 
Enrollment
Risk
Fail
Cens
Prob
SE
0 
142 
0 
0 
1.000
0.000
1 
142 
16 
13 
0.881
0.028
2 
113 
7 
15 
0.823
0.036
3 
91 
3 
13 
0.794
0.041
4 
75 
1 
9 
0.782
0.045
5 
65 
0 
14 
0.782
0.051
6 
51 
0 
19 
0.782
0.064
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Unfavorable risk 2 Arm
Years from Study 
Enrollment
Risk
Fail
Cens
Prob
SE
7 
32 
0 
13 
0.782
0.082
8 
19 
0 
11 
0.782
0.122
9 
8 
0 
8 
0.782
0.365
Figure 1: EFS of HOD99 UR2 patients
             
11.2.4  Accrual and study duration
Table 12 shows the observed annual accrual rate for unfavorable risk patients treated on 
HOD99 protocol. An average of 15-16 patients were enrolled annually, therefore the 
study will need approximate 2 years to accrual 32 patients for primary objective 1 and 
approximate 5-6 years to accrual 77 patients for primary objective 2. For the primary 
objective 2, the final analysis of EFS will be conducted after last evaluable patient 
enrolled on the study and followed 2 years.
Table 12: Yearly Accrual for HOD99 Unfavorable Risk 2 Arm
Year
# of Eligible Patients Enrolled
Year 1: 6/11/2002 – 6/10/2003
13
Year 2: 6/11/2003 – 6/10/2004
15
Year 3: 6/11/2004 – 6/10/2005
19
Year 4: 6/11/2005 – 6/10/2006
17
Year 5: 6/11/2006 – 6/10/2007
20
Year 6: 6/11/2007 – 6/10/2008
9
Year 7: 6/11/2008 – 6/10/2009
16
Year 8: 6/11/2009 – 6/10/2010
16
Year 9: 6/11/2010 – 6/10/2011
17
Total
142
Average yearly accrual: 15.78
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11.3
Secondary Objectives
11.3.1
To estimate the number of patients with adequate response according to the 
definitions in the Euro-Net C1. 
Responsible investigator: Matt Ehrhardt, M.D.
Responsible statistician: Hui Zhang, Ph.D.
The proportions of patients with adequate response according to the definitions in the 
Euro-Net C1 will be estimated together with a 95% confidence interval.
11.3.2
To evaluate the safety of Adcetris® in the AEPA/CAPDac regimen in children 
with unfavorable risk HL.
Responsible investigator: Matt Ehrhardt, MD
Responsible statistician: Hui Zhang, Ph.D.
To describe acute hematologic, neuropathic, and infectious toxicities as they relate to 
transfusion requirements, growth factor support, episodes of febrile neutropenia and 
hospitalizations, according to the NCI Common Terminology Criteria for Adverse Events 
(CTCAE), version 4.0.
Summary statistics will be provided for hematologic, neuropathic and infectious 
toxicities as they relate to transfusion requirements, growth factor support, episodes of 
febrile neutropenia and hospitalizations, according to the NCI Common Terminology 
Criteria for Adverse Events (CTCAE), version 4.0.
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11.3.3
To study the association between the incidence and patterns of local failure 
and original lymph node region and volume of radiation.
Responsible investigator:  Matt Ehrhardt, MD and Matthew Krasin, M.D. 
Responsible statistician: Hui Zhang, Ph.D.
Cumulative incidence model will be used to study the association between local failure 
and original lymph node region and volume of radiation.  Person Chi-square test will be 
used to study the association between patterns of local failure and original lymph node 
region and volume of radiation.
11.3.4
To assess the patient reported symptoms and health-related quality of life in 
children with high risk HL compared to those treated on the unfavorable HOD99 
treatment arm.
Responsible investigator: Belinda Mandrell, PhD 
Responsible statistician: Hui Zhang, Ph.D.
The patient reported symptoms distress scale (SDS) and responses to the items of the 
PedsQL physical functioning subscale will be summarized by descriptive statistics. 
Spearman correlation coefficients will be used to assess the correlation of the physical 
functioning subscale between time points. The mixed effects linear model for repeated 
measures will also be used to assess the change in QoL and symptom distress over time 
and to investigate the association between symptom distress and QoL. The results will be 
compared to that of those treated on the unfavorable arm 2 of HOD99.
11.4
Exploratory Objectives
11.4.1
To compare the ratings of neuropathic toxicity according to the NCI Common 
Terminology Criteria for Adverse Events, version 4.0 to the Pain Quality Assessment 
Scale (PQAS©). 
Responsible investigator:  Belinda Mandrell, PhD
Responsible statistician:  Hui Zhang, Ph.D.
Summary statistics will be provided to compare the ratings of neuropathic toxicity 
according to the NCI CTC v4.0 to the PQAS©.
11.4.2
To describe the pharmacokinetics of Adcetris® when used as part of 
AEPA/CAPDac for a pediatric HL population
Responsible investigator:  Matt Ehrhardt,MD
Responsible statistician:  Hui Zhang, Ph.D.
Summary statistics will be provided for PK data of Adcetris®.  This will be done 
according to previous protocols involving Adcetris®.
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11.4.3
To describe the immunogenicity of Adcetris® and the relationship between 
early response and presence of anti-chimeric anti-body.
Responsible investigator:  Matt Ehrhardt, MD
Responsible statistician:  Hui Zhang, Ph.D.
Summary statistics will be provided for this objective.
11.4.4
To explore the association between CD30 density in Reed Sternberg cells in 
paraffin embedded tumor tissue and early response and event-free survival.
Responsible investigator:   Matt Ehrhardt, MD
Responsible statistician:  Hui Zhang, Ph.D.
The association between CD30 density in Reed Sternberg cells within paraffin-embedded 
tumor tissue and early response/EFS will be explored by regression analysis.  We will 
request 10 unstained slides of 5-7 microns thick tissue sections for immunohistochemical 
analysis of CD30 expression.  These studies will be completed by the Molecular Clinical 
Trials Core at St. Jude Children’s Research Hospital under the direction of 
11.4.5
To explore the association between soluble CD30 and early response, event-
free survival and symptom/quality of life.
Responsible investigator:    Matt Ehrhardt, MD
Responsible statistician:  Hui Zhang, Ph.D.
The association between soluble CD30 and early response, EFS and symptom/quality of 
life will be explored by regression analysis.
11.4.6 To identify pharmacogenetic predictors for treatment-related outcomes in the 
context of AEPA/CAPDac.
Responsible investigator:   Matt Ehrhardt, MD
Responsible statistician:  Hui Zhang, Ph.D.
Regression model will be used to study the pharmacogenetic predictors for treatment-
related outcomes in the context of AEPA/CAPDac. 
Estimated completion of accrual date is May 2020 (7 years).  Estimated study completion 
date is May 2030.
11.4.7
Objective: Compare dosimetrically, the ability of PBRT to spare adjacent 
normal tissues compared to photon based radiation therapy
Responsible investigator: Matthew Krasin, M.D., Chia-ho Hua, Ph.D., and Jonathan 
Farr, Ph.D.
Responsible statistician: Hui Zhang, Ph.D.
The dosage derived to spare adjacent normal tissues using PBRT based radiation therapy 
will be compared to photon therapy. Summary statistics of dosage will be given and non-
parametric test will be to test the difference.
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12.0
OBTAINING INFORMED CONSENT
12.1
Consent/Assent at Enrollment
The process of informed consent for HLHR13 will follow institutional policy. The 
informed consent process is an ongoing one that begins at the time of diagnosis and ends 
after the completion of therapy. Informed consent should be obtained by the attending 
physician or his/her designee, in the presence of at least one non-physician witness. 
Initially, informed consent will be sought for the institutional banking protocol (research 
study), blood transfusion and other procedures as necessary. After the diagnosis of high 
risk HL is established, we will invite the patient to participate in the HLHR13 protocol.   
Throughout the entire treatment period, participants and their parents receive constant 
education from health professionals at SJCRH and collaborating sites, and are 
encouraged to ask questions regarding alternatives and therapy. All families have ready 
access to chaplains, psychologists, social workers, and the St. Jude ombudsperson for 
support, in addition to that provided by the primary physician and other clinicians 
involved in their care.
We will also obtain verbal assent from children 7 to 14 years old and written assent for 
all participants >14 years of age. Participants who reach the age of majority while on 
study will be re-consented for continued participation on HLHR13, according to Cancer 
Center and institutional policy.
12.2
Consent at Age of Majority
The age of majority in the state of Tennessee is 18 years old.  Research participants must 
be consented at the next clinic visit after their 18th birthday.  If an affiliate or 
collaborating site is located in a country or state where a different age of majority applies, 
that location must consent the participants according to their local laws.  
12.3
Consent When English is Not the Primary Language
When English is not the patient, parent, or legally authorized representative’s primary 
language, the Social Work department will determine the need for an interpreter.  This 
information documented in the participant’s medical record.  Either a certified interpreter 
or the telephone interpreter’s service will be used to translate the consent information.  
The process for obtaining an interpreter and for the appropriate use of an interpreter is 
outlined on the Interpreter Services, OHSP, and CPDMO websites.
Collaborating sites will follow institutional policy for consenting non-English speaking 
participants (and will provide institutional policy to St. Jude).
12.4
Collection of Collaborating Institutions’ Consent Forms
Signed collaborating institution’s consent forms will be faxed to the CPDMO Eligibility 
Office at 
. 
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13.0
REFERENCES
1.  Guidance for industry: patient-reported outcome measures: use in medical product 
development to support labeling claims: draft guidance. Health Qual Life Outcomes 
2006;479.
2. Ansell SM, Connors JM, Park SI, O'Meara MM, Younes A. Frontline Therapy with 
Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed 
Advanced Stage Hodgkin Lymphoma. ASH Annual Meeting Abstracts 
2012;120(21):798.
3. Brundage MD, Pater JL, Zee B. Assessing the reliability of two toxicity scales: 
implications for interpreting toxicity data. J Natl Cancer Inst 1993;85(14):1138-1148.
4. Bruner DW. Should patient-reported outcomes be mandatory for toxicity reporting in 
cancer clinical trials? J Clin Oncol 2007;25(34):5345-5347.
5. Cavaletti G, Frigeni B, Lanzani F, Piatti M, Rota S, Briani C et al. The Total Neuropathy 
Score as an assessment tool for grading the course of chemotherapy-induced peripheral 
neurotoxicity: comparison with the National Cancer Institute-Common Toxicity Scale. J 
Peripher Nerv Syst 2007;12(3):210-215.
6. Chen R, Gopal AK, Smith SE, Ansell SM, Rosenblatt JD, Klasa R. Results of a pivotal 
phase 2 study of brentuximab vedotin (SGN-35) in patients with relapsed or refractory 
Hodgkin lymphoma. American Society of Hematology Annual Meeting Abstract 283. 
2010. 
7. Clanton NR, Klosky JL, Li C, Jain N, Srivastava DK, Mulrooney D et al. Fatigue, 
vitality, sleep, and neurocognitive functioning in adult survivors of childhood Cancer: A 
report from the childhood cancer survivor study. Cancer 2011.
8. Cleeland CS, Sloan JA. Assessing the Symptoms of Cancer Using Patient-Reported 
Outcomes (ASCPRO): searching for standards. J Pain Symptom Manage 
2010;39(6):1077-1085.
9. Department of Health and Human Services, National Institutes of Health, National 
Cancer Institute OoA. Development of the Patient-Reported Outcomes version of the 
Common Terminology Criteria for Adverse Events (PRO-CTCAE). Solicitation Number: 
N02-PC-85002-29 editor.  9-30-2008. 
10. Donaldson SS, Link MP, Weinstein HJ, Rai SN, Brain S, Billett AL et al. Final results of 
a prospective clinical trial with VAMP and low-dose involved-field radiation for children 
with low-risk Hodgkin's disease. J Clin Oncol 2007;25(3):332-337.
11. Fanale M, Franklin A, Radhakrishnan R, Termuhlen A, Gopal AK, Shustov A et al. 
Complete Remissions Observed in a Subset of Paediatric Patients With CD30-expressing 
Malignant Lymphomas Treated in Clinical Studies of Brentuximab Vedotin (SGN-35). 
European Multidisciplinary Cancer Congress.Stockholm, Sweden . 2011. 
12. Fanale MA, Forero-Torres A, Rosenblatt JD, Advani RH, Franklin AR, Kennedy DA et 
al. A Phase I Weekly Dosing Study of Brentuximab Vedotin in Patients with 
Relapsed/Refractory CD30-Positive Hematologic Malignancies. Clin Cancer Res 
2012;18(1):248-255.
13. Friedman D, Wolden S, Constine L, Chen L, McCarten K, Fitzgerald TJ et al. 
AHOD0031: A Phase III Study of Dose-Intensive Therapy for Intermediate Risk 
Hodgkin Lymphoma: A Report From the Children's Oncology Group. Blood 116(21), 
766. 2011. 
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14. Friedmann AM, Hudson MM, Weinstein HJ, Donaldson SS, Kun L, Tarbell NJ et al. 
Treatment of unfavorable childhood Hodgkin's disease with VEPA and low-dose, 
involved-field radiation. J Clin Oncol 2002;20(14):3088-3094.
15. Fromme EK, Eilers KM, Mori M, Hsieh YC, Beer TM. How accurate is clinician 
reporting of chemotherapy adverse effects? A comparison with patient-reported 
symptoms from the Quality-of-Life Questionnaire C30. J Clin Oncol 2004;22(17):3485-
3490.
16. Hinds PS, Quargnenti AG, Wentz TJ. Measuring symptom distress in adolescents with 
cancer. J Pediatr Oncol Nurs 1992;9(2):84-86.
17. Hodgson DC, Hudson MM, Constine LS. Pediatric hodgkin lymphoma: maximizing 
efficacy and minimizing toxicity. Semin Radiat Oncol 2007;17(3):230-242.
18. Hua C, Hoth KA, Wu S, Kun LE, Metzger ML, Spunt SL et al. Incidence and correlates 
of radiation pneumonitis in pediatric patients with partial lung irradiation. Int J Radiat 
Oncol Biol Phys 2010;78(1):143-149.
19. Hudson MM, Krasin M, Link MP, Donaldson SS, Billups C, Merchant TE et al. Risk-
adapted, combined-modality therapy with VAMP/COP and response-based, involved-
field radiation for unfavorable pediatric Hodgkin's disease. J Clin Oncol 
2004;22(22):4541-4550.
20. 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.
21. Jenkinson C, Wright L, Coulter A. The SF 36 health survey questionnaire. ...if used 
within its limits. BMJ 1993;307(6901):449.
22. Jensen MP, Gammaitoni AR, Olaleye DO, Oleka N, Nalamachu SR, Galer BS. The pain 
quality assessment scale: assessment of pain quality in carpal tunnel syndrome. J Pain 
2006;7(11):823-832.
23. Kelly KM, Sposto R, Hutchinson R, Massey V, McCarten K, Perkins S et al. BEACOPP 
chemotherapy is a highly effective regimen in children and adolescents with high-risk 
Hodgkin lymphoma: a report from the Children's Oncology Group. Blood 
2011;117(9):2596-2603.
24. Krasin MJ, Rai SN, Kun LE, Merchant TE, Metzger ML, Kaste SC et al. Patterns of 
treatment failure in pediatric and young adult patients with Hodgkin's disease: local 
disease control with combined-modality therapy. J Clin Oncol 2005;23(33):8406-8413.
25. Lamba JK, Pounds S, Cao X, Downing JR, Campana D, Ribeiro RC et al. Coding 
polymorphisms in CD33 and response to gemtuzumab ozogamicin in pediatric patients 
with AML: a pilot study. Leukemia 2009;23(2):402-404.
26. LaMonte CS, Yeh SD, Straus DJ. Long-term follow-up of cardiac function in patients 
with Hodgkin's disease treated with mediastinal irradiation and combination 
chemotherapy including doxorubicin. Cancer Treat Rep 1986;70(4):439-44.
27. Longo DL, Young RC, Wesley M, Hubbard SM, Duffey PL, Jaffe ES et al. Twenty years 
of MOPP therapy for Hodgkin's disease. J Clin Oncol 1986;4(9):1295-306.
28. Mauz-Korholz C, Hasenclever D, Dorffel W, Ruschke K, Pelz T, Voigt A et al. 
Procarbazine-free OEPA-COPDAC chemotherapy in boys and standard OPPA-COPP in 
girls have comparable effectiveness in pediatric Hodgkin's lymphoma: the GPOH-HD-
2002 study. J Clin Oncol 2010;28(23):3680-3686.
29. Metzger ML, Billett A, Link MP. The impact of drug shortages on children with cancer--
the example of mechlorethamine. N Engl J Med 2012;367(26):2461-2463.
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30. Metzger ML, Weinstein HJ, Hudson MM, Billett AL, Larsen EC, Friedmann A et al. 
Association between radiotherapy vs no radiotherapy based on early response to VAMP 
chemotherapy and survival among children with favorable-risk Hodgkin lymphoma. 
JAMA 2012;307(24):2609-2616.
31. Mulrooney DA, Ness KK, Neglia JP, Whitton JA, Green DM, Zeltzer LK et al. Fatigue 
and sleep disturbance in adult survivors of childhood cancer: a report from the childhood 
cancer survivor study (CCSS). Sleep 2008;31(2):271-281.
32. Nachman JB, Sposto R, Herzog P, Gilchrist GS, Wolden SL, Thomson J et al. 
Randomized Comparison of Low-Dose Involved-Field Radiotherapy and No 
Radiotherapy for Children With Hodgkin's Disease Who Achieve a Complete Response 
to Chemotherapy. J Clin Oncol 2002;20(18):3765-3771.
33. Okeley NM, Miyamoto JB, Zhang X, Sanderson RJ, Benjamin DR, Sievers EL et al. 
Intracellular activation of SGN-35, a potent anti-CD30 antibody-drug conjugate. Clin 
Cancer Res 2010;16(3):888-897.
34. Relling MV, Gardner EE, Sandborn WJ, Schmiegelow K, Pui CH, Yee SW et al. Clinical 
Pharmacogenetics Implementation Consortium guidelines for thiopurine 
methyltransferase genotype and thiopurine dosing. Clin Pharmacol Ther 2011;89(3):387-
391.
35. Rock EP, Scott JA, Kennedy DL, Sridhara R, Pazdur R, Burke LB. Challenges to use of 
health-related quality of life for Food and Drug Administration approval of anticancer 
products. J Natl Cancer Inst Monogr 2007;(37):27-30.
36. Roper K, McDermott K, Cooley ME, Daley K, Fawcett J. Health-related quality of life in 
adults with Hodgkin's disease: the state of the science. Cancer Nurs 2009;32(6):E1-17.
37. Santoro A, Bonadonna G, Valagussa P, Zucali R, Viviani S, Villani F et al. Long-term 
results of combined chemotherapy-radiotherapy approach in Hodgkin's disease: 
superiority of ABVD plus radiotherapy versus MOPP plus radiotherapy. J Clin Oncol 
1987;5(1):27-37.
38. Schellong G. The balance between cure and late effects in childhood Hodgkin's 
lymphoma: the experience of the German-Austrian Study-Group since 1978. German-
Austrian Pediatric Hodgkin's Disease Study Group. Ann Oncol 1996;7 Suppl 467-72.
39. Schwartz CL, Constine LS, Villaluna D, London WB, Hutchison RE, Sposto R et al. A 
risk-adapted, response-based approach using ABVE-PC for children and adolescents with 
intermediate- and high-risk Hodgkin lymphoma: the results of P9425. Blood 
2009;114(10):2051-2059.
40. Shustov AR, Advani R, Brice P, Bartlett NL, Rosenblatt JD, Illidge T et al. Complete 
Remissions with Brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory 
Systemic Anaplastic Large Cell Lymphoma. Blood 116, 423-424. 2010. 
41. Trotti A, Colevas AD, Setser A, Basch E. Patient-reported outcomes and the evolution of 
adverse event reporting in oncology. J Clin Oncol 2007;25(32):5121-5127.
42. Varni JW, Burwinkle TM, Katz ER, Meeske K, Dickinson P. The PedsQL in pediatric 
cancer: reliability and validity of the Pediatric Quality of Life Inventory Generic Core 
Scales, Multidimensional Fatigue Scale, and Cancer Module. Cancer 2002;94(7):2090-
2106.
43. Weiner MA, Leventhal B, Brecher ML, Marcus RB, Cantor A, Gieser PW et al. 
Randomized study of intensive MOPP-ABVD with or without low-dose total-nodal 
radiation therapy in the treatment of stages IIB, IIIA2, IIIB, and IV Hodgkin's disease in 
pediatric patients: a Pediatric Oncology Group study. J Clin Oncol 1997;15(8):2769-
2779.
St. Jude Children's Research Hospital
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HLHR13
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IRB Approval date: 
Protocol document date: 09-18-2023
44. Wu J XX. Group sequential trial design against historical control under Weibull model. 
Journal of Biometrics and Biostatistics , in press 2014. 
45. 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):861-870.
46. Younes A, Bartlett NL, Leonard JP, Kennedy DA, Lynch CM, Sievers EL et al. 
Brentuximab vedotin (SGN-35) for relapsed CD30-positive lymphomas. N Engl J Med 
2010;363(19):1812-1821.
47. Younes A, Connors JM, Park SI, Hunder NN, Ansell SM. Frontline Therapy with 
Brentuximab Vedotin Combined with ABVD or AVD in Patients with Newly Diagnosed 
Advanced Stage Hodgkin Lymphoma. American Society of Hematology Annual 
Meeting. 2011. 
St. Jude Children's Research Hospital
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 APPENDIX I: Ann Arbor Staging Classification of Hodgkin Lymphoma
A. 
Stage Grouping
(See the diagram below for definitions of regions.)
Stage I: 
Involvement of single lymph node region (I) or localized involvement of a single 
extra-lymphatic organ or site (IE).
Stage II: 
Involvement of 2 or more lymph node regions on the same side of the diaphragm 
(II) or localized contiguous involvement of a single extra-lymphatic organ or site 
and its regional lymph node(s) with involvement of 1 or more lymph node regions 
on the same side of the diaphragm (IIE).
Stage III: 
Involvement of lymph node regions on both sides of the diaphragm (III), which may 
also be accompanied by localized contiguous involvement of an extra-lymphatic organ 
or site (IIIE), by involvement of the spleen (IIIS), or both (IIIE+S).
Stage IV: 
Disseminated (multifocal) involvement of 1 or more extra-lymphatic organs or 
tissues, with or without associated lymph node involvement, or isolated extra-
lymphatic organ involvement with distant (non-regional) nodal involvement.
B. 
Symptoms and Presentations
"A" Symptoms: 
Lack of "B" symptoms.
"B" Symptoms: 
At least one of the following:

Unexplained weight loss > 10% in the preceding 6 months;

Unexplained recurrent fever > 38°C in the preceding month; or

Recurrent drenching night sweats in the preceding month.
C. 
Bulk disease
Each of the following presentations is considered "bulk" disease:

Large mediastinal mass: tumor diameter > 1/3 the thoracic diameter (measured 
transversely at the level of the dome of the diaphragm on a 6 foot upright PA CXR). In 
the presence of hilar nodal disease the maximal mediastinal tumor measurement may be 
taken at the level of the hilus.  This should be measured as the maximum mediastinal 
width (at a level containing tumor and any normal mediastinal structures at the level) 
over the maximum thoracic ratio.

Large extra-mediastinal nodal aggregate: A continuous aggregate of nodal tissue that 
measures > 6 cm in the longest transverse diameter in the axial plane in any nodal area.

Macroscopic splenic nodules: focal defects in the spleen seen on CT, PET or MRI 
imaging studies consistent with Hodgkin lymphoma will be deemed to be the functional 
equivalent of “bulk” disease in this study.
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D. Enumeration of Number of Regions of Nodal Involvement
Each of these 20 regions is counted separately for purposes of determining clinical group.
Peripheral regions
o
Right neck; cervical, supraclavicular, occipital, and pre-auricular
o
Left neck; cervical, supraclavicular, occipital, and pre-auricular
o
Right infraclavicular
o
Left infraclavicular
o
Right axilla and pectoral
o
Left axilla and pectoral
o
Right epitrochlear and brachial
o
Left epitrochlear and brachial
Central regions
o
Waldeyer's ring (including base of tongue)
o
Mediastinum (including paratracheal)
o
Right hilar
o
Left hilar
o
Mesenteric
o
Paraaortic (including retrocrural, portal and celiac)
o
Splenic/splenic hilar
Lower regions
o
Right iliac
o
Left iliac
o
Right inguinal and femoral
o
Left inguinal and femoral
o
Right popliteal
o
Left popliteal
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Clinical criteria for nodal involvement – upper torso
The following will be considered Hodgkin lymphoma positive nodes, provided they are not 
obviously infected.

Any cervical or axillary node > 1.5 cm in longest transverse diameter on physical 
examination, ultrasound, CT or MRI scan

Any cluster of matted or adherent nodes

Any enlarged supraclavicular nodes

Any mediastinal adenopathy

Any FDG-positive nodes
Clinical criteria for nodal involvement – lower torso
Below the diaphragm the following areas of involvement will be considered positive for 
Hodgkin lymphoma unless they are pathologically proven to be negative. With the exception of 
the mesenteric region, nodes > 1.0 cm in the longest transverse diameter should be considered as 
lymphomatous in the absence of a compelling alternative explanation.

Any FDG-positive nodes, liver or spleen

A spleen or liver that has focal defects on CT or ultrasound or MRI. A maximum of 3 
target lesions per organ should be measured and will be utilized for response
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APPENDIX II: Response Criteria According to Euro-NET C1
Response assessment for secondary objective 1.2.1 will be done blinded and retrospectively by 
central review. Images will be collected and assessed according to the definitions outlined below.
A. DEFINITION OF TREATMENT RESPONSE
A.1.Local response definitions for nodal involvement with measurable tumor volume
At staging all measurable nodal sites (i.e. all nodal except for the spleen and Waldeyer’s 
ring) are grouped in separately measurable reference volumes. Reference volumes can 
include multiple sites if these are contiguous. The composition of these reference volumes is 
defined and documented. Initial volumes of reference volumes are measured. Volumes are 
approximated as ellipsoids. If a, b, c denote the principal axes of the ellipsoid the volume is 
calculated as V= (a x b x c)/2. In this protocol overall response to treatment is determined 
according to a systematic assessment of tumor response in all involved sites. In those sites 
where the tumor is measurable from CT/MRI scanning the change in tumor volume is 
compared the original pre-treatment reference volume and then assigned a treatment response 
for that local site.
A.1.1. Local Complete remission (local CR)
A reference volume is in "local complete remission“(in short: local CR) if:

the residual tumor volume is less or equal 5% of the reference volume (CT/MRI) and

the residual tumor volume is less or equal 2 ml
A.1.2. Local complete remission unconfirmed (local CRu)
A reference volume is in "local complete remission unconfirmed “(in short: local CRu) if:

No local CR and

the residual tumor volume is less or equal 25% of the reference volume (CT/MRI) or 
the residual tumor volume is less or equal to 2 ml
A.1.3. Local partial remission (local PR)
A reference volume is in "local partial remission“(in short: local PR) if:

No local CR or local CRu and

the residual tumor volume is less or equal 50% of the reference volume (CT/MRI) or 
the residual tumor volume is less or equal 5 ml (to safeguard against artifacts due to 
measurement errors).
A.1.4. Local no change (local NC)
A reference volume is in "local no change” (in short: local NC) if

no local CR or local CRu or local PR and

no local Progression
A.1.5. Local Progression (local PRO)
A reference volume is in "local progression” (in short: local PRO) if

The residual tumor volume is larger than 125% of the reference volume or 
significantly increases compared to the best previous response – be aware of possible 
measurement error in small tumor volume.
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A.2.Local response definitions for extra-nodal involvement or for nodal involvement 
with non-measurable tumor volume
For all extra-nodal sites or for nodal involvement with non-measurable tumor volume three 
response categories are distinguished by radiological or clinical criteria: 

Locally undetectable

Locally detectable

Locally progressive
Only “Locally undetectable” is consistent with overall CR.
Note: In case of multi-focal bone or bone marrow involvement multiple sites are 
assessed separately. Initial bone or bone marrow involvement is only assessed be FDG-PET 
assuming it is still detectable by conventional imaging.
A.3.Overall (patient level) response definitions
Overall (patient level) response categories are obtained from the worst local response in 
reference volumes and the worst local response in non-measurable nodal or extra-nodal 
disease as illustrated in the following figure:
Fig. 1. Definition of overall response
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A.3.1. Complete remission (CR)
"Complete remission“(in short: CR) is achieved if in restaging

all disease symptoms have disappeared and

no new lymphatic or extra-lymphatic lesions have occurred and

all initially involved extra-nodal sites or involved regions with non-measurable 
tumor volume are locally undetectable and

all reference volumes are in local CR
A.3.2. Complete remission unconfirmed (CRu)
"CR unconfirmed“(in short: CRu) is achieved if in restaging

no CR and

all disease symptoms have disappeared and

no new lymphatic or extra-lymphatic lesions have occurred and

all initially involved extra-nodal sites or involved regions with non-measurable 
tumor volume are not locally progressive and

all reference volumes are at least in local CRu
A.3.3. Partial remission (PR)
"Partial remission” (in short: PR) is achieved if in restaging

no CR or CRu and

all disease symptoms have disappeared and

no new lymphatic or extra-lymphatic lesions have occurred and

all initially involved extra-nodal sites or involved regions with non-measurable 
tumor volume are not locally progressive and

all reference volumes are at least in local PR
A.3.4. No change (NC)
"No change” (in short: NC) is achieved if in restaging

no CR or CRu or PR and

no PRO
A.3.5. Progression (PRO) / Relapse (R)
Progression / Relapse of the disease occurs if

recurrence or occurrence of new disease symptoms which cannot be explained 
otherwise or

occurrence of new lymphatic or extra-lymphatic lesions or

at least one initially involved extra-nodal site or involved region with non-
measurable tumor volume is locally progressive or at least one reference volume 
is in local PRO
A progression / relapse of the disease is called

progression if it occurs until three months after the end of therapy (last day of 
chemotherapy application (including Prednisone/prednisolone) or last day of 
radiotherapy respectively).

early relapse if it occurs between three and twelve months after the end of therapy.

late relapse if it occurs later than twelve months after the end of therapy.
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B. EARLY FDG-PET RESPONSE ASSESSMENT
After two cycles of chemotherapy early response reassessment including FDG-PET is 
performed. FDG-PET examinations are assessed only for initially involved regions 
(except in case of suspected progression).
B.1.Definition local FDG-PET response
For each initially involved reference volume or non-measurable nodal or extra-nodal site a 
local PET response is defined based on the initial PET and the response assessment PET 
results as illustrated in:
Fig. 2:  Definition local FDG-PET response
Definition local FDG-PET response

Local PET response positive if the response assessment PET is positive anywhere in 
the reference volume or involvement site.

Local PET response unclear, if the response assessment PET is unclear or the 
response assessment PET is negative, but the initial PET was discordantly negative.

Local PET response negative if the response assessment PET is negative and the 
initial PET was positive or unclear (i.e. not discordantly negative).
NOTE: A PET examination is locally unclear if:

Not done

Not evaluable due to technical problems in rare cases of questionable PET results.
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HLHR13
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B.2.Definition worst local FDG-PET response
In case of Local PET response unclear a further distinction is made by local CT/MRI 
response:

Locally PET unclear, but local CR or locally undetectable (by CT/MRI)

Locally PET unclear, but not local CR or locally detectable (by CT/MRI)
The worst local PET response is defined based on the following order relation:
“Local PET response positive” worse than
“Locally PET unclear, but not local CR or locally detectable” worse than
“Locally PET unclear, but local CR or locally undetectable” worse than
“Local PET response negative”
C. RESPONSE GROUP DEFINITION
If no tumor progression is found, response groups are obtained from the overall response and 
the worst local PET response in reference volumes and in non-measurable nodal or extranodal 
disease as illustrated in Fig. 5 and Table 14:
Figure 3: Response group definition
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Table Response groups in non-progressing patients
The distinction between AR1 and AR2 is made because in TG-1 AR1 the GPOH 95 study has already 
shown that omitting radiotherapy is safe, while in TG-1 AR2 this is an open study question.
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APPENDIX III: Collection, Processing, Storage and Shipment of Biologic Samples
A. Expression of CD30 in tumor tissue (CD30 density) 
Tumor tissue
Archival formalin-fixed, paraffin embedded tumor sections will be assessed by 
immunohistochemistry for CD30 expression in Reed Sternberg cells.  Immunohistochemistry 
will be performed on formalin-fixed, paraffin embedded tissue specimens using commercially 
available antibodies to CD30, evaluated and graded semi-quantitatively for the percentage of RS 
cells stained and the intensity (0, +, ++, +++) of staining.  The incidence of CD30 expression in 
RS cells and potential correlation with PR or CR will be explored via descriptive methods. 
Shipment of samples
Please send 8-10 unstained slides of 5 micron thickness from FFPE tissue to the following 
address:  
Tissue Resources Core Facility (TCRF)
St. Jude Children’s Research Hospital
MS315, Room D1053
262 Danny Thomas Boulevard
Memphis, TN  38105
Phone:
E-mail:
B. Soluble CD30 (all sites) Assessments
Cycle
Day
Time 
Relative Time
sCD30a
C1
1
Pre-dose
Prior to Adcetris
X
C3
1
Pre-dose
Prior to Adcetris
X
EOTb
X
asoluble CD30- samples – collected at all participating sites
bEOT, End of Therapy – at off therapy evaluation 
Blood for sCD30 (all sites)
Blood will be drawn pre cycle one, pre cycle 3 and end of therapy for evaluation of sCD30.
Draw one 2.5 ml gold top serum separation tube, invert the tube five times and allow blood to 
clot for 30 minutes at room temperature. Within 1 hour of collection, centrifuge SST a minimum 
of 1500 x g for 15 minutes until clot and serum are well separated.
Following centrifugation for sCD30 obtain at least 0.5 ml. Freeze the samples immediately at -
70°C (samples can be batched and sent at the end of the study period for all patients together).
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HLHR13
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IRB Approval date: 
Protocol document date: 09-18-2023
Each site will store the samples at their institution and send batch to Covance at the end of the 
study:
Katherine T. Landschulz, PhD
Principal Scientist and Manager
Biomarker Center of Excellence
Covance Laboratories, Inc
671 S. Meridian Road
Greenfield, IN 46140
Tel:  
 
C. Pharmacogenetics
All research participants at St. Jude Children’s Research Hospital will be asked to enroll on the 
institutional protocol PGEN5, while patients from external sites will be consented for banking of 
specimens for research as a part of the therapeutic protocol. Participation on this part of the 
protocol is voluntary. A blood sample will be collected at any time point in all consenting 
research participants. A total of 10 ml whole blood will be obtained in EDTA (purple top) 
vacutainer. Blood samples from external sites will be shipped overnight to St. Jude on coldpack. 
DNA extraction from mononuclear cells will be performed according to standard techniques. 
Genotyping for pharmacogenetic polymorphisms will be performed using standard molecular 
techniques in the Department of Pharmaceutical Sciences, St. Jude Children’s Research Hospital.  
Samples from collaborating sites should be shipped to:
Jun J. Yang Ph.D.
Assistant Member
Dept. of Pharm. Sci., Room I5506
St. Jude Children's Research Hospital
262 Danny Thomas Pl., MS313
Memphis, TN 38105
Tel: 
, Fax: 
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
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St. Jude Children’s Research Hospital 
Department of Pathology, Tissue Resources Core Facility
262 Danny Thomas Place
Memphis, TN  38105 Tel: 901-595-4827  Fax: 901-595-2432
                                                                                                  
                
  
                                       
HLHR13 Specimen Data and Shipping Form
CD30 Density (Tumor Tissue)
Amendment 7.0, dated: 01-30-2018
IRB Approval date: 
Protocol document date: 09-18-2023
Patient demographics
Referring Institution’s Patient ID#: ______________
Patient Name: __________________________________
Sex:   M     F     
Date of birth: _____________
Hospital/clinic: __________________________________
Patient physician: ___________________________    Phone : _______________   
Fax: _______________
………………………………………………………………………………………………
Specimen demographics
Date specimen obtained: ______________ Date specimen shipped: ______________
Anatomic Site of Tumor:  ________________________________
Diagnosis:     __________________________________________
            Collection Time point
Specimen Type
Initial diagnostic specimen
No. of FFPE slides: 
Shipping Address:
Tissue Resources Core Facility (TRCF)
St. Jude Children’s Research Hospital
MS 315, Room D1053
262 Danny Thomas Place
Memphis, TN 38105
 
Shipping Instructions:
Ship specimens Monday through Thursday via FedEx priority overnight, at ambient temperature.
Inform the TRCF of shipment and FedEx tracking number at email address above.
St. Jude Children's Research Hospital
IRB NUMBER: Pro00003725
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