A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin Lymphoma (cHL) in Children and Young Adults
Phase: PHASE3
Conditions: Ann Arbor Stage IIB Hodgkin Lymphoma, Ann Arbor Stage IIIB Hodgkin Lymphoma, Ann Arbor Stage IVA Hodgkin Lymphoma, Ann Arbor Stage IVB Hodgkin Lymphoma, Childhood Hodgkin Lymphoma, Classic Hodgkin Lymphoma
Sponsor: National Cancer Institute (NCI)

  
 
 
i 
 
Group Chair 
Douglas S. Hawkins, MD 
Seattle Children’s Research 
Institute  
Mailstop: JMB 9 
1900 9th Avenue 
Seattle, WA 98101 
P 206 884 1107 
doug.hawkins@seattlechildrens 
.org  
 
Group Vice Chair 
Lia Gore, MD 
lia.gore@cuanschutz.edu  
 
Group Statistician 
Todd Alonzo, PhD 
talonzo@childrensoncology 
group.org 
 
Chief Operating Officer 
Elizabeth O’Connor, MPH 
econnor@childrensoncology 
group.org  
 
Executive Director of  
Administration 
Deborah L. Crabtree, MS 
crabtreed@email.chop.edu 
 
Group Administration Office 
Children’s Hospital of 
Philadelphia 
3501 Civic Center Blvd. 
CTRB 10062 
Philadelphia, PA 19104 
P 215 590 6359 
F 215 590 7544 
 
Group Operations Center  
and 
Statistics & Data Center  
(SDC) Headquarters 
800 Royal Oaks Drive 
Suite 210 
Monrovia, CA 91016 
P 626 241 1500 
F 626 445 4334 
 
SDC Gainesville Office 
6011 NW 1st Place 
Suite 10 
Gainesville, FL 32607 
P 352 273 0566 
F 352 392 8162 
 
 
 
A National Cancer Institute- 
supported member group  
of the National Clinical  
Trials Network 
 
 
 
 
June 22, 2020 
 
Martha Kruhm, MS, RAC 
Head, Protocol and Information Office  
Operations and Informatics Branch 
Cancer Therapy Evaluation Program 
Division of Cancer Treatment and Diagnosis 
National Cancer Institute 
Executive Plaza North Room 730 
Bethesda, MD 20892 
 
Dear Ms. Kruhm, 
 
Enclosed please find Amendment #6 for protocol AHOD1331, A Randomized Phase 3 
Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk Classical Hodgkin 
Lymphoma (cHL) in Children and Young Adults, for CTEP review.  
 
This amendment will: 
• 
expand the window to complete the Time 6 timepoint for CIPN and CEA 
assessments 
• 
and allow institutions flexibility in how CIPN and CEA assessments are 
administered. 
Revisions to the protocol and consent documents are detailed in the pages below. Minor 
administrative updates (such as the correction of typographical errors or updates to the 
numbers of referenced sections) are tracked but not specified below.  
 
Please contact me with any questions or concerns.  
 
 
Sincerely,  
 
Tiffany Liu, MS, MA, Protocol Coordinator (for) 
 
Sharon Castellino, MD, AHOD1331 Study Chair 
Kara Kelly, MD, COG Hodgkin Disease Chair 
Douglas Hawkins, MD, Children’s Oncology Group Chair 
 
 

 
 
 
 
 
ii 
 
 
SUMMARY OF CHANGES: PROTOCOL DOCUMENT 
In accordance with the above discussion, the following specific revisions have been made to the protocol. 
Additions are in boldfaced font and deletions in strikethrough font. 
 
# 
Section 
Page(s) 
Change 
1. 
Title Page 
& 
Throughout 
Throughout 
Version dates and amendment number have been updated. 
2. 
Study 
committee 
6-8 
The study committee has been updated to reflect the current roster 
and contact information. 
3. 
7.3 
65 
Expanded the window to complete follow-up assessments for the 
following time points: Time 36 ± 3 6 months and Time 48 ± 3 
6 months.  
4. 
Appendix VII 
156-157 
• 
Corrected an error for internal consistency:  
“Study measures will be collected by CRAs from each 
designated rater at each participating institution at 
five six scheduled time points, beginning with the initiation 
of chemotherapy at ‘baseline’ through 36 months following 
the completion of therapy (see Table 1 below).” 
• 
Removed the following statements to allow institutions 
flexibility in how assessments are administered:  
i. “The Time 4, 5, and 6 assessments should be done in 
person, as well.” 
ii. “The timing of the assessments during a planned in 
clinic visit will also optimize response rates over more 
remote data collection.”  
• 
Expanded the window to complete the Time 6 CIPN follow-up 
assessment from +/- 3 months to +/- 6 months to ensure 
optimal response rate. 
• 
Updated a sentence about what the Time 6 assessments will 
allow researchers to estimate for protocol consistency.  
5. 
Appendix VIII 
159-160 
• 
Removed the following statement to allow institutions flexibility 
in how assessments are administered: 
“c. 
Method of Administration: Self-administered”  
• 
Expanded the window to complete the Time 6 CEA follow-up 
assessment from +/- 3 months to +/- 6 months to ensure 
optimal response rate. 
 
 
 
 

AHOD1331 
 
AHOD1331 
 
 
Version Date: 06/22/2020 
 
1 
 
 
 
CHILDREN’S ONCOLOGY GROUP 
 
AHOD1331 
 
A Randomized Phase 3 Study of Brentuximab Vedotin (SGN-35) for Newly Diagnosed High-Risk 
Classical Hodgkin Lymphoma (cHL) in Children and Young Adults 
 
 
A Groupwide Phase III Study (Limited to US and Canada sites) 
 
 
 
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, AND SHOULD NOT BE COPIED, REDISTRIBUTED OR USED FOR 
ANY OTHER PURPOSE. MEDICAL AND SCIENTIFIC INFORMATION CONTAINED WITHIN THIS PROTOCOL IS NOT 
INCLUDED TO AUTHORIZE OR FACILITATE THE PRACTICE OF MEDICINE BY ANY PERSON OR ENTITY. RESEARCH 
MEANS A SYSTEMATIC INVESTIGATION, INCLUDING RESEARCH DEVELOPMENT, TESTING AND EVALUATION, 
DESIGNED TO DEVELOP OR CONTRIBUTE TO GENERALIZABLE KNOWLEDGE. THIS PROTOCOL IS THE RESEARCH 
PLAN DEVELOPED BY THE CHILDREN’S ONCOLOGY GROUP TO INVESTIGATE A PARTICULAR STUDY QUESTION OR 
SET OF STUDY QUESTIONS AND SHOULD NOT BE USED TO DIRECT THE PRACTICE OF MEDICINE BY ANY PERSON OR 
TO PROVIDE INDIVIDUALIZED MEDICAL CARE, TREATMENT, OR ADVICE TO ANY PATIENT OR STUDY SUBJECT. THE 
PROCEDURES IN THIS PROTOCOL ARE INTENDED ONLY FOR USE BY CLINICAL ONCOLOGISTS IN CAREFULLY 
STRUCTURED SETTINGS, AND MAY NOT PROVE TO BE MORE EFFECTIVE THAN STANDARD TREATMENT. ANY PERSON 
WHO REQUIRES MEDICAL CARE IS URGED TO CONSULT WITH HIS OR HER PERSONAL PHYSICIAN OR TREATING PHYSICIAN 
OR VISIT THE NEAREST LOCAL HOSPITAL OR HEALTHCARE INSTITUTION. 
 
 
NCI Supplied Agent:  
Brentuximab Vedotin (SGN-35 NSC# 749710) 
IND sponsor for Brentuximab Vedotin: DCTD, NCI 
 
 
STUDY CHAIR 
Sharon M. Castellino, MD, MSc 
Children's Healthcare of Atlanta 
Pediatric Hematology Oncology 
Emory University School of Medicine 
2015 Uppergate Drive, ECC 436 
Atlanta, GA 30322 
Phone:(404) 785-3240 
Fax: (404) 785-3600 
Email:  sharon.castellino@choa.org  
 
Activated: 
03/16/2015 
Version Date: 
06/22/2020 
Closed: 
08/02/2019 
Amendment #: 
6 

 
 
AHOD1331 
Version Date: 06/22/2020 
 
2 
CONTACT INFORMATION 
 
To submit site registration 
documents: 
For patient enrollments: 
Submit study data 
Regulatory documentation must 
be submitted to the CTSU via the 
Regulatory Submission Portal. 
Regulatory Submission Portal: 
(Sign in at www.ctsu.org, 
and select the Regulatory 
Submission sub-tab under the 
Regulatory tab.)  
 
Institutions with patients waiting 
that are unable to use the Portal 
should alert the CTSU Regulatory 
Office immediately at 1-866-651-
2878 to receive further instruction 
and support. 
 
Contact the CTSU Regulatory 
Help Desk at 1-866-651-2878 for 
regulatory assistance. 
Please refer to the patient enrollment 
section of the protocol for instructions 
on using the Oncology Patient 
Enrollment Network (OPEN) which can 
be accessed at 
https://www.ctsu.org/OPEN_SYSTEM/ 
or https://OPEN.ctsu.org. 
 
Contact the CTSU Help Desk with any 
OPEN-related questions at 
ctsucontact@westat.com. 
Data collection for this 
study will be done 
exclusively through 
Medidata Rave. Please 
see the Data 
Submission Schedule in 
the CRF packet for 
further instructions.  
 
 
The most current version of the study protocol and all supporting documents must be downloaded 
from the protocol-specific Web page of the CTSU Member Web site located at https://www.ctsu.org. 
Access to the CTSU members’ website is managed through the Cancer Therapy and Evaluation 
Program - Identity and Access Management (CTEP-IAM) registration system and requires user log on 
with CTEP-IAM username and password. Permission to view and download this protocol and its 
supporting documents is restricted and is based on person and site roster assignment housed in the 
CTSU RSS.  
For clinical questions (i.e. patient eligibility or treatment-related) contact the Study PI of the Lead 
Protocol Organization. 
For non-clinical questions (i.e. unrelated to patient eligibility, treatment, or clinical data 
submission) contact the CTSU Help Desk by phone or e-mail:  
CTSU General Information Line – 1-888-823-5923, or ctsucontact@westat.com. All calls and 
correspondence will be triaged to the appropriate CTSU representative.  
The CTSU Website is located at https://www.ctsu.org. 
 
 
 
 

 
 
AHOD1331 
Version Date: 06/22/2020 
 
3 
TABLE OF CONTENTS 
 
SECTION 
PAGE 
CONTACT INFORMATION 
2 
TABLE OF CONTENTS 
3 
STUDY COMMITTEE 
6 
ABSTRACT 
9 
EXPERIMENTAL DESIGN SCHEMA 
10 
1.0 
GOALS AND AIMS (SCIENTIFIC AIMS) 
11 
1.1 
Primary Aims 
11 
1.2 
Secondary Aims 
11 
1.3 
Exploratory Aims 
11 
2.0 
BACKGROUND 
12 
2.1 
Introduction and Rationale for Development 
12 
2.2 
Study of Brentuximab Vedotin (BV; AdcetrisTM) 
13 
2.3 
Defining High-Risk cHL 
15 
2.4 
Rationale for AVEPC Chemotherapy Back Bone 
16 
2.5  
Correlative studies (detailed in Appendices V, VI, VII, and VIII) 
18 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
20 
3.1 
Study Enrollment 
20 
3.2 
Patient Eligibility Criteria 
23 
4.0 
TREATMENT PLAN 
25 
4.1 
Overview of Treatment Plan 
25 
4.2 
Standard Therapy ABVE-PC 
27 
4.3 
Experimental Therapy Bv-AVEPC 
31 
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
35 
5.1 
Dose Modifications for Brentuximab Vedotin 
35 
5.2 
Dose Modifications for Commercial Agents 
39 
6.0 
DRUG INFORMATION 
41 
6.1 
BRENTUXIMAB VEDOTIN      (03/21/2018) 
41 
6.2 
BLEOMYCIN        (05/06/11) 
48 
6.3 
CYCLOPHOSPHAMIDE INJECTION     (03/13/13) 
50 
6.4 
DOXORUBICIN       (05/09/11) 
51 
6.5 
ETOPOSIDE – INJECTION      (11/15/16) 
53 
6.6 
FILGRASTIM , TBO-FILGRASTIM, FILGRASTIM-SNDZ  (11/15/16) 
56 
6.7 
PEGFILGRASTIM       (02/10/16) 
57 
6.8 
PREDNISO(LO)NE       (11/16/17) 
59 
6.9 
VINCRISTINE SULFATE      (08/16/12) 
60 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
62 
7.1 
Required Clinical, Laboratory and Disease Evaluations 
63 

 
 
AHOD1331 
Version Date: 06/22/2020 
 
4 
7.2 
Specimen Submission Schedule for Patients who Consent to the Biology Studies 
64 
7.3 
Follow-up 
65 
7.4  
Pharmacokinetics (PK) Studies 
66 
8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
67 
8.1 
Criteria for Removal from Protocol Therapy 
67 
8.2 
Off Study Criteria 
67 
9.0 
STATISTICAL CONSIDERATIONS 
67 
9.1 
Statistical Design 
67 
9.2 
Patient Accrual and Expected Duration of Trial 
67 
9.3 
Statistical Analysis Methods 
68 
10.0 
EVALUATION CRITERIA 
81 
10.1 
Common Terminology Criteria for Adverse Events (CTCAE) 
81 
10.2 
Baseline Imaging Lesion Evaluation at Diagnosis 
81 
10.3 
Response Criteria 
84 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
88 
11.1 
Purpose 
88 
11.2 
Determination of reporting requirements 
88 
11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
89 
11.4 
Special Situations for Expedited Reporting 
89 
11.5 
Reporting Requirements for Specialized Adverse Events 
91 
11.6 
Exceptions to Expedited Reporting 
92 
11.7 
Reporting Requirements - Investigator Responsibility 
93 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS 
93 
11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
95 
11.10 Protocol Specific Additional Instructions and Expedited Reporting Exceptions 
96 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated pathway
 
96 
11.12 Routine Adverse Event Reporting 
97 
12.0 
RECORDS AND REPORTING 
97 
12.1 
CDUS 
97 
12.2 
CRADA/CTA 
97 
13.0 
PATHOLOGY GUIDELINES 
99 
13.1 
Pathology Guidelines and Specimen Procurement Requirements 
99 
13.2 
Tissue Specimen Submission for Correlative Biology Studies 
99 
14.0 
IMAGING STUDIES REQUIRED 
101 
14.1 
[18F]Fluorodeoxyglucose (FDG) PET 
101 
14.2 
Computed Tomography (CT) with contrast 
101 
14.3 
CT during PET/CT 
102 
14.4 
Central Review of Imaging Studies 
102 
15.0 
RADIOTHERAPY GUIDELINES 
105 
15.1 
General Principles – Risk-Adapted RT 
105 

 
 
AHOD1331 
Version Date: 06/22/2020 
 
5 
15.2 
Indications for Radiotherapy 
105 
15.3 
Radiotherapy Dose and Schedule for SRL Lesions 
105 
15.4 
Timing of Radiotherapy and Starting Criteria 
106 
15.5 
Credentialing Requirements 
106 
15.6 
Equipment 
107 
15.7 
Target Volumes 
108 
15.8 
Target Dose 
116 
15.9 
Treatment Technique 
118 
15.10 Treatment Position 
119 
15.11 Organs at Risk 
119 
15.12 Dose Calculations and Reporting 
120 
15.13 Quality Assurance Documentation 
120 
15.14 Definitions of Deviation in Protocol Performance 
122 
APPENDIX I: CLINICAL AND STAGING CRITERIA FOR HODGKIN LYMPHOMA 
123 
APPENDIX II: RECOMMENDED GUIDELINES FOR IMAGING 
126 
APPENDIX III: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
131 
APPENDIX IV: MODIFIED (“BALIS”) PEDIATRIC SCALE OF PERIPHERAL 
NEUROPATHIES 
133 
APPENDIX V: CORRELATIVE IMAGING STUDIES 
134 
APPENDIX VI: CORRELATIVE BIOLOGY STUDIES 
143 
APPENDIX VII: CORRELATIVE PERIPHERAL NEUROPATHY (CIPN) STUDY 
154 
APPENDIX VIII: COST EFFECTIVENESS OF BRENTUXIMAB VEDOTIN FOR US 
INSTITUTIONS ONLY 
159 
APPENDIX IX: CTEP AND CTSU REGISTRATION PROCEDURES 
164 
APPENDIX X: POSSIBLE DRUG INTERACTIONS 
167 
APPENDIX XI: YOUTH INFORMATION SHEETS 
171 
REFERENCES 
175 
 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AHOD1331 
Version Date: 06/22/2020 
 
6 
STUDY COMMITTEE 
STUDY CHAIR 
STUDY COMMITTEE MEMBERS 
Sharon M. Castellino, MD, MSc 
Cindy L. Schwartz, MD, MPH 
Children's Healthcare of Atlanta - Egleston 
Hematology/Oncology 
Pediatrics/Hematology-Oncology 
Children's Hospital of Wisconsin  
2015 Uppergate Drive, ECC 436 
Oncology 
Atlanta, GA 30322 
8701 W. Watertown Plk Rd. MFRC 3018 
Phone: (404) 785-3240 
Milwaukee, WI 53226 
Fax: 
(404) 785-3600 
Phone (414) 955-4195 
Email:  Sharon.Castellino@choa.org 
Fax 
(414) 955-6543 
 
Email: cschwartz@mcw.edu 
STUDY VICE CHAIR 
 
Frank G. Keller, MD 
Kara Kelly, MD 
Children’s Healthcare of Atlanta-Egleston 
Roswell Park Cancer Institute 
Pediatrics Hematology/Oncology 
Pediatric Division 
2015 Uppergate Drive, 4th Floor 
Elm and Carlton Streets 
Atlanta, GA  30322 
Buffalo, NY  14263 
Phone: (407) 785-3124 
Phone: (716) 845-2333 
Fax: 
(407) 727-4455 
Email: kara.kelly@roswellpark.org 
E-mail: frank.keller@choa.org 
 
 
David C. Hodgson, MD 
STUDY STATISTICIAN 
Radiation Oncology 
Qinglin Pei, PhD 
Hospital for Sick Children 
Statistics 
Princess Margaret Hospital 
COG Data Center, Gainesville 
Radiotherapy 
6011 NW 1st. Place 
610 University Avenue 
Gainesville, FL 32607 
Toronto, ON  M5G 2M9 
Phone: (352) 273-0552 
Canada 
Fax: 
(352) 392-8162 
Phone: (416) 946-2126 
E-mail: qpei@cog.ufl.edu 
Fax: 
(416) 946-6556 
 
Email david.hodgson@rmp.uhn.on.ca 
STUDY COMMITTEE MEMBERS 
 
Terzah M. Horton, MD, PhD 
Kenneth Berwick Roberts, MD 
Baylor College of Medicine 
Radiation Oncology 
Pediatrics-Hematology/Oncology 
Yale University 
1102 Bates Avenue, Suite 750 
Therapeutic Radiology 
Houston, TX  77030 
P.O. Box 208040 
Phone: (832) 824-4269 
New Haven, CT  06520 
Fax: 
(832) 824-1206 
Phone: (203) 785-2957 
Email: tmhorton@txch.org 
Fax: 
(203) 785-4622 
 
Email: kenneth.roberts@yale.edu 
Anne-Marie Charpentier, MD 
 
Radiation Oncology 
Angela S. Punnett, MD 
Centre Hospitalier Universitaire Sainte-Justine 
Hematology/Oncology 
Service Hematology/Oncology 
Hospital for Sick Children 
3175 chemin Cote Sainte-Catherine 
Hematology/Oncology 
Montreal QC  H3T 1C5 
555 University Avenue 
Canada 
Toronto, ON  M5G 1X8 
Phone: (514) 345-4931 
Canada 
Fax: 
(514) 412-7537 
Phone: (416) 813-7500 
Email: anne-marie.charpentier@umontreal.ca  
Email: angela.punnett@sickkids.ca 
 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AHOD1331 
Version Date: 06/22/2020 
 
7 
STUDY COMMITTEE MEMBERS 
STUDY COMMITTEE MEMBERS 
Steve Yoon-Ho Cho, MD 
Kathleen M. McCarten, MD 
Diagnostic Imaging 
Diagnostic Imaging 
University of Wisconsin Hospital and Clinics 
Rhode Island Hospital, Diagnostic Imaging 
Wisconsin Institute for Medical Research, WIMR 713 
593 Eddy Street 
1111 Highland Ave  
Providence, RI  02903 
Madison, WI 53705 
Phone: (401) 444-6883 
Phone: (608) 263-5048 
Email: KMcCarten@lifespan.org 
Fax:  
(608) 265-7390 
 
Email: scho@uwhealth.org 
Jennifer Hall Aldrink, MD 
 
Surgery 
Stephan D. Voss, MD, PhD 
Nationwide Children's Hospital 
Diagnostic Imaging 
Pediatric Surgery 
Dana-Farber/Harvard Cancer Institute 
700 Children's Drive, ED379 
Radiology 
Columbus, OH  43205 
Children's Hospital Boston 
Phone: (614) 722-0440 
300 Longwood Avenue 
Email: jennifer.aldrink@nationwidechildrens.org 
Boston, MA 2115 
 
Phone: (617) 355-8377 
Adina Alazraki, MD 
Fax:  
(617) 730-0573 
Radiology 
Email:  stephan.voss@childrens.harvard.edu 
Children’s Healthcare of Atlanta - Egleston 
 
1405 Clifton Road 
Bradford Hoppe, MD, MPH 
Decatur, GA  30322 
Radiation Oncology 
Phone: (404) 785-6532 
Mayo Clinic Florida Radiation Oncology 
Fax:  
 (404) 785-1216 
4500 San Pablo Rd. 
Email:   adina.alazraki@choa.org 
Jacksonville, FL 32224 
 
Phone: (904) 953-2000 
Brandy Strickland Snyder, PharmD 
Email: hoppe.bradford@mayo.edu  
Pharmacy 
 
Wake Forest University Health Sciences 
Tara Olive Henderson, MD, MPH 
Medical Center Blvd 
Hematology/Oncology 
Winston Salem, NC  27157 
University of Chicago Comprehensive Cancer Center 
Phone: (336) 713-6555 
Pediatric Oncology 
Fax:  
(336) 713-3401 
5841 S. Maryland Avenue, MC 4060 
Email: bstrickl@wakehealth.edu 
Chicago, IL  60637 
 
Phone: (773) 702-6808 
Andrea Nicole Marcogliese, MD 
Fax: 
(773) 702-9881 
Baylor College of Medicine 
Email: thenderson@peds.bsd.uchicago.edu 
Department of Pathology 
 
6621 Fannin Street, Suite AB1195 
Susan K. Parsons, MD, MRP 
Houston, TX  77030 
Hematology/Oncology 
Phone: (832) 824-5189 
Tufts Medical Center 
Fax: 
(832) 825-1032 
800 Washington Street  
Email: ansheeha@texaschildrenshospital.org 
Boston, MA  02111 
 
Phone: (617) 636-1450 
Hollie Anne Lai, MD 
Fax: 
(617) 636-6280 
Diagnostic Imaging 
Email: sparsons@tuftsmedicalcenter.org 
Children's Hospital of Orange County 
 
1201 West La Veta Avenue 
 
Orange, CA 92868 
 
Phone: (714) 509-9081 
 
Fax: 
(714) 509-9078 
 
Email: hlai@choc.org 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AHOD1331 
Version Date: 06/22/2020 
 
8 
STUDY COMMITTEE MEMBERS 
CLINICAL RESEARCH ASSOCIATE 
Ruth Anne Herring, MSN, CPNP 
Sally Muehle, CCRA  
Nursing 
Clinical Research Associates 
UT Southwestern/Simmons Cancer Center-Dallas 
Rainbow Babies and Childrens Hospital 
Center for Cancer and Blood Disorders 
11100 Euclid Avenue  
1935 Medical District Drive 
Cleveland, OH 44106 
Dallas, TX  75235 
Phone: (216) 983-3178 
Phone: (214) 456-3149 
Fax:  
(216) 844-5431 
Fax: 
(214) 456-3593 
Email: sally.muehle@uhhospitals.org 
Email: RuthAnne.Herring@childrens.com 
 
 
COG PROTOCOL COORDINATOR 
Joel M. Reid, PhD 
Tiffany Liu, MS, MA  
Pharmacology 
Children's Oncology Group - Operations Center 
Mayo Clinic 
Phone: (626) 241-1616 
17-42C Guggenheim Building 
E-mail: tliu@childrensoncologygroup.org 
200 First Street SW 
 
Rochester, MN 55905 
 
Phone: (507) 284-0822 
 
Fax: 
(507) 284-3906 
 
Email: reid.joel@mayo.edu 
 
 
 
Joyce Chipo Mhlanga, MBChB  
 
Diagnostic Imaging 
 
Washington University School of Medicine 
 
Mallinckrodt Institute of Radiology 
 
510 S. Kingshighway Blvd, Campus Box 8223 
 
Saint Louis, MO 63110 
 
Phone: (314) 362-2807 
 
Fax: 
(314) 362-2806 
 
Email:  jmhlanga@wustl.edu 
 
 
 
Hema K. Dave, MD 
AGENT  
NSC# 
IND# 
Hematology/Oncology 
Brentuximab vedotin 
749710 
 
Children's National Medical Center 
Bleomycin 
125066 
Exempt 
Blood and Marrow Transplantation 
Cyclophosphamide 
26271 
Exempt 
111 Michigan Ave NW 
Doxorubicin 
712227 
Exempt 
1st floor, West Wing, Suite 300 
Etoposide 
141540 
Exempt 
Washington, DC 20010 
Filgrastim  
614629 
Exempt 
Phone: (202) 476-6250 
Pegfilgrastim  
614371 
Exempt 
Email: hkdave@cnmc.org 
Prednisone 
10023 
Exempt 
 
Vincristine 
67574 
Exempt 
Eric P. Eutsler, MD 
 
 
 
Diagnostic Imaging 
 
 
 
3320 S. Bay Hill Drive  
 
 
 
Center Valley, PA 18034  
 
 
 
Phone: (610) 442-0892 
 
 
 
Email: eutsler@gmail.com 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SEE SECTIONS 13 (PATHOLOGY), SECTION 7.2 (BIOLOGY TABLE), SECTION 7.3 (FOLLOW UP 
TABLE) AND APPENDIX VI (BIOLOGY DETAILS) FOR SPECIMEN SHIPPING ADDRESSES. 

  
THIS PROTOCOL IS FOR RESEARCH PURPOSES ONLY, SEE PAGE 1 FOR USAGE POLICY 
AHOD1331 
Version Date: 06/22/2020 
 
9 
 
The Children's Oncology Group has received a Certificate of Confidentiality from the federal government 
that will help us protect the privacy of our research subjects. The Certificate protects against the involuntary 
release of information about your subjects collected during the course of our covered studies. The 
researchers involved in the studies cannot be forced to disclose the identity or any information collected in 
the study in any legal proceedings at the federal, state, or local level, regardless of whether they are criminal, 
administrative, or legislative proceedings. However, the subject or the researcher may choose to voluntarily 
disclose the protected information under certain circumstances. For example, if the subject or his/her 
guardian requests the release of information in writing, the Certificate does not protect against that 
voluntary disclosure. Furthermore, federal agencies may review our records under limited circumstances, 
such as a DHHS request for information for an audit or program evaluation or an FDA request under the 
Food, Drug and Cosmetics Act. The Certificate of Confidentiality will not protect against mandatory 
disclosure by the researchers of information on suspected child abuse, reportable communicable diseases, 
and/or possible threat of harm to self or others. 
 
 
ABSTRACT 
While contemporary combined-modality therapy in children and adolescents results in 5-10 year survival 
rates of more than 90% when patients of all stages are evaluated, there remain subgroups of Hodgkin 
Lymphoma (HL) patients in whom initial cure is suboptimal, and hence these subgroups are deemed as 
high risk. Evidence supporting the use of response-directed therapy in pediatric HL has been demonstrated 
in POG 9425, CCG 59704 and AHOD0031. High-risk subgroups of HL patients may have EFS rates of 
less than 85%, indicating a need for novel therapy approaches beyond escalation of standard chemotherapy 
with current conventional agents. SEER data have suggested that advances in HL survival among 
adolescents and young adults (AYAs) may be less robust compared with both older and younger 
populations.1 
 
The hybrid regimen, ABVE-PC, modified from both DBVE-PC regimen of POG 9425 and BEACOPP of 
CCG 59704, continues to be a tolerable combination of dose-intensive conventional therapy in classical 
Hodgkin Lymphoma (cHL). Brentuximab vedotin (Bv, AdcetrisTM), an anti-CD30 murine/human chimeric 
monoclonal antibody (cAC10; Brentuximab) linked to monomethylauristatin E (MMAE; vedotin), is able 
to target the Reed-Sternberg Cell (HLRS) in newly diagnosed disease.2 The primary goal of the current 
study will be to examine the treatment efficacy (defined by EFS) of a chemotherapy regimen including Bv 
in high-risk cHL. High-risk cHL patients will be randomized to one of 2 therapy arms: the control arm of 
ABVE-PC or the experimental arm of Bv-AVEPC. Randomization will occur at the time of enrollment. In 
keeping with prior studies of response-based treatment, secondary goals will be to determine the response 
rate after two cycles of therapy on each arm. Those patients who remain FDG-PET positive after 2 cycles, 
will receive response-based involved site radiation therapy (ISRT). The expected accrual duration is about 
4 years. In addition, correlative studies of biology, pharmacokinetics, imaging, radiation, neuropathy and 
health-related quality of life are incorporated in the evaluation of this new targeted agent for high-risk cHL. 
 
 

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EXPERIMENTAL DESIGN SCHEMA
Bv-AVEPC=Brentuximab vedotin/ Doxorubicin//Vincristine/Etoposide/Prednisone/Cyclophosphamide
ABVE-PC = Doxorubicin/Bleomycin/Vincristine/Etoposide/Prednisone/Cyclophosphamide
PD = Progressive disease
RRL = Rapid responding lesion/nodal site. Favorable response by PET2. See Table 10.3.1
SRL = Slow responding lesion/nodal site. Unfavorable response by PET2. See Table 10.3.1
LMA = Large Mediastinal Adenopathy (see Appendix I).
Response Adapted Targeted: ISRT (2100 cGy) to nodal sites with SRL or to initial LMA (regardless of response to 
chemotherapy).
ISRT = Involved site radiation therapy (see Section 15)
Follow-up
Response Adapted 
Targeted ISRT to any 
SRL and any LMA
Follow-up
Response Adapted 
Targeted ISRT to any SRL 
and any LMA
Follow-up
Study Entry
Randomize to 
Bv-AVEPC or 
ABVE-PC
(Experimental Arm)
2 cycles of
Bv-AVEPC 
(Standard Arm)
2 cycles of 
ABVE-PC 
PET for SRL or RRL
determination by nodal site
OFF PROTOCOL 
THERAPY
PD
PET for SRL or RRL
determination by nodal site
3 cycles of
Bv-AVEPC
3 cycles of
ABVE-PC 

  
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11
1.0 
GOALS AND AIMS (SCIENTIFIC AIMS) 
1.1 
Primary Aims 
 
1.1.1 
To assess the event free survival (EFS) of a novel regimen incorporating 
brentuximab vedotin (Bv; AdcetrisTM) in the chemotherapy backbone of 
doxorubicin 
(Adriamycin), 
vincristine, 
etoposide, 
prednisone 
and 
cyclophosphamide (Bv-AVEPC) in newly diagnosed high-risk cHL compared to 
those treated with ABVE-PC. 
 
1.2 
Secondary Aims 
 
1.2.1 
To determine whether children/young adults with high-risk cHL treated with Bv-
AVEPC have a higher rate of early response (determined by FDG-PET) and a 
reduction in response-directed radiation therapy (RT) compared to those treated 
with ABVE-PC. 
 
1.2.2  To compare the rate of neuropathy (> Grade 3) among patients treated on the Bv-
AVEPC (experimental arm) to patients treated on the ABVE-PC (standard arm). 
 
1.3 
Exploratory Aims 
Childhood International Prognostic Score (CHIPS) 
 
1.3.1 
To validate and compare the Childhood Hodgkin International Prognostic Score 
(CHIPS) to conventional Ann Arbor Stage (Stages II B with bulk, III B, IV A or B) 
in predicting outcome in high-risk childhood cHL. 
 
Biology 
 
1.3.2 
To determine the incidence of preferentially expressed antigen in melanoma 
(PRAME) and testis-specific antigens in EBV- cHL tumors and the incidence of 
EBV antigens (EBNA1, LMP1, LMP2) in EBV+ cHL tumors, with the goal of 
developing strategies to integrate cellular therapy into treatment for newly 
diagnosed high-risk cHL.  
 
Imaging  
 
1.3.3 
To incorporate qualitative visual FDG-PET into response-directed treatment 
algorithms and explore quantitative FDG-PET and CT definitions of tumor burden 
and response for incorporation into next generation pediatric cHL risk-
stratification schemes, exploring the extension of these algorithms to young adults.  
 
Radiation Therapy 
 
1.3.4 
To evaluate the reduction in normal tissue irradiation associated with the current 
treatment approach compared to the volume of historic IFRT fields. 
 
1.3.5 
To evaluate EFS and patterns of relapse following protocol-specified RT 
utilization and treatment volumes. 
 

  
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Patient Reported Outcomes (PRO) of Peripheral Neuropathy and Health-Related Quality 
of Life  
 
1.3.6 
To characterize the extent of chemotherapy induced peripheral neuropathy (CIPN), 
as reported by patients and parent proxies, through serial administration of the 
FACT-GOG-NTX. 
 
1.3.7 
To describe the Health-Related Quality of Life (HRQL) consequences of 
peripheral neuropathy over time by correlating total neuropathy scale scores with 
the individual items with the CHRIs-Global scale (e.g., physical health, pain, 
emotional functioning). 
 
1.3.8 
To perform a cross validation of the FACT-GOG-NTX with the TNS-PV to 
determine the performance of both measures with the use of brentuximab vedotin 
in a limited institutional approach in children and young adults with cHL (See 
Appendix VII). 
 
Economic (For US Institutions Only) 
 
1.3.9 
To assess the resource use and cost implications of Bv in combination with 
chemotherapy and radiotherapy (RT) for newly diagnosed high-risk cHL in 
children and young adults (See Appendix VIII). 
 
Follow-up of Deauville score 3 lesions on FDG-PET imaging (confirmed by central 
imaging review)  
 
1.3.10 To estimate the risk of relapse among RRL subjects that have at least one lesion 
that is Deauville 3 at PET 2. 
 
The pharmacokinetics of brentuximab vedotin 
 
1.3.11 To characterize the pharmacokinetics of brentuximab vedotin in children 
< 13 years of age. 
 
 
2.0 
BACKGROUND 
 
2.1 
Introduction and Rationale for Development 
A challenge in treating Hodgkin Lymphoma (HL) is finding the optimal balance between 
achieving tumor free survival and minimizing treatment-related morbidity and mortality. 
While contemporary combined modality therapy in children and adolescents and young 
adults results in 5-10 year survival rates of more than 90% when patients of all stages are 
evaluated, there remain subgroups of HL patients for whom initial cure rates are 
suboptimal. It is among these high-risk patients that intensification of treatment with 
current conventional agents is inadequate. While the peak age for Hodgkin Lymphoma is 
20-34 years of age, young adults (18-21 years) may also benefit from the study of novel 
approaches used in pediatric and adolescent Hodgkin’s populations. 
 
Despite risk-adapted, response-based approaches current therapy in adults and pediatric 
high-risk HL, which rely on initial or salvage regimens containing high doses of alkylating 
agents, anthracyclines, and RT, are associated with significant risk of premature second 

  
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13
malignancies, cardiovascular disease, and pulmonary toxicity. Hence, despite favorable 
early outcomes, death rates from treatment-associated morbidity escalate for decades 
following initial remission.3-6 Despite decreases in radiation fields and doses with 
contemporary therapy, the cumulative incidence of Second Malignant Neoplasms (SMN) 
remains elevated.7 Our overarching goal is to improve disease control while minimizing 
treatment burden by incorporating a new agent (brentuximab vedotin, Bv) targeting CD30 
on the Reed-Sternberg Cell (HLRS) into the standard chemotherapy backbone treatment 
regimen (ABVE-PC) for CHL that has been modified to eliminate the bleomycin.  
 
High-risk subgroups of HL patients may have EFS < 85%, indicating a need for novel 
therapy approaches beyond escalation of standard chemotherapy. In adults, the use of 6 
cycles of ABVD therapy for early unfavorable or high-stage Hodgkin lymphoma has 
reported progression free survival ranges between 68% and 74%.8-10 The majority of 
studies of high-risk pediatric HL report EFS of 75-85%, with Stage IVB patients 
consistently having the poorest outcomes.11 The dose-intensive pediatric regimens ABVE-
PC (adriamycin, bleomycin, vincristine, etoposide, prednisone, cyclophosphamide) and 
OEPA/COPDac for high-stage disease have demonstrated 5-yr EFS of 85-87%, with 
outcomes in subsets of high-risk patients ranging from 70-94%. The recent pediatric study 
CCG 59704, reported an EFS of 94% for high-risk patients (Stages IIB and IIIB with bulk, 
IV) using BEACOPP in an intensive, multidrug regimen with high cumulative alkylator 
and anthracycline doses; this demonstrates the principle of achieving high disease-free 
survival with initial therapy, but with significant risk of long- term adverse sequelae of 
treatment.11  
 
The pediatric experience with dose-intensive regimens has suggested that short-term 
toxicities and the burden of therapy are generally well tolerated. Many centers deliver 
ABVE-PC as outpatient therapy. With the goal of improved disease control and reduced 
cumulative alkylator and anthracycline exposure, we propose the evaluation of the targeted 
agent brentuximab vedotin [(Bv); AdcetrisTM] into a well-tolerated backbone of dose-dense 
chemotherapy (Bv-AVEPC) for high-risk cHL patients in a randomized approach. Themes 
of dose density, response-based therapy and tailored delivery of radiotherapy will be 
extended from prior COG and legacy group studies. Consistent with recent studies in adult 
and pediatric HL, we will define the high-risk group to include Ann Arbor Stages: IIB with 
bulk disease, IIIB, IVA or IVB. We exclude Stage IIB without bulk disease patients based 
on AHOD0031 data where Stage IIB patients without bulk disease have 3-year EFS at 
90%. 
 
In this trial, we will compare 5 cycles of ABVE-PC to 5 cycles of Bv-AVEPC, using 
2 cycle response status to delineate those high-risk patients who will subsequently receive 
involved site radiotherapy (ISRT) following 5 cycles. ISRT will be delivered to sites of 
slow response to initial chemotherapy, and to sites of initial large mediastinal adenopathy 
(LMA). The primary outcome will be EFS in the ABVE-PC and Bv-AVEPC groups.  
 
2.2 
Study of Brentuximab Vedotin (BV; AdcetrisTM) 
Bv, an anti-CD30 murine/human chimeric monoclonal antibody (cAC10; brentuximab) 
linked to monomethylauristatin E (MMAE; vedotin), is an opportunity to target the specific 
biology of cHL in newly diagnosed disease.2 In a single agent phase II trial of Bv in adult 
patients with relapsed HL following autologous transplant the objective response rate was 
75% (34% complete response; 40% partial response) with a median response duration of 
6.7 months.12 Additionally, when Bv was added to a multi-agent chemotherapy regiment 
with adriamycin, vinblastine and dacarbazine (AVD) in adults with newly diagnosed 

  
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Stage IIA bulky or Stage IIB-IV disease in adults an MTD for Bv was not reached and the 
regiment appeared to be relatively safe.13  
 
The approved dose of Bv is 1.8 mg/kg every 3 weeks. Primary Bv-associated toxicities 
include peripheral sensory neuropathy that is cumulative and reversible and 
myelosuppression. The corporate trial (ECHELON-1 NCT# 01712490; Millennium, 
Seattle Genetics) extended the experience in adults to compare the efficacy of 6 cycles of 
ABVD to 6 cycles Bv-AVD in de novo Stage III or IV Hodgkin disease. Utilizing a Bv 
dose of 1.2 mg/kg on days 1 and 15, the phase III study endpoint is modified progression 
free survival, with failure defined as need for any further therapy (radiation or 
chemotherapy inclusive) beyond 6 cycles. Modified progression free survival benchmarks 
have been set at 82.5% for the experimental arm versus an expected 75% PFS for the 
standard ABVD arm (Personal correspondence, Seattle Genetics). The recently published 
results of this trial limited to adults (ECHELON 1; AVD versus Bv) were released at a 
median follow-up of 24.6 months. There were 664 patients enrolled on the A+AVD arm and 
670 patients on the ABVD arm. The primary endpoints of 2-year modified progression free 
survival in the A+AVD and ABVD groups were 82.1% and 77.2% respectively (hazard ratio 
for event of progression, death, or modified progression, 0.77; p=0.03). Myelosuppression 
and peripheral neuropathy are the primary AEs of concern in the Bv arm.14 
 
The use of Bv in pediatric patients with refractory or relapsed HL or ALCL has been 
reported in several case reports.15-18 The ongoing dose-escalation Phase 1/2 study 
(NCT01492088) in pediatric patients is evaluating pharmacokinetics, safety and efficacy 
of Bv as monotherapy in pediatric patients with relapsed or refractory disease.19 The 
maximum tolerated dose and the recommended dose of Bv for phase 2 portion of the study 
was determined to be 1.8 mg/kg every 3 weeks. While the overall response rates appear 
favorable (47-64%), there is currently insufficient data to ascertain efficacy in children.20,21 
Treatment emergent adverse events appear similar to that noted in adult trials. There is 
currently limited information regarding safety and efficacy of Bv in children < 6 years of 
age. While HL is rare in younger children, in the recent series of COG trials for HL, an 
estimated 2% of patients were < 6 years at enrollment. Hence study of this agent is 
warranted in younger children with de novo Hodgkin Lymphoma. 
 
In the published experience of Bv in pediatrics, in 9 children age 12-17 years (5 of whom 
had HL) there were no common events > Grade 3 and no patients discontinued treatment 
due to an adverse event.22 The ongoing phase II study (AHOD1221) of Bv with 
gemcitabine for relapsed HL will provide further data in the pediatric and adolescent 
population. We also anticipate additional safety data from the recently opened St. Jude 
Consortium phase II trial evaluating the safety of Bv in place of vincristine using a 
chemotherapy backbone of OEPA/COPDac for high-risk HL in children and adolescents 
(personal correspondence, Metzger). 
 
We propose to incorporate Bv into a modified version of ABVE-PC, termed Bv-AVEPC. 
Bv will be given at the 1.8 mg/kg dose on Day 1 of cycle. Bleomycin will be eliminated 
from the backbone in the experimental arm due to the potential risk of pulmonary toxicity 
when Bv is administered with bleomycin, as was observed in adult phase II trials13, as well 
as data from studies suggesting that bleomycin has a less critical role in contemporary 
multi-agent regimens.23  
 
Vincristine is deliberately retained in the experimental arm at Day 8 (but not Day 1) to 
allow comparison and minimize variability between the arms as much as possible, and to 

  
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maintain the dose intensity of the experimental arm (see Tables 2-3). The incidence of 
Grade 3 or higher motor or sensory neuropathy utilizing 3 to 5 cycles of the backbone 
regimen ABVE-PC over 3 preceding COG and POG studies (enrolling greater than 
2000 subjects) has been consistently less than 3%. However, given theoretical concerns of 
additive neurotoxicity of dual tubulin inhibitors in the experimental arm, peripheral 
neuropathy will be closely monitored, with stopping rules for significantly higher than 5% 
incidence of Grade 3 or 4 peripheral neurotoxicity measured by Balis scale (See 
Appendix IV) among the first 100 patients treated on Bv-AVEPC. Rates of peripheral 
neuropathy will be monitored for Bv-AVEPC following Cycle 2 and Cycle 5 of therapy. If 
stopping rules are met, the experimental arm will be modified to remove Day 8 vincristine. 
In the event that this is a necessary change, we anticipate minimal reduction in dose 
intensity of the experimental arm.  
 
All therapy will be given on a 21 day schedule with concomitant growth factor support to 
mitigate myelosuppressive toxicity. 
 
2.3 
Defining High-Risk cHL 
There has been no consensus on defining risk groups by Ann Arbor Stage in pediatric or 
adult North American HL. The recently closed AHOD0831 study categorized Stage IIIB 
and IVB patients as high risk. Prior to that, CCG 5942 categorized Stage IV to treatment 
group 3 (most intensive treatment). The P9425 categorized Stages IIB, IIIB and IVA and 
B as high risk. The St. Jude/Stanford/DFCI consortium assigned IIB, IIIB, IV as high risk 
and the German Pediatric HOD HD2002 study assigned Stages IIBE, IIIAE, IIIB, IVA, 
IVB, IVE as advanced stage disease.24 
 
Table 1: Definitions of High-Risk HL in Prior Pediatric Studies compared to AHOD1331 
 
GHOD 
2002 
St. Jude/Stanford/DFCI 
P9425 
CCG5942 
AHOD0831 
AHOD1331 
IIBE 
IIB 
IIB 
 
 
IIB Bulk 
IIIAE, IIIB 
IIIB 
IIIB 
 
III B 
IIIB 
IV 
IV 
IV  
IV 
IV B 
IV 
 
Our current proposal has defined stages to high risk based on a combination of other 
group’s categorization and based on outcomes from the recent series of COG and POG 
legacy studies given the experience with the ABVE-PC based chemotherapy. Despite 
Stage IIB patients having EFS > 90% on P9425 which included 3 or 5 cycles of 
chemotherapy and RT to all, on AHOD0031 Stage IIB patients with bulk disease had sub-
optimal outcome (3 yr. EFS 75%) , compared to Stage IIB patients without bulk disease (3 
yr. EFS 90%). The rationale for omission of Stage IIIA from the proposed high-risk therapy 
approach is that on AHOD0031 this group (n= 305 Stage IIIA cHL ages < 18; 18% of 
AHOD0031 population) had excellent outcomes with ABVE-PC based therapy. 
Specifically the 3-yr EFS was 88.1% (s.e. 1.9%). Similarly, on POG 9425, where patients 
received either 3 or 5 cycles ABVE-PC and RT, the 5-year EFS for Stage IIIA patients 
(n=18) was 94% (s.e. 5%). Hence, we do not feel it is justified to increase therapy to 
5 cycles of ABVE-PC (over 4 cycles given in AHOD0031) with more intensive 
cyclophosphamide for this favorable risk group. In addition, this favorable risk group (with 
an estimated 48 patients per year) will increase the baseline EFS in the standard ABVE-
PC arm and thereby potentially decrease our ability to detect a benefit of Bv in the 
experimental arm. 
 

  
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We will therefore include Ann Arbor Stages IIB with bulk, Stage IIIB and all Stage IV 
patients in this study. Consistent with AHOD0031, bulk will be defined as any large 
mediastinal adenopathy (LMA) or nodal aggregate > 6 cm. Refer to Appendix I for 
additional detail.  
 
2.4 
Rationale for AVEPC Chemotherapy Back Bone 
Efficacy, tolerability and safety of the ABVE-PC regimen have been well studied in 
children.25,26 ABVE-PC was introduced in 1997 in P9425, modifying ABVD by 
(1) substituting vincristine for the more myelosuppressive vinblastine, (2) replacing 
dacarbazine with etoposide, (3) adding cyclophosphamide and prednisone to enhance 
efficacy, and (4) increasing dose density by giving chemotherapy every 3 weeks with use 
of filgrastim to prevent prolonged marrow nadir.25 AHOD0031 retained the backbone with 
some changes in dosing to reduce the 4 cycle cumulative doxorubicin dose to 200 mg /m2, 
and AHOD0831 modified the cyclophosphamide dose to augment the cumulative 
alkylating agent therapy. Importantly, the risk of etoposide- induced secondary malignancy 
has been < 0.5%, combining data from POG 9425 and COG AHOD0031, that provides a 
large experience over the time period during which topoisomerase induced secondary 
leukemias are expected to occur. This observation is also noted in reports regarding the 
OEPA and BEACOPP regimens. The addition of etoposide in these regimens has allowed 
for a decrease in alkylator therapy thus limiting infertility risk in young patients, while 
preserving or improving disease outcomes. Additionally, the anthracycline exposure is 
lower with 5 cycles of ABVE-PC (250 mg/m2 in our proposed study) compared to the 
6-8 cycles of ABVD (300-400 mg/m2) more commonly employed in adult regimens. As 
noted above, the incidence of Grade 3 or higher peripheral motor and sensory neuropathy 
has been less than 3%. While North American adult HL groups have mainly utilized ABVD 
based chemotherapy for 6 or more cycles in high-risk settings, European adult HL groups 
favor the more dose intensive BEACOPP regimen. ABVE-PC entered clinical use in the 
Pediatric Oncology Group ~15 years ago as a dose-intensive regimen designed to provide 
more efficacious therapy while decreasing cumulative anthracycline and alkylator 
exposure compared to ABVD and MOPP/COPP regimens. The dose-dense backbone of 
ABVE-PC appears to provide better efficacy than standard ABVD, is administered over a 
shorter time period and delivers lower cumulative doses of anthracycline, thus improving 
immediate and long-term quality of life. With the substitution of Bv, we anticipate further 
reduction in treatment burden by avoiding bleomycin and by enhancing rapid response 
rates, thereby limiting radiation exposure. 
 
In adults, the use of 6-8 cycles of ABVD therapy for early unfavorable or high-stage HL, 
has reported progression free survival ranges between 68% and 74%.8-10 There are limited 
data using ABVD in pediatric patients. In a prior CCG trial where Fryer et. al.27 
administered 12 cycles ABVD to children with advanced-stage HL (n=64), the pulmonary 
toxicity rate was high at 9%, predominantly occurring before RT was given. The overall 
survival of this study was 87% at 3 years, sub-optimal by today’s standards. P9425 showed 
an 85% five- year EFS and 95% overall survival for high-risk patients (Stages IIB, IIIB 
and IV) using ABVE-PC and radiotherapy. On that study, 63% of patients were rapid early 
responders requiring only 3 cycles (9 weeks) of chemotherapy and IFRT; slow responders 
received 2 additional cycles of chemotherapy. The higher reported EFS outcomes utilizing 
the ABVE-PC regimen allow us to set our proposed EFS targets higher in pediatric 
advanced-stage HL, as the long-term toxicities of salvage regimens remain a significant 
concern in children, adolescents and young adults. A theme of the dose- intensive regimens 
is that dose density improves disease control, minimizing the potential need for salvage 
therapies associated with significant late sequelae of treatment. Tables 2 and 3 (below) 

  
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17
compare the dose density of the chemotherapy agents in each regimen, and the cumulative 
doses of agents for some relevant regimens used to treat high-stage HL. 
 
Table 2. Comparison of dose density of selected regimens (mg or IU/m2/week)  
 
 
ABVD 
Bv-
AVD 
ABVE
-PC* 
Bv-
AVEPC 
OEPA COPDac 
OEPA x2 
COPDac x4 
Esc- 
BEACOPP 
Doxorubicin 
12.5 
12.5 
16.67 
16.67 
20 
 
6.67 
11.67 
Bleomycin 
5 
- 
5 
 
 
 
 
3.3 
Vincristine 
- 
- 
0.93 
0.47 
1.125 
0.75 
.875 
0.46 
Etoposide 
- 
- 
125 
125 
156 
 
52 
200 
Cyclophosphamide 
- 
- 
400 
400 
 
250 
167 
400 
Prednisone 
- 
- 
93 
93 
210 
140 
163 
187 
Procarbazine 
- 
- 
- 
 
 
 
 
233 
Vinblastine 
3 
3 
- 
 
 
 
 
- 
DTIC 
188 
188 
 
 
 
188 
125 
 
Brentuximab vedotin 
 
0.6 
 
0.6 
 
 
 
 
* As used in this current proposed trial and AHOD0831. AHOD0031 and P9425 provided 
267 mg/m2/wk of weekly cyclophosphamide. P9425 provided 20 mg/m2 of weekly 
doxorubicin.  
 
Table 3. Comparison of cumulative dose exposure of selected regimens (mg or U/m2) 
 
 
ABVD  
x 6 
Bv-AVD 
x 6 
ABVE-PC* 
x 5 
Bv-
AVEPC x5 
OEPA x2 
COPDac x 4 
Esc- 
BEACOPP x 6 
Doxorubicin 
300 
300 
250 
250 
160 
210 
Bleomycin 
120 
- 
75 
- 
 
60 
Vincristine 
- 
- 
15 
7.5 
21 
12 
Etoposide 
- 
- 
1875 
1875 
1250 
3600 
Cyclophosphamide 
- 
- 
6000 
6000 
4000 
7200 
Prednisone 
- 
- 
1400 
1400 
3922 
3360 
Procarbazine 
- 
- 
- 
- 
 
4200 
Vinblastine 
72 
72 
- 
- 
 
- 
DTIC 
4500 
4500 
 
 
3000 
 
Brentuximab vedotin 
 
14.4 
 
9 
 
 
* As used on in this current proposed trial and AHOD0831. AHOD0031 provided 
3200 mg/m2 of cyclophosphamide. P9425 provided 180-300 mg/m2 of doxorubicin 
depending on the number of cycles administered.  
 
In summary, we propose that ABVE-PC is the North American standard for dose-dense 
chemotherapy in pediatric HL, and is the most rational backbone upon which to base the 
addition of a new targeted agent. 
 

  
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2.5  
Correlative studies (detailed in Appendices V, VI, VII, and VIII) 
2.5.1  Imaging Modalities in HL 
FDG-PET will be the key clinical determinant of early response in this study. 
However CT tumor volume at baseline and the change in tumor burden 
(represented by CT tumor volume between the baseline and post-cycle 2 imaging) 
will be explored for potential prognostic significance (see Appendix V). 
 
2.5.2  Biology Studies in HL 
Despite the enhanced understanding of the biology of HL, few studies have 
incorporated molecular markers or EBV biology into initial-risk classification or 
response modification. Studies of immune function in HL patient following 
chemotherapy and during follow-up will enhance understanding of host response 
and tumor microenvironment. Further information about the correlative biology 
studies can be found in Appendix VI.  
 
2.5.3  CIPN, Health Related Quality of Life, and Cost Effectiveness Analysis in HL 
Despite the use of vinca alkaloids in many HL regimens, the incidence, prevalence 
and trajectory of peripheral neuropathy has not been studied in this population. 
Neuropathy is a recognized side effect of Bv containing regimens in adult 
lymphoma patients. Chemotherapy induced peripheral neuropathy (CIPN) 
involves three principal manifestations: sensory; motor; and autonomic. 
Manifestations vary by drug class, and cumulative exposure. The combination of 
Bv and vincristine in the experimental arm of the current study warrants evaluation 
of the incidence and pattern of peripheral neuropathy in children, adolescents and 
young adults with HL. The possible impact of peripheral neuropathy on quality of 
life is also an increasing area of attention warranted in HL populations especially 
given the long life expectancy (see Appendix VII). 
 
Patient report of HRQL will also be useful is establishing quality adjusted life years 
in comparing and analyzing the cost effectiveness of the Bv containing regimen to 
the standard regimen in this population with high risk disease (see Appendix VIII).  
 
Note: the CEA and CIPN sub-studies reached accrual and were closed to further 
patient entry as of September 8, 2017. Subjects already enrolled on these studies 
should continue to submit all required measures through Time Point #6 as 
indicated in Appendix VII and Appendix VIII. 
 
2.5.4  Radiation Dosimetry  
A key step toward reduced toxicity and late effects risk in HL is a reduction of 
radiation use and normal tissue volume exposure while controlling disease. The 
use of involved site RT (ISRT) with contemporary radiation approaches holds this 
promise. In fact the European H10 trial for adults and the Euronet PHL-C2 trial in 
children employ involved node RT (INRT) following chemotherapy. Involved site 
RT (ISRT) refers to treatment conceptually similar to INRT, but has modifications 
allowing for uncertainty of the exact margins of the involved nodes to be targeted 
in the clinical target volume. With the contemporary capacity for CT planning 
ISRT is thought to be the best modality in a multi-site trial approach. The goal is 
to accurately target diseased nodes, while minimizing normal tissue volume 
exposure.28,29 We will capture dosimetry to key organs which have proven to be 

  
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19
the source of late morbidity after successful HL therapy. Dose volume histograms 
shall be collected for the following organs at risk: female breast, heart, lungs, 
thyroid, liver, and kidney. 
 
2.5.5 
CHIPS 
Prospective evaluation and validation of a new prognostic score, CHIPS, among 
children and adolescents with Ann Arbor Stage IIB bulk, IIIB and IV cHL is 
planned. The CHIPS is a new childhood HL prognostic scoring system which 
emerged from multivariable predictive modeling of presenting clinical 
characteristics on the recently completed intermediate risk AHOD0031 trial.30 The 
four clinical features most predictive of EFS were:  
1. Stage IV disease;  
2. Large mediastinal mass (> 1/3 thoracic diameter);  
3. Fever (T ≥ 38oC); and 
4. Low albumin (< 3.5 g/dL).  
 
One point is assigned for each adverse presenting feature. The distribution of 
CHIPS for AHOD0031 patients was: score 0: 36%, score 1: 39.4%, score 2: 19.5%, 
and score 3: 5.1%. There were no CHIPS 4 patients on AHOD0031 because 
patients with Stage IV disease and fever would not have been eligible for the study. 
In data from AHOD0031, CHIPS clearly discriminates groups beyond classical 
Ann Arbor Staging criteria. Distinct differences in 3-year EFS were noted by 
CHIPS: 0, 93%; 1, 86%; 2, 77%; 3, 71%30. Our proposed study is therefore a 
prospective collection and validation of CHIPS in this high-risk population; in 
combination with data from AHOD0031, we will define more precise risk groups 
for future reduction or escalation of therapy. Given the absence of a standard or 
consensus for defining risk groups in cHL, we anticipate that validation of CHIPS 
in participants ≤ 21 years of age could introduce a powerful stratification tool for 
future trials to incorporate.  
 
2.5.6 
Pharmacokinetics (PK) of Brentuximab Vedotin 
The safety and efficacy of brentuximab vedotin has been evaluated in adults with 
relapsed classical HL or systemic ALCL, and the maximum tolerated dose (MTD) 
determined to be 1.8 mg/kg (max dose of 1800 mg) every 3 weeks.31 Although less 
commonly used, weekly dosing was studied in an adult phase I dose escalation 
trial that determined the maximum tolerated weekly dose to be 1.2 mg/kg.32 The 
pharmacokinetic analysis to date is derived from data from five phase 1 and 2 
studies that included adult patients. These combined data demonstrate the linear 
pharmacokinetics 
of 
the 
antibody 
drug 
conjugate 
(ADC) 
and 
monomethymuriamine (MMAE). In addition, MMAE exposures appear to be 
lower than ADC exposure, and body weight seems to be a significant covariate.33 
We currently have very limited PK data for brentuximab vedotin in pediatric 
patients, and current dosing has been extrapolated from adult studies. Brentuximab 
vedotin is currently dosed at 1.8 mg/kg on Day 1 of every 21-day cycle of 
AHOD1331. 
 
Flerlage et al. recently demonstrated a strong relationship between patient weight 
and clearance of ADC and MMAE, in a sampling (n=16) of their phase II trial (St. 
Jude’s Research Hospital HLHR13) in pediatric patients with advanced HL.34 The 
inclusion of weight significantly explained 75, 84, 61, and 94% of the inter-

  
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individual variability in the ADC clearance, ADC volume, MMAE clearance, and 
MMAE apparent volume, respectively. Overall, the ADC AUC and Cmax in their 
pediatric study were lower than those reported in adult studies (25 and 11%, 
respectively, at dose of 1.2 mg/kg and 35 and 16%, respectively, at dose of 
1.8 mg/kg). Flerlage et al. also noted ADC clearance and volume differed by sex, 
with clearance and volume estimated 17% higher (p = 0.08 and p = 0.03, 
respectively) in boys compared to girls.34 However, the range of exposures for 
these patients have previously been demonstrated to be active (i.e., were associated 
with partial or complete responses) in adult patients as monotherapy in initial phase 
1 studies, thus it is likely that in a multi-agent regimen, these exposures would be 
expected to be efficacious. 
 
We propose that enrolling subjects under age 13 (i.e., 12 years 11 months and 
younger) should be sufficient to capture PK data in lower weight pediatric subjects 
to inform the PK modeling results. In summary, addition of this aim to AHOD1331 
with Amendment #2B will provide additional needed pediatric date for the every 
21 day dosing and evaluate the PK of brentuximab vedotin in combination with 
the AVE-PC backbone of chemotherapy. 
 
 
3.0 
STUDY ENROLLMENT PROCEDURES AND PATIENT ELIGIBILITY 
 
3.1 
Study Enrollment 
 
3.1.1 
Patient Registration 
Prior to enrollment on this study, patients must be assigned a COG patient ID 
number. This number is obtained via the Patient Registry module in OPEN once 
authorization for the release of protected health information (PHI) has been 
obtained. The COG patient ID number is used to identify the patient in all future 
interactions with COG. If you have problems with the registration, please refer to 
the online help. For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com.  
 
In order for an institution to maintain COG membership requirements, every patient 
with a known or suspected neoplasm needs to be offered participation in APEC14B1, 
Project:EveryChild A Registry, Eligibility Screening, Biology and Outcome Study. 
 
A Biopathology Center (BPC) number will be assigned as part of the registration 
process. Each patient will be assigned only one BPC number per COG Patient ID. 
For additional information about the labeling of specimens please refer to the 
Pathology and/or Biology Guidelines in this protocol. 
 
Please see Appendix IX for detailed CTEP Registration Procedures for Investigators 
and Associates, and Cancer Trials Support Unit (CTSU) Registration Procedures 
including: how to download site registration documents; requirements for site 
registration, submission of regulatory documents and how to check your site’s 
registration status. 
 
3.1.2 
IRB Approval 
Each investigator or group of investigators at a clinical site must obtain IRB 
approval for this protocol and submit IRB approval and supporting documentation 

  
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to the CTSU Regulatory Office before they can be approved to enroll patients.  
Assignment of site registration status in the CTSU Regulatory Support System 
(RSS) uses extensive data to make a determination of whether a site has fulfilled 
all regulatory criteria including but not limited to the following: 
• 
An active Federal Wide Assurance (FWA) number 
• 
An active roster affiliation with the Lead Network or a participating 
organization 
• 
A valid IRB approval 
• 
Compliance with all protocol specific requirements. 
 
In addition, the site-protocol Principal Investigator (PI) must meet the following 
criteria: 
• 
Active registration status 
• 
The IRB number of the site IRB of record listed on their Form FDA 1572 
• 
An active status on a participating roster at the registering site. 
 
For information about the submission of IRB/REB approval documents and other 
regulatory documents as well as checking the status of study center registration 
packets, please see Appendix IX.  
 
Institutions with patients waiting that are unable to use the Portal should alert the 
CTSU Regulatory Office immediately at 1-866-651-2878 in order to receive 
further instruction and support. For general (non-regulatory) questions call the 
CTSU General Helpdesk at: 1-888-823-5923. 
 
Study centers can check the status of their registration packets by querying the 
Regulatory Support System (RSS) site registration status page of the CTSU 
members’ web site by entering credentials at https://www.ctsu.org. For sites under 
the CIRB initiative, IRB data will automatically load to RSS. 
 
Note: Sites participating on the NCI CIRB initiative and accepting CIRB 
approval for the study are not required to submit separate IRB approval 
documentation to the CTSU Regulatory Office for initial, continuing or 
amendment review. For sites using the CIRB, IRB approval information is 
received from the CIRB and applied to the RSS in an automated process. Signatory 
Institutions must submit a Study Specific Worksheet for Local Context (SSW) to 
the CIRB via IRBManager to indicate their intent to open the study locally. The 
CIRB’s approval of the SSW is then communicated to the CTSU Regulatory 
Office.  In order for the SSW approval to be processed, the Signatory Institution 
must inform the CTSU which CIRB-approved institutions aligned with the 
Signatory Institution are participating in the study. Other site registration 
requirements 
(i.e., 
laboratory 
certifications, 
protocol-specific 
training 
certifications, or modality credentialing) must be submitted to the CTSU 
Regulatory Office or compliance communicated per protocol instructions. 
 
3.1.3 
Study Enrollment 
Patient enrollment will be facilitated using the Oncology Patient Enrollment 
Network (OPEN). OPEN is a web-based registration system available on a 24/7 
basis. To access OPEN, the site user must have an active CTEP-IAM account 
(check at https://ctepcore.nci.nih.gov/iam) and a 'Registrar' role on either the lead 

  
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protocol organization (LPO) or participating organization roster. Registrars must 
hold a minimum of an AP registration type.  If a DTL is required for the study, the 
registrar(s) must also be assigned the OPEN Registrar task on the DTL. 
 
All site staff will use OPEN to enroll patients to this study. It is integrated with the 
CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient position in the Rave database. OPEN can be accessed at 
https://open.ctsu.org or from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org. To assign an IVR or NPIVR as the treating, 
crediting, consenting, drug shipment (IVR only), or investigator receiving a 
transfer in OPEN, the IVR or NPIVR must list on their Form FDA 1572 in RCR 
the IRB number used on the site’s IRB approval. If a DTL is required for the study, 
the IVR or NPIVR must also be assigned the appropriate OPEN-related tasks on 
the DTL. 
 
Prior to accessing OPEN, site staff should verify the following: 
• 
All eligibility criteria have been met within the protocol stated timeframes.  
• 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
Note: The OPEN system will provide the site with a printable confirmation of 
registration and treatment information. Please print this confirmation for your 
records. 
 
Further instructional information is provided on the CTSU members' web site 
OPEN tab or within the OPEN URL (https://open.ctsu.org). For any additional 
questions 
contact 
the 
CTSU 
Help 
Desk 
at 
1-888-823-5923 
or 
ctsucontact@westat.com. 
 
3.1.4 
Timing 
Patients must be enrolled before treatment begins. The date protocol therapy is 
projected to start must be no later than five (5) calendar days after the date of study 
enrollment. All clinical and laboratory studies to determine eligibility must be 
performed within 14 days prior to enrollment unless otherwise indicated in the 
eligibility section below. 
 
3.1.5 
Inclusion of Women and Minorities 
Both men and women of all races and ethnic groups are eligible for this study.  
 
3.1.6 
Randomization 
Randomization will take place at the time a patient is enrolled via OPEN. The patient 
will be randomly assigned 1:1 to Bv-AVEPC arm or ABVE-PC arm. Randomization 
will be stratified by clinical characteristics (Stage IIB with bulk vs. Stage IIIB vs. 
Stage IVA vs. Stage IVB).  
 
 

  
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3.2 
Patient Eligibility Criteria 
 
Important note: The eligibility criteria listed below are interpreted literally and cannot 
be waived. All clinical and laboratory data required for determining eligibility of a 
patient enrolled on this trial must be available in the patient's medical/research record 
that will serve as the source document for verification at the time of audit.  
 
All clinical and laboratory studies to determine eligibility must be performed within 
14 days prior to enrollment unless otherwise indicated. Laboratory values used to 
assess eligibility must be no older than fourteen (14) days at the start of therapy. 
Laboratory tests need not be repeated if therapy starts within fourteen (14) days of 
obtaining labs to assess eligibility. If a post-enrollment lab value is outside the limits 
of eligibility, or laboratory values are > 14 days old, then the following laboratory 
evaluations must be re-checked within 48 hours prior to initiating therapy: CBC with 
differential, bilirubin, ALT (SGPT), albumin and serum creatinine. If the recheck is 
outside the limits of eligibility, the patient may not receive protocol therapy and will 
be considered off protocol therapy.  
 
Imaging studies and bone marrow evaluations must be obtained within 21 days prior 
to start of protocol therapy. Repeat the tumor imaging if necessary (see Section 14.3). 
Histologic core bone marrow biopsy is required in children < 18 years of age 
regardless of FDG-PET results. Exceptions to the bone marrow requirement in cases 
of patients with airway compromise, can be applied if adequate documentation of 
contraindication to the procedure is noted. However, bone marrow can be obtained 
after the initiation of emergency steroid therapy in such cases as per Section 4.2 and 
Section 4.3. 
 
See Section 7.1 for required studies to be obtained prior to starting protocol therapy. 
 
INCLUSION CRITERIA 
 
3.2.1 
Age 
Ages ≥ 2 - < 22 years at the time of enrollment. 
 
3.2.2 
Diagnosis 
Patients with newly diagnosed, pathologically confirmed cHL meeting one of the 
following Ann Arbor stages are eligible: 
• 
Stage IIB with bulk*  
• 
Stage IIIB 
• 
Stage IVA 
• 
Stage IVB 
 
* Bulk is defined in Appendix I. If study eligibility by staging is uncertain, 
consultation with IROC RI may be obtained prior to study enrollment. 
 
 

  
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3.2.3 
Organ Function Requirements 
3.2.3.1 
Adequate Renal Function Defined As: 
- Creatinine clearance or radioisotope GFR  70 mL/min/1.73 m2 or 
- A serum creatinine based on age/gender as follows: 
Age 
Maximum Serum Creatinine (mg/dL) 
 
Male 
Female 
2 to < 6 years 
0.8 
0.8 
6 to < 10 years 
1 
1 
10 to < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
≥ 16 years 
1.7 
1.4 
The threshold creatinine values in this table were derived from 
the Schwartz formula for estimating35 utilizing child length and 
stature data published by the CDC. 
 
3.2.3.2 
Adequate Liver Function Defined As: 
- Total bilirubin  1.5 x upper limit of normal (ULN) for age, and 
- SGOT (AST) or SGPT (ALT) < 2.5 x upper limit of normal (ULN) for 
age. 
 
3.2.3.3 
Adequate Cardiac Function Defined As: 
- Shortening fraction of  27% by echocardiogram, or 
- Ejection fraction of  50% by radionuclide angiogram. 
 
3.2.3.4 
Adequate Pulmonary Function Defined As: 
- FEV1/FVC > 60% by pulmonary function test (PFT), unless due to large 
mediastinal mass from HL. 
- For children who are unable to cooperate for PFTs, the criteria are: no 
evidence of dyspnea at rest, no exercise intolerance, and a pulse oximetry 
reading of > 92% on room air. 
 
3.2.4 
Exclusion Criteria 
3.2.4.1 
Patients with nodular lymphocyte-predominant HL. 
 
3.2.4.2 
Patients with an immunodeficiency that existed prior to diagnosis, such 
as primary immunodeficiency syndromes, organ transplant recipients 
and children on current systemic immunosuppressive agents are not 
eligible. 
 
3.2.4.3 
Patients who are pregnant. (Since fetal toxicities and teratogenic effects 
have been noted for several of the study drugs, a negative pregnancy test 
is required for female patients of childbearing potential). 
 
3.2.4.4 
Lactating females who plan to breastfeed. 
 
3.2.4.5 
Sexually active patients of reproductive potential who have not agreed 
to use an effective contraceptive method for the duration of their study 
participation and for 30 days after the last dose of chemotherapy. 

  
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3.2.4.6 
Patients known to be positive for HIV are not eligible. 
 
3.2.4.7 
Patients who have received any previous chemotherapy or radiation 
therapy are not eligible.  
 
3.2.4.8 
Patients who received systemic corticosteroids within 28 days of 
enrollment on this protocol, except as specified (See Section 4.2), are 
not eligible. 
 
Note: Please see Section 4.1.1 for the concomitant therapy restrictions for patients 
during treatment.  
 
3.2.5 
Regulatory Requirements  
3.2.5.1 
All patients and/or their parents or legal guardians must sign a written 
informed consent. 
 
3.2.5.2 
All institutional, FDA, and NCI requirements for human studies must be 
met. 
 
 
4.0 
TREATMENT PLAN 
 
4.1 
Overview of Treatment Plan 
Therapy will consist of five cycles of ABVE-PC or Bv-AVEPC. Each cycle is 21 days. 
After Cycle 2 (approximately Days 18-22), FDG-PET will be done to determine response. 
Upon central review, individual lesions will be defined as rapidly responding lesions (RRL) 
if the Cycle 2 FDG-PET is negative, defined as Deauville score less than or equal to 3 (less 
than or equal to that of liver). See Table 10.3.1 
 
Individual lesions/nodal sites will be defined as slow responding lesion (SRL) if the FDG-
PET after 2 cycles of therapy is positive, defined as Deauville score of 4 or 5 (greater than 
liver). See Table 10.3.1  
 
Baseline studies should be submitted for central review to IROC Rhode Island (previously 
QARC) at the time of enrollment. Eligibility criteria (including definitions of bulk and 
LMA) will be reviewed and confirmed at the time of response assessment after Cycle 2. 
Timely submission of studies to IROC Rhode Island is required to avoid unnecessary 
delays in therapy (see Section 14). Cycle 3 of chemotherapy may commence before 
results of central review are available, but central review is required prior to 
initiation of the RT plan following Cycle 5. Following completion of 5 cycles of 
chemotherapy, patients will receive response-adapted ISRT (2100 cGy) targeting regions 
of LMA and SRL. All radiotherapy treatment plans must be submitted to IROC Rhode 
Island for review and approval prior to the start of radiotherapy (see Section 15). 
 
Timing of protocol therapy administration, response assessment studies, and surgical interventions are 
based on schedules derived from the experimental design or on established standards of care. Minor 
unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease evaluations (and 
up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, procedure and/or 
anesthesia scheduling issues are acceptable (except where explicitly prohibited within the protocol). 

  
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NOTE: For patients with involvement of the spleen, vaccination against pneumococcus, 
Haemophilus influenza and meningococcus is strongly recommended prior to therapy. If 
not performed at this time, it should be administered prior to beginning radiation therapy. 
 
Patients with progressive or recurrent disease at any time point (see Section 10.3) will go 
off protocol therapy and treated at the discretion of the treating physician. Patients will 
remain on study until they meet one of the off study criteria (see Section 8). 
 
4.1.1 
Concomitant therapy 
4.1.1.1 No other cancer chemotherapy or immunomodulating agents will be used 
routinely. 
a. Corticosteroid therapy is only permissible for anaphylactic reactions, 
adrenal insufficiency, and severe asthma or as a breakthrough anti-
emetic. 
 
4.1.1.2 Appropriate antibiotics, blood products, antiemetics, fluids, electrolytes 
and general supportive care are to be used as necessary. See COG 
Supportive Care Guidelines:  
https://childrensoncologygroup.org/index.php/cog-supportive-care-
guidelines. 
 
4.1.1.3 Concomitant use of strong cytochrome 3A4 inhibitors or inducers, or P-gp 
inhibitors (see Appendix III), has the potential to affect the exposure to 
monomethyl auristan E (MMAE). Moderate or strong CYP3A4 inhibitors 
or P-gp inhibitors are not permitted in this trial. Specifically, oral 
aprepitant and IV fosaprepitant are weak to moderate CYP3A4 
inhibitors and substrates. Therefore, we recommend caution for the use of 
these agents in patients receiving Brentuximab vedotin. Refer to agent-
specific drug information for additional details. The use of a single 
2 mg/kg (maximum 80 mg) dose of oral aprepitant does not appear to 
cause clinically significant CYP3A4 inhibition and is permitted on Day 1 
of each treatment cycle if a patient fails first line anti-emetic prophylaxis 
regimens. Use of aprepitant or fosaprepitant on either study arm should be 
documented on the study Case Report Forms (CRFs) where indicated. 
 
4.1.1.4 Concomitant use of dexrazoxane with the ABVE-PC backbone should be 
considered with caution, due to concerns of increased risk of 
myelosuppression and associated adverse events including typhlitis.25 Use 
of dexrazoxane should be at investigator discretion and noted on the study 
CRFs where indicated.  
 
 
 

  
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4.2 
Standard Therapy ABVE-PC 
 
NOTES:  
• 
All doses will be based on actual body surface area or weight (where 
applicable). Only brentuximab vedotin, vincristine and colony stimulating 
factor doses will be capped (refer to details below). 
• 
For patients with involvement of the spleen, vaccination against 
pneumococcus, Haemophilus influenza and meningococcus is strongly 
recommended prior to therapy. If not performed at this time, it should be 
administered prior to beginning radiation therapy. Waiting to immunize 
until after Cycle 5 may be affected by muted immune response at that time. 
 
Standard therapy consists of 5 cycles of ABVE-PC. Each cycle is 21 days in duration. The 
administration schedule below describes 1 cycle of ABVE-PC and should be repeated for 
each cycle. Steroids as antiemetics are permitted per institutional guidelines. However, the 
use of aprepitant, fosaprepitant, or netupitant/palonosetron in the anti-emetic regimen 
should be approached with caution and needs to be documented on the CRFs on either 
study arm. (See Section 4.1.1.3 for additional information.) 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website 
at: https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusion. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
DOXOrubicin: Slow IV push or intermittent infusion 
Days 1 and 2. 
Dose: 25 mg/m2/dose.  
Administer at a concentration not to exceed 2 mg/mL by slow IV push over 1-5 minutes or 
by intermittent infusion over 1-15 minutes; may prolong to 60 minutes if institutional 
policies mandate. It is suggested that DOXOrubicin be administered through the tubing of 
rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
See the special precautions in Section 6.4.4. 
 
Bleomycin: IV or subcutaneous 
Note: the dose is different on each day of administration. 
Day 1: 5 Units/m2/dose.  
Day 8: 10 Units/m2/dose.  
 
IV: Infuse over a minimum of 10 minutes (no greater than 1 unit/minute) and at a 
concentration not to exceed 3 units/mL.  
Subcutaneous: A concentration of 3-15 units/mL can be used for subcutaneous 
administration. Aspirate prior to injection to avoid injection into a blood vessel. 
 
See the special precautions in Section 6.2.4 
 

  
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VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional 
policy 
Days 1 and 8. 
Dose: 1.4 mg/m2/dose (maximum dose 2.8 mg).  
 
See the special precautions in Section 6.9.4 
 
Etoposide: IV over at least 60-120 minutes 
Days 1-3. 
Dose: 125 mg/m2/dose.  
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if 
hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour) 
(hypotension risk). The use of an in-line filter during the infusion is suggested. 
 
See the special precautions in Section 6.5.4 
 
Prednisone: PO (may be given IV as methylprednisolone) 
Days 1-7. 
Dose: 20 mg/m²/dose PO BID. (Total daily dose is 40 mg/m²/day PO, divided BID). May 
round up to nearest 2.5 mg tablet. If patient is unable to take prednisone by mouth, 
methylprednisolone may be given IV at 80% of the dose. 
 
CYCLE 1 only: Patients who present with need for emergent treatment for respiratory 
distress or spinal cord compression may receive prednisone or dexamethasone for up to 
4 days immediately prior to completion of diagnostic work-up and before other 
chemotherapy agents are given. In these cases, a chest X-ray and if possible, a CT scan of 
the neck, chest, abdomen and pelvis must have been performed and if feasible, a biological 
specimen obtained for definitive diagnosis prior to the administration of prednisone. The 
remainder of the diagnostic work-up should proceed as quickly as tolerated. If oral 
corticosteroids cannot be tolerated, methylprednisolone may be substituted at equipotent 
prednisone doses. The cumulative equipotent dose of glucocorticoids administered for 
emergent respiratory distress or spinal cord compression should be considered part of the 
total 280 mg/m² for this cycle. If methylprednisolone or dexamethasone was used, the dose 
should be converted to prednisone-equivalent dose and this should be considered part of 
the total prednisone dose noted above. 
 
Cyclophosphamide: IV over 30-60 minutes 
Days 1 and 2. 
Dose: 600 mg/m2/dose.  
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to 
avoid hypotonic solution) or further diluted.  
Hydrate according to institutional guidelines. 
Mesna is not required for this dose of cyclophosphamide, but may be administered at 
institutional discretion or with hematuria (see Section 5.2.3). 
 
 

  
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Granulocyte Colony-Stimulating Factor (GCSF) 
Patients should receive either Filgrastim or Pegfilgrastim as outlined below: 
 
Filgrastim: subcutaneous preferred (may be given IV) 
Dose: 5 micrograms/kg/dose daily, beginning Day 4, 5, 6, 7, 8, or Day 9 inclusive, per 
institutional policy, and continuing until ANC > 1000 µL post nadir. Every attempt should 
be made to keep cycles on a 21-day schedule, and therefore stop GCSF by Day 20. 
 
Note: Biosimilar forms of recombinant filgrastim (tbo-filgrastim or filgrastim-sndz) are 
permitted at institutional discretion. 
 
Pegfilgrastim is permitted: Dose: 100 microgram/kg x 1 dose (max 6 mg) on Day 4, 5, 
or 6. 
 
See Section 5.0 for Dose Modifications based on toxicities.  
 
The therapy delivery map (TDM) for standard therapy is on the next page. 
Following completion of Cycle 1, Cycle 2 starts on Day 22 or when ANC  750/L (with 
patients off filgrastim for at least 2 days or 14 days post pegfilgrastim) and platelets are 
 75,000/L (whichever occurs later). 
 
Following the completion of Cycle 2, patients must be assessed to evaluate for 
response (see Section 10.3). All initial eligibility criteria, including definitions of bulk 
and LMA, will be centrally confirmed at this time. THIS RESPONSE EVALUATION 
REQUIRES CENTRAL REVIEW. Cycle 3 of chemotherapy may commence on time, 
and should not be delayed for the central review result. If an enrolled patient is found 
to not meet study eligibility staging criteria at the time of central review for early response 
assessment (after 2 cycles of chemotherapy) the treating institution will be informed and 
the patient will be deemed to be ineligible. 
 
Central review of response and LMA is necessary prior to submission and initiation 
of the radiation therapy plan. Any radiation therapy delivered not consistent with the 
central review response and LMA categorization will be considered a major protocol 
violation.  
 
Following the response assessment at the completion of Cycle 2, therapy starts on Day 22 
or when ANC  750/L (with patients off filgrastim for at least 2 days or 14 days post 
pegfilgrastim) and platelets are  75,000/L (whichever occurs later). All subjects receive 
3 additional cycles of ABVE-PC, unless they have progressive disease or other criteria for 
coming off protocol therapy (see Section 8.1). 
 
Those subjects without initial LMA (see Appendix I) and without any SRL (see 
Table 10.3.1) of disease complete therapy after 3 additional cycles of chemotherapy. 
Patients with initial LMA or any SRL will receive RT (see Section 15) after chemotherapy. 
Patients with progressive disease (see Section 10.3) will go off protocol therapy and will 
be treated at their physician's discretion. Retrieval chemotherapy and stem cell 
transplantation using applicable COG clinical trials should be considered.  
 

  
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4.2.1 Therapy for Patients Randomized to Standard Treatment of ABVE-PC 
There are five cycles of ABVE-PC. Each cycle lasts 21 days. One cycle is described on this therapy 
delivery map. This TDM is on 1 page. Use a copy of this page for each cycle.  
 
_______________________ 
 
___________ 
Patient’s COG ID# 
 
DOB 
Criteria to start each cycle after the initial cycle of therapy: ANC  750/L (with patient off filgrastim for at least 2 days) and platelets are  75,000/L (whichever occurs later). 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
DOXOrubicin 
(DOXO) 
Slow IV push over 1-5 min or 
intermittent infusion over 1-
15 min 
25 mg/m2/dose 
1 and 2 
See Section 4.2 for further details. 
a. Prior to every cycle: History & physical (document 
all involved lymph nodes), CBC/Diff, Electrolytes, 
BUN, Creatinine, AST or ALT, Bili. 
b. Prior to Cycle 3 only: Bilateral bone marrow biopsy 
(only if + at diagnosis, any age), CT with IV contrast, 
and FDG-PET%. 
c. Prior to Cycle 4 only: ECHO (or MUGA), PFTs, and 
DLCO if > 5 yrs. 
d. After Cycle 5 or prior to RT: History & physical 
(document nodal exam), CBC/Diff, Electrolytes, 
BUN, Creatinine, AST or ALT, Bili, Biopsy, Bilateral 
bone marrow biopsy (only if + after Cycle 2, any age), 
CT with IV contrast, and FDG-PET#. 
e. Day 8, Cycles 2 and 5: CIPN/CEA assessments (only 
if enrolled before CIPN/CEA closed to accrual).  
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE. (See Section 7.1) 
See Section 7.2 Biology Studies Submission Schedule. 
If no RT, Cycle 5 reporting period ends 4-6 weeks post 
last therapy dose, after scans (and CEA/CIPN if applicable).  
If RT, Cycle 5 reporting period ends on Day 1 of RT. 
Bleomycin 
(BLEO) 
IV over at least 10 min or SubQ 
5 Units/m2/dose 
1 
See Section 4.2 for further details. 
10 Units/m2/dose 
8 
VinCRIStine 
(VCR) 
IV Push over 1 min (Or infusion 
via minibag as per institutional 
policy). 
1.4 mg/m2/dose 
Maximum dose: 
2.8 mg. 
 
1 and 8 
See Section 4.2 for further details.  
Etoposide 
(ETOP) 
IV over at least 60-120 min 
125 mg/m2/dose 
1-3 
Slow rate of administration if hypotension 
occurs. 
See Section 4.2 for further details. 
Prednisone 
(PRED) 
PO 
20 mg/m2/dose BID 
1-7 
Total Daily Dose: 40 mg/m2/day, divided BID.
IV methylprednisolone may be substituted 
for oral prednisone at 80% of the dose. 
See text specific to Cycle 1 in Section 4.2 
Cyclophosphamide (CPM) 
IV over 30-60 min 
600 mg/m2/dose 
1 and 2 
See Section 4.2 for further details. 
Filgrastim or biosimilar  
(G-CSF)  
 
SubQ preferred  
(may be given IV) 
 
5 mcg/kg/dose 
 
 
Daily, begin Day 
4,5,6,7,8 or 9, per 
institutional 
policy. 
Continue until ANC > 1,000/L post nadir. 
Pegfilgrastim is permitted (100 mcg/kg SubQ 
(max 6 mg) x 1 dose on Day 4, 5 or 6). 
 
Enter Cycle #: _____ 
 
Ht _______ cm 
 
Wt _______ kg 
 
BSA _______ m2 
Date 
Due 
Date 
Given 
Day 
DOXO 
_______ mg 
BLEO 
______ Units 
VCR 
_______ mg 
ETOP 
_______ mg 
PRED (BID dosing) 
_______ mg _______mg 
CPM 
_______ mg 
G-CSF 
_______ mcg 
Studies 
Comment 
 
 
 
Enter calculated dose above and actual dose administered below 
(See Section 7.1) 
 
 
 
1 
_______ mg 
______ Units 
_______ mg 
_______ mg 
_______ mg  _______mg 
_______ mg 
 
a, b%, and c 
 
 
 
2 
_______ mg 
 
 
_______ mg 
_______ mg  _______mg 
_______ mg 
 
 
 
 
 
3 
 
 
 
_______ mg 
_______ mg  _______mg 
 
 
 
 
 
 
4 
 
 
 
 
_______ mg  _______mg 
 
_______ mcg 
 
 
 
 
5 
 
 
 
 
_______ mg  _______mg 
 
_______ mcg 
 
 
 
 
6 
 
 
 
 
_______ mg  _______mg 
 
_______ mcg 
 
 
 
 
7 
 
 
 
 
_______ mg  _______mg 
 
_______ mcg 
 
 
 
 
8 
 
_____ Units 
_______ mg 
 
 
 
_______ mcg 
e (Cycle 2 and 5) 
 
 
 
9 
 
 
 
 
 
 
_______ mcg^ 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
21 
Response is assessed at end of Cycle 2. Cycle 3 should commence on time, and should not be delayed for the central review 
response. The next cycle starts on Day 22 or when ANC  750/L (with patient off filgrastim for at least 2 days) and platelets 
are  75,000/L (whichever occurs later).  
d# 
 
^ Continue G-CSF until ANC > 1,000/µL post nadir. First day of G-CSF: ____/____/____ Last day of G-CSF: ____/____/____ 
Circle Filgrastim or Pegfilgrastim or Tbo-Filgrastim or Filgrastim-sndz 
% Between Days 18-22 of Cycle 2. #Perform PET5 only if PET2 was Deauville ≥4. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE. 
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31
 
4.3 
Experimental Therapy Bv-AVEPC 
 
NOTE: For patients with involvement of the spleen, vaccination against pneumococcus, 
Haemophilus influenza and meningococcus is strongly recommended prior to therapy. If 
not performed at this time, it should be administered prior to beginning radiation therapy. 
Waiting to immunize until after Cycle 5 may be affected by muted immune response at 
that time.  
 
Experimental therapy consists of 5 cycles of Bv-AVEPC. Each cycle is 21 days in duration. 
Each cycle commences on Day 1 if the ANC  750/L and platelets are  75,000/L. The 
administration schedule below describes 1 cycle of Bv-AVEPC and should be repeated for 
each cycle. Steroids as antiemetics are permitted per institutional guidelines. However, the 
use of aprepitant, fosaprepitant, or netupitant/palonosetron in the anti-emetic regimen, 
while not prohibited, should be approached with caution and needs to be documented on 
the CRFs on either study arm. (See Section 4.1.1.3 for additional information). 
 
See the Parenteral Chemotherapy Administration Guidelines (CAGs) on the COG website 
at: https://www.cogmembers.org/_files/disc/Pharmacy/ChemoAdminGuidelines.pdf for 
special precautions and suggestions for patient monitoring during the infusion. As 
applicable, also see the CAGs for suggestions on hydration, or hydrate according to 
institutional guidelines. 
 
Brentuximab vedotin*: IV over 30 minutes  
Day 1 (prior to other chemotherapy) 
Dose: 1.8 mg/kg/dose. (Maximum dose is 180 mg based on manufacturer prescribing 
information and 100 kg maximum weight) 
 
Special precautions: Brentuximab should be administered on Day 1 prior to other 
chemotherapy. Brentuximab vedotin should be administered over approximately 
30 minutes and cannot be mixed with other medications. In-line filters should not be used 
during the IV administration. 
 
*Brentuximab vedotin is supplied by the NCI and should not be dispensed from 
regular (commercial) pharmacy supply. 
 
Dosing is based on patient weight according to the institutional standard. Actual weight 
will be used except for patients weighing greater than 100 kg. The dose for patients with 
weight greater than 100 kg will be calculated based on 100 kg. 
 
Refer to Section 6.1 for additional details regarding dilution and stability. 
 
DOXOrubicin: Slow IV push or intermittent infusion 
Days 1 and 2. 
Dose: 25 mg/m2/dose.  
Administer at a concentration not to exceed 2 mg/mL by slow IV push over 1-5 minutes or 
by intermittent infusion over 1-15 minutes, may prolong to 60 minutes if institutional 
policies mandate. It is suggested that DOXOrubicin be administered through the tubing of 
rapidly infusing solution of D5W or 0.9% NaCl and that it is infused into a large vein. 
 
See special precautions in Section 6.4.4. 
 

  
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32
Etoposide: IV over at least 60-120 minutes 
Days 1-3. 
Dose: 125 mg/m2/dose.  
Infuse diluted solution (concentration ≤ 0.4 mg/mL); slow rate of administration if 
hypotension occurs. Rate should not exceed 300 mg/m2/hour (10 mg/kg/hour) 
(hypotension risk). The use of an in-line filter during the infusion is suggested. 
 
See special precautions in Section 6.5.4. 
 
Prednisone: PO (may be given IV as methylprednisolone) 
Days 1-7. 
Dose: 20 mg/m²/dose PO BID. (Total daily dose is 40 mg/m²/day PO, divided BID). May 
round up to nearest 2.5 mg tablet.  
If patient is unable to take prednisone by mouth, methylprednisolone may be given IV at 
80% of the dose. 
 
CYCLE 1 only: Patients who present with need for emergent treatment for respiratory 
distress or spinal cord compression may receive prednisone or dexamethasone for up to 
4 days immediately prior to completion of diagnostic work-up and before other 
chemotherapy agents are given. In these cases, a chest X-ray and if possible, a CT scan of 
the neck, chest, abdomen and pelvis must have been performed and if feasible, a biological 
specimen obtained for definitive diagnosis prior to the administration of prednisone. The 
remainder of the diagnostic work-up should proceed as quickly as tolerated. If oral 
corticosteroids cannot be tolerated, methylprednisolone may be substituted at equipotent 
prednisone doses. The cumulative equipotent dose of glucocorticoids administered for 
emergent respiratory distress or spinal cord compression should be considered part of the 
total 280 mg/m² for this cycle. If methylprednisolone or dexamethasone was used, the dose 
should be converted to prednisone-equivalent dose and this should be considered part of 
the total prednisone dose noted above. 
 
Cyclophosphamide: IV over 30-60 minutes 
Days 1 and 2. 
Dose: 600 mg/m2/dose.  
May be administered as undiluted drug (20 mg/mL, reconstitute with 0.9% NaCl only to 
avoid hypotonic solution) or further diluted. 
Hydrate according to institutional guidelines. 
Mesna is not required for this dose of cyclophosphamide, but may be administered at 
institutional discretion or with hematuria (see Section 5.2.3). 
 
VinCRIStine: IV push over 1 minute or infusion via minibag as per institutional 
policy 
Day 8 (ONLY) 
Dose: 1.4 mg/m2/dose (maximum dose 2.8 mg).  
 
See special precautions in Section 6.9.4. 
 
 

  
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33
 
Granulocyte Colony-Stimulating Factor (GCSF) 
Patients should receive either Filgrastim or Pegfilgrastim as outlined below: 
 
Filgrastim: subcutaneous preferred (may be given IV) 
Dose: 5 micrograms/kg/dose daily, beginning Day 4, 5, 6, 7, 8 or Day 9, inclusive, per 
institutional policy, and continuing until ANC > 1000 µL post nadir. Every attempt should 
be made to keep cycles on a 2-day schedule, and therefore stop GCSF by day 20. 
 
Note: Biosimilar forms of recombinant filgrastim (tbo-filgrastim or filgrastim-sndz) are 
permitted per institutional policy. 
 
Pegfilgrastim is permitted: Dose: 100 microgram/kg x 1 dose (max 6 mg) on Day 4, 5 or 
6. 
 
See Section 5.0 for Dose Modifications based on toxicities.  
 
The therapy delivery map (TDM) is on the next page. Following completion of Cycle 1, 
Cycle 2 starts on Day 22 or when ANC  750/L (with patients off filgrastim for at least 
2 days or 14 days post pegfilgrastim) and platelets are  75,000/L (whichever occurs 
later). 
 
Following completion of Cycle 2, patients must be assessed to evaluate for response 
(see Section 10.3). All initial eligibility criteria, including definitions of bulk and LMA, 
will be centrally confirmed at this time. THIS RESPONSE EVALUATION 
REQUIRES CENTRAL REVIEW. Cycle 3 of chemotherapy may commence on time, 
and should not be delayed for the central review results of assessment. If an enrolled 
patient is found to not meet study eligibility staging criteria at the time of central review 
for early response assessment (after 2 cycles of chemotherapy) the treating institution will 
be informed and the patient will be deemed to be ineligible. 
 
Central Review of response and LMA is necessary prior to submission and initiation 
of the radiation therapy plan. Any radiation therapy delivered not consistent with the 
central review response and LMA categorization will be considered a major protocol 
violation.  
 
Following the response assessment at completion of Cycle 2, therapy starts on Day 22 or 
when ANC  750/L (with patients off filgrastim for at least 2 days or 14 days post 
pegfilgrastim) and platelets are  75,000/L (whichever occurs later). All subjects receive 
3 additional cycles of Bv-AVEPC, unless they have progressive disease or other criteria 
for coming off protocol therapy (see Section 8.1). 
 
Those subjects without initial LMA (see Appendix I) and without any SRL (see Table 
10.3.1) of disease complete therapy after 3 additional cycles of chemotherapy. Patients 
with initial LMA or any SRL will receive RT (see Section 15) after chemotherapy. Patients 
with progressive disease (see Section 10.3) will go off protocol therapy and will be treated 
at their physician's discretion. Retrieval chemotherapy and stem cell transplantation using 
applicable COG clinical trials should be considered. 
 

  
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34
4.3.1 Therapy for Patients Randomized to Experimental Treatment of Bv-AVE-PC 
There are five cycles of Bv-AVEPC. Each cycle lasts 21 days. One cycle is described on this therapy delivery map. 
This TDM is on 1 page. Use a copy of this page for each cycle.  
 
_______________________ 
 
___________ 
Patient’s COG ID# 
 
DOB 
Criteria to start each cycle: ANC  750/L (with patient off filgrastim for at least 2 days) and platelets are  75,000/L (whichever occurs later). No count criteria for cycle 1 only. 
DRUG 
ROUTE 
DOSAGE 
DAYS 
IMPORTANT NOTES 
OBSERVATIONS 
Brentuximab 
vedotin (BREN) 
Provided by NCI 
IV over 30 minutes 
1.8 mg/kg/dose 
(Max dose 180 mg) 
1 
Give prior to other chemotherapy. Do NOT 
give as IV push. Do not use an in-line filter. 
Do not use commercial supply 
a. Prior to every cycle: History & physical (document 
all lymph nodes), CBC/Diff, Electrolytes, BUN, 
Creatinine, AST or ALT, Bili.  
b. Prior to Cycle 3 only: Bilateral bone marrow biopsy 
(only if + after diagnosis, any age), CT with IV contrast 
and FDG-PET%. 
c. Prior to Cycle 4 only: ECHO or MUGA, PFTs, and 
DLCO if > 5 yrs 
d. After Cycle 5 or prior to RT: History & physical 
(document nodal exam), CBC/Diff, Electrolytes, BUN, 
Creatinine, AST or ALT, Bili, Biopsy, Bilateral bone 
marrow biopsy (only if + after Cycle 2, any age), CT 
with IV contrast, and FDG-PET#.  
e. Day 8, Cycles 2 and 5: CIPN/CEA assessments (only 
if enrolled before CIPN/CEA aim closed to accrual). 
 
OBTAIN OTHER STUDIES AS REQUIRED FOR 
GOOD PATIENT CARE. (See Section 7.1) 
Specimen Submission Schedules: See Section 7.2 for 
Biology Studies; See Section 7.4 for PK Studies as 
relates to Cycles 4 & 5. 
 
If no RT, Cycle 5 reporting period ends 4-6 weeks post last 
therapy dose after scans (and CEA/CIPN if applicable). 
If RT, Cycle 5 reporting period ends on Day 1 of RT. 
DOXOrubicin 
(DOXO) 
Slow IV push over 1-
5 min or intermittent 
infusion over 1-15 min 
25 mg/m2/dose 
1 and 2 
 
Etoposide 
(ETOP) 
IV over at least 60-
120 min 
125 mg/m2/dose 
1-3 
Slow rate of administration if hypotension 
occurs. 
See Section 4.3 for further details. 
Prednisone 
(PRED) 
PO 
20 mg/m2/dose BID 
1-7 
Total Daily Dose: 40 mg/m2/day, divided BID.  
IV methylprednisolone may be substituted for 
oral prednisone at 80% of the dose. 
See text specific to Cycle 1 in Section 4.3. 
Cyclophosphamide 
(CPM) 
IV over 30-60 min 
600 mg/m2/dose 
1 and 2 
See Section 4.3for further details. 
Filgrastim  
or biosimilar 
(G-CSF) 
SubQ preferred  
(may be given IV) 
5 mcg/kg/dose 
Daily, begin on Day 
4,5,6,7,8, or Day 9, per 
institutional policy. 
Continue until ANC > 1,000/L post nadir. 
Pegfilgrastim is permitted (100 mcg/kg SubQ 
(max 6 mg) x 1 dose on Day 4, 5 or 6). 
VinCRIStine 
(VCR) 
IV Push over 1 min (or 
infusion via minibag as 
per institutional policy). 
1.4 mg/m2/dose 
Maximum dose: 2.8 mg. 
 
8 (only) 
 
See Section 4.3 for further details. 
 
Enter Cycle #: _____ 
 
Ht _______ cm 
 
Wt _______ kg 
 
BSA _______ m2 
Date 
Due 
Date 
Given 
Day 
BREN 
_______ mg 
DOXO 
_______ mg 
ETOP 
_______ mg 
PRED (BID dosing) 
_______ mg _______ mg 
CPM 
_______ mg 
G-CSF^ 
_______ mcg 
VCR 
_______ mg 
Studies 
 (See Section 7.1) 
Comment 
 
 
 
Enter calculated dose above and actual dose administered below 
 
 
1 
_______ mg 
_______ mg 
_______ mg 
_______ mg  _______ mg 
_______ mg 
 
 
a, b%, and c 
 
 
 
2 
 
_______ mg 
_______ mg 
_______ mg  _______ mg 
_______ mg 
 
 
 
 
 
 
3 
 
 
_______ mg 
_______ mg  _______ mg 
 
 
 
 
 
 
 
4 
 
 
 
_______ mg  _______ mg 
 
_______ mcg 
 
 
 
 
 
5 
 
 
 
_______ mg  _______ mg 
 
_______ mcg 
 
 
 
 
 
6 
 
 
 
_______ mg  _______ mg 
 
_______ mcg 
 
 
 
 
 
7 
 
 
 
_______ mg  _______ mg 
 
_______ mcg 
 
 
 
 
 
8 
 
 
 
 
 
_______ mcg^ 
_______ mg 
e (Cycle 2 and 5) 
 
 
 
9 
 
 
 
 
 
 
 
 
 
 
 
15 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
d# 
 
 
 
21 
 
 
 
 
 
 
 
 
 
 
 
 
Response is assessed at end of Cycle 2. Cycle 3 should commence on time, and should not be delayed for the central review response. 
The next cycle starts on Day 22 or when ANC  750/L (with patient off filgrastim for at least 2 days) and platelets are  75,000/L (whichever occurs later). 
^ Continue G-CSF until ANC > 1,000/µL post nadir. First day of G-CSF: ____/____/____ Last day of G-CSF: ____/____/____ 
Circle either Filgrastim or Pegfilgrastim or Tbo-filgrastim or Filgrastim-sndz 
% Between Days 18-22 of Cycle 2. # Perform PET5 only if PET2 was Deauville ≥4. SEE PROTOCOL SECTION 5.0 FOR DOSE MODIFICATIONS. SEE COG MEMBER WEB SITE FOR SUPPORTIVE CARE 
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35
5.0 
DOSE MODIFICATIONS FOR TOXICITIES 
 
5.1 
Dose Modifications for Brentuximab Vedotin  
 
Treatment Modification Guidelines for brentuximab vedotin-related Adverse Events are 
outlined in the tables below. 
 
Dose Level 
Dose 
Starting Dose 
1.8 mg/kg (max dose 180 mg) 
Dose Reduction for Toxicity #1 
1.2 mg/kg (max dose 120 mg) 
Dose Reduction for Toxicity #2 
0.8 mg/kg (max dose 80 mg) 
 
Event 
CTCAE v5.0 
Grade 
Action to be Taken 
Allergic 
reactions,  
or  
Acute infusional 
reactions/ 
cytokine release 
syndrome 
Grade 1 
• Continue at same dose level. 
Grade 2 
 
For first reaction: 
• Hold the infusion and wait 30 to 60 minutes (depending upon 
the reaction severity). 
• Treat reactions with oral diphenhydramine 1 mg/kg (max 
50 mg), or follow local institution guidelines. Depending on 
the reaction severity, dexamethasone 0.2 mg/kg (max 10 mg) 
or equivalent corticosteroid oral should be used. 
• Upon resolution of the symptoms, at the physician’s 
discretion, it may be possible to resume treatment by 
administering an H2 blocker such as ranitidine or famotidine 
approximately 30 minutes before restarting the infusion. 
Acetaminophen can also be considered. Resume  
brentuximab vedotin infusion at half the previously 
administered rate until completion 
For subsequent doses:  
• Utilize diphenhydramine with or without acetaminophen as 
pre-treatment for all subsequent infusions. 
• Dosing should be administered over the shortest period that 
was well tolerated. 
If Grade 2 infusion reactions recur despite the above measures, 
either during re-challenge or subsequent treatments: 
• Take the measures outlined above. 
• With subsequent dosing, add dexamethasone 0.2 mg/kg (max 
10 mg) IV or equivalent to medications above prior to 
infusion. 
Grade 3 
• Stop infusion immediately. 
• Administer diphenhydramine 1 mg/kg IV (max 50 mg), 
dexamethasone 0.2 mg/kg (max 10 mg) IV (or equivalent), 
bronchodilators for bronchospasms, and other medications as 
medically indicated. 
• Once symptoms recover, brentuximab vedotin should not be 
resumed for that cycle. 
• Subsequent cycles of brentuximab vedotin may be considered 
at physicians’ discretion, after a discussion and approval by 
CTEP.  

  
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Event 
CTCAE v5.0 
Grade 
Action to be Taken 
• All subsequent infusions should use the following 
premedications prior to infusion: acetaminophen, 
diphenhydramine 1 mg/kg IV (max 50 mg), dexamethasone 
0.2 mg/kg (max 10 mg) IV (or equivalent). In addition, the 
infusion should be administered at 50% of the previous 
infusion rate. 
Grade 4 
• Stop infusion immediately. 
• Administer diphenhydramine 1 mg/kg (max 50 mg) IV, 
dexamethasone 0.2 mg/kg (max 10 mg) IV (or equivalent), 
and other anaphylaxis medications as indicated. 
• Epinephrine or bronchodilators should be administered as 
indicated. 
• Hospital admission for observation may be indicated. 
• Permanently discontinue brentuximab vedotin. 
Anaphylaxis 
Any Grade 
• If anaphylaxis occurs, immediately and permanently 
discontinue administration of brentuximab vedotin and 
administer appropriate medical therapy. 
Pancreatitis 
Grade 2 
• Withhold dose until toxicity has returned to baseline, then 
continue on protocol therapy but should resume at one dose 
reduction. 
• If Grade 2 pancreatitis recurs after one dose reduction, the 
patient must be removed from protocol therapy. 
Grade 3-4 
• Permanently discontinue brentuximab vedotin. 
Peripheral Neuropathy 
 
Investigational Arm 
The investigational arm of this protocol incorporates two agents with 
potential peripheral neuropathic toxicity. Dose modifications for 
peripheral neuropathy are determined by the day of treatment cycle, and 
are designed to maintain brentuximab vedotin dose intensity as much 
as possible, at the expense of vincristine dose intensity. The modified 
Balis scale (see Appendix IV) of peripheral neuropathy is to be used to 
assign a grade of neuropathy. 
 
Dose Level 
Dose 
Starting Dose 
1.8 mg/kg  
(max dose 180 mg) 
Dose Reduction 
for Toxicity #1 
1.2 mg/kg  
(max dose 120 mg) 
Dose Reduction 
for Toxicity #2 
0.8 mg/kg  
(max dose 80 mg) 
 
 
 

  
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37
Event 
CTCAE v.5.0 
Grade 
Action to be Taken 
Peripheral Neuropathy 
 
*Grades are per the 
Modified Balis scale in 
Appendix IV 
Grade 1* 
Continue at same dose level. 
Grade 2* 
 
Day 1 
• Continue Brentuximab vedotin at same dose level. 
Day 8 vincristine of this cycle should be dose reduced to 
1 mg/m2 (max 2 mg), or held if already dose reduced on 
a prior cycle. Increase vincristine to full dose with next 
cycle if neuropathy improves to ≤ Grade 1. 
Day 8 
• Decrease vincristine to 1 mg/m2 (max 2 mg). If 
neuropathy has improved to ≤ Grade 1 by Day 8 of the 
next cycle, then resume vincristine at full dose. 
Grade 3* 
 
Day 1 
• Treatment should be delayed up to 1 week after all 
other parameters to proceed are met to see if 
neuropathy improves to ≤ Grade 2. If neuropathy 
returns to ≤ Grade 2 then proceed with next cycle and 
reduce brentuximab vedotin by one dose level (see 
above). If neuropathy remains Grade 3, then 
brentuximab vedotin should be held for this cycle and 
then reduced by one dose level for subsequent 
treatments assuming neuropathy has returned 
to ≤ Grade 2. 
• Day 8 vincristine should be held for this and all 
subsequent cycles. 
• Patients who develop Grade 3 neuropathy after 2 dose 
reductions of brentuximab vedotin, will have 
brentuximab vedotin discontinued. 
• If treatment has to be delayed for peripheral 
neuropathy more than once, then brentuximab vedotin 
should be held for the remainder of treatment. 
Day 8 
• Hold vincristine for this and all subsequent cycles. 
Grade 4* 
• Discontinue brentuximab vedotin and vincristine. 
Pneumonitis 
Grade 1 
• Continue at same dose level. 
Grade 2 
• If suspected, strongly consider administration of oral 
or intravenous corticosteroid in single daily or two 
divided doses. The suggested dose for patients who 
develop pulmonary toxicity is methylprednisolone 
1 mg/kg IV every 12 hours for a minimum of seven 
days. 
Grade 3-4 
• If suspected, strongly consider administration of oral 
or intravenous corticosteroid in single daily or two 
divided doses. The suggested dose for patients who 
develop pulmonary toxicity is methylprednisolone 
1 mg/kg IV every 12 hours for a minimum of seven 
days. 
• Discontinue brentuximab vedotin. 

  
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38
Event 
CTCAE v.5.0 
Grade 
Action to be Taken 
Progressive Multifocal 
Leukoencephalopathy 
(PML) 
 
(Grade per 
“Leukoencephalopathy”) 
Any Grade 
If PML is suspected, a diagnostic work-up should be 
performed. The work-up may include, but not limited to, the 
following: 
• Neurologic examinations and neurology consultation, 
as warranted. 
• Brain MRI. Features suggestive of PML include 
presence of unifocal or multifocal lesions, mainly of 
the white matter, that are typically non-enhancing and 
do not have mass effect. 
• PCR analysis. JCV DNA, detectable in CSF or in a 
brain biopsy, is suggestive of PML. 
Brentuximab vedotin dosing should be held if any grade of 
PML is suspected.  
If PML is confirmed, brentuximab vedotin should be 
permanently discontinued. 
The study chair and CRA should be notified of any case of 
PML within 48 hours 
Lymphopenia 
Grade 1-4 
• Continue at same dose level. 
Neutropenia 
Grade 1-2 
• Continue at same dose level. 
Grade 3-4  
• Patients who are unable to start a cycle > 35 days after 
the start of the previous cycle (> 14 day delay) with 
myeloid growth factor support due to neutropenia with 
no other dose-limiting toxicity should have 
brentuximab vedotin reduced by 1 dose level. 
Thrombocytopenia 
Grade 1-2 
• Continue at same dose level. 
Grade 3-4 
• Thrombocytopenia is expected on this protocol. 
Continue at current dose level. 
Non-hematologic events 
(not including electrolyte 
abnormalities) 
Grade 1-2 
• Continue at same dose level. 
Grade 3-4 
• Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline, then continue on protocol therapy 
but should resume at one dose reduction. 
• If same non-hematological Grade 3-4 toxicity recurs 
after one dose reduction, brentuximab vedotin should 
be omitted. 
Electrolyte Abnormalities Grade 1-4 
• Continue at same dose level, provided electrolyte 
toxicity is not medically consequential and has been 
readily corrected. 
• If electrolyte abnormality is medically consequential, 
refer to guidelines above for non-hematologic events. 
 
 
 

  
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5.2 
Dose Modifications for Commercial Agents 
 
5.2.1 
Hematologic Toxicity 
Full dose chemotherapy should begin on Day 22 if the ANC ≥ 750/L (with patient 
off G-CSF for at least 2 days before a cycle of chemotherapy) and platelets are 
≥ 75,000/L. If a patient has not recovered by Day 22, resume chemotherapy as soon 
as hematological recovery is documented (ANC ≥ 750/L, platelets ≥ 75,000L).  
 
5.2.2 
Hepatic Toxicity 
If patient has direct bilirubin > 1.5x upper limit of normal (ULN) when 
chemotherapy is due to be given, hold. Resume chemotherapy when direct 
bilirubin is < 1.5x ULN.  
 
5.2.3 
Hematuria 
Microscopic hematuria 
For transient microscopic hematuria (no more than 2 abnormal urinalyses on 
2 separate days during a cycle of therapy), do not modify the cyclophosphamide 
dose. Administer with increased hydration (3500 - 4000 mL/m2/day) using a total 
daily mesna dose equal to 60% of the daily cyclophosphamide dose. 
 
For persistent microscopic hematuria (more than 2 abnormal urinalyses during a 
cycle of therapy), do not modify the cyclophosphamide dose. Administer with 
increased hydration (3500 - 4000 mL/m2/day) using a total daily mesna dose equal 
to 100% of the daily cyclophosphamide dose. 
 
Note: Document mesna doses in the comments of the Therapy Delivery Map. 
 
5.2.4 
Gross hematuria 
All episodes of gross hematuria should be evaluated in conjunction with a pediatric 
surgical consult. Further testing, such as cystoscopy, urine culture, excretory 
urogram, and voiding cystogram should be considered based on good clinical 
judgment. 
 
For transient gross hematuria (only 1 episode, which clears to less than gross 
hematuria) during or following a cycle of therapy, hold cyclophosphamide until 
hematuria clears. When hematuria clears, restart at 50% of the previous 
cyclophosphamide dose. Use hydration of 3500 - 4000 mL/m2/day and mesna at 
100% the cyclophosphamide dose as a continuous infusion over 24 hrs. The 
cyclophosphamide dose may be escalated back to 100%, if tolerated, and mesna 
given at 100% as continuous infusion. 
 
For persistent gross hematuria after completion of a cycle of therapy, hold 
subsequent cyclophosphamide doses until the urine clears to less than gross 
hematuria. Reinstitute cyclophosphamide at 50% of initial dose, with hydration of 
3500 - 4000 mL/m2/day and the mesna at 100% of the cyclophosphamide dose 
given as a continuous infusion over 24 hours. If this regimen is tolerated, 
cyclophosphamide dose may be escalated back to the original (100%) dose and 
mesna given at 100% as continuous infusion during cyclophosphamide doses. 
 

  
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For persistent or recurrent gross hematuria on the mesna continuous infusion 
regimen, discontinue cyclophosphamide. 
 
5.2.5 
Pulmonary 
If DLCO (corrected for anemia) in any diffusion capacity test is < 50% of the 
initial value or predicted value or if both DLCO and FEV/FVC show rapid parallel 
decrease, obtain blood gases, discontinue further bleomycin. 
 
In patients unable to cooperate with PFTs, bleomycin should be discontinued if 
patient is symptomatic (respiratory distress with rest or minimal exertion) or 
O2 sat < 92%. 
 
5.2.6 
Cardiac 
Patients will get an echocardiogram (or MUGA) following 3 cycles of 
chemotherapy. If the fractional shortening is < 28% (or the ejection fraction is 
< 50%), or the lower limit of institutional normal on 2 successive echocardiograms 
(or MUGAs) at least a week apart, the doxorubicin in subsequent cycles should be 
held. If, at any time, the patient develops signs and symptoms of congestive heart 
failure (e.g., pulmonary or peripheral edema, dyspnea on exertion, poor feeding, 
increased liver size, deterioration in exercise tolerance or Grade IV cardiac 
toxicity) or prolongation of QTc, that are not attributable to other causes such as 
sepsis or renal failure, hold doxorubicin and perform repeat ECG and 
echocardiogram (or MUGA) prior to next planned cycle. 
 
5.2.7 
Peripheral Neurotoxicity 
Toxicity grading of neurotoxicity is to be based on the modified Balis scale of 
peripheral neuropathy (See Appendix IV). 
 
Dose modifications of vincristine dosing in the experimental arm (Bv-AVEPC) 
arm should be as per Section 5.1, and are notably different than the standard arm 
(ABVE-PC). 
 
Standard arm only: The modified Balis scale (see Appendix IV) of peripheral 
neuropathy is to be used to assign a grade of neuropathy. Vincristine should be 
held or reduced only for incapacitating neurotoxicity (e.g., ≥ Grade 3 by Balis 
Scale). Vincristine can be resumed when the symptoms have improved to Grade 1 
toxicity or completely resolved. If held, the subsequent dose will be given at a 25% 
dose reduction (maximum dose 2.1 mg). Neuropathy ≥ Grade 2 needs to be 
reported even if no dose modification is made on the standard arm 
(See Section 11.5.4 and 11.12). 
 
5.2.8 
Constipation 
Constipation or ileus (≥ Grade 3) or typhlitis: Hold vincristine dose(s); institute 
aggressive regimen to treat constipation if present. When symptoms improve to 
Grade 1 toxicity or less resume vincristine at 25% dose reduction (maximum dose: 
2.1 mg); escalate to full dose with subsequent courses as tolerated. 
 
5.2.9 
Hypersensitivity Reaction to Etoposide 
If with any dose, patient exhibits signs or symptoms of hypersensitivity reaction 
(HSR) in relation to administration of etoposide the infusion should be 

  
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discontinued and appropriate treatment per institutional guidelines initiated. If 
additional doses of etoposide are scheduled for the patient to complete therapy, 
etoposide phosphate (Etopophos) should be substituted at equivalent doses. 
Pretreatment will consist of patient’s first morning scheduled treatment prednisone 
dose and diphenhydramine 1 mg/kg IV or PO (maximum 50 mg). Appropriate 
monitoring for HSR signs or symptoms should be instituted during the etoposide 
phosphate infusion with emergency anaphylactic treatment available. Drug 
administration should be discontinued and appropriate treatment instituted should 
a reaction also occur with this product. No further doses of etoposide or etoposide 
phosphate should be attempted.  
 
5.2.10 Hypersensitivity Reaction (HSR) to Bleomycin 
If with any dose, patient exhibits signs/symptoms of HSR in relation to 
administration of bleomycin, the infusion should be discontinued and appropriate 
treatment per institutional guidelines initiated. If additional doses of bleomycin are 
scheduled for the patient to complete therapy, pretreatment will consist of 
diphenhydramine 1 mg/kg IV or PO (maximum 50 mg), and giving the last (14th) 
dose of prednisone on the morning of Day 8 concurrent with the Day 8 bleomycin. 
Appropriate monitoring for HSR signs/symptoms should be instituted during the 
bleomycin infusion with emergency anaphylactic treatment available. Drug 
administration should be discontinued and appropriate treatment instituted should 
a reaction also occur. No further doses of bleomycin should be attempted. 
 
 
6.0 
DRUG INFORMATION  
Please see Appendix X for known drug interactions associated with the drugs used in this study. 
 
6.1 
BRENTUXIMAB VEDOTIN  
 
 
 
 
(04/03/2019) 
(SGN-35, AdcetrisTM, NSC#749710)  
 
6.1.1  Source and Pharmacology  
Brentuximab vedotin is a CD30-directed antibody-drug conjugate (ADC) 
consisting of three components: the chimeric IgG1 antibody cAC10, specific for 
human CD30, the microtubule disrupting agent MMAE, and a protease-cleavable 
linker that covalently attaches MMAE to cAC10. Approximately 4 molecules of 
MMAE are attached to each antibody molecule. Brentuximab vedotin is produced 
by chemical conjugation of the antibody and small molecule components. The 
antibody is produced by mammalian (Chinese hamster ovary) cells, and the small 
molecule components are produced by chemical synthesis. Brentuximab vedotin 
has an approximate molecular weight of 153 kDa. 
 
Brentuximab vedotin consists of a chimeric IgG1 antibody directed against CD30 
and a small molecule (MMAE) microtubule disrupting agent, which is covalently 
attached to the antibody via a linker. Nonclinical data suggest that the anticancer 
activity of brentuximab vedotin is due to the binding of the ADC to CD30-
expressing cells, subsequent internalization of the ADC-CD30 complex, and 
release of MMAE via proteolytic cleavage. Binding of MMAE to tubulin disrupts 
the microtubule network within the cell, subsequently inducing cell cycle arrest 
and apoptotic death of the cells. 
 

  
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Binding of MMAE (in vitro) to human plasma proteins ranged from 68-82% and 
thus MMAE is not likely to displace or to be displaced by highly protein-bound 
drugs. In vitro, MMAE was a substrate of P-gp but not a potent inhibitor of P-gp. 
In vivo data suggest that a small fraction of MMAE released from brentuximab 
vedotin is metabolized. In vitro data indicates that the active metabolite of 
brentuximab vedotin, monomethyl auristatin E (MMAE) is a substrate and an 
inhibitor of CYP3A4 but is neither a sensitive substrate nor a strong 
inhibitor/inducer of CYP3A4. However, patients should be monitored for potential 
drug-interaction when administered drugs known to be a strong CYP 3A4 
inhibitor/inducer with brentuximab vedotin. In vitro, MMAE is a substrate of P-gp 
transporter and is not an inhibitor of P-gp. See Appendix III for a list of CYP3A4 
inducers and inhibitors. 
 
MMAE appeared to follow metabolite kinetics, with the elimination of MMAE 
appearing to be limited by its rate of release from ADC. Approximately 24% of 
the total MMAE administered as part of the ADC during a brentuximab vedotin 
infusion (at 1.8 mg/kg) was recovered in both urine and feces over a 1-week period. 
Of the recovered MMAE, approximately 72% was recovered in the feces and the 
majority of the excreted MMAE was unchanged. 
 
6.1.2  Toxicity 
 
Comprehensive Adverse Events and Potential Risks list (CAEPR) 
for 
SGN-35 (brentuximab vedotin, NSC 749710) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single list of reported 
and/or potential adverse events (AE) associated with an agent using a uniform presentation of events by 
body system. In addition to the comprehensive list, a subset, the Specific Protocol Exceptions to 
Expedited Reporting (SPEER), appears in a separate column and is identified with bold and italicized 
text. This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to expedited 
reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pdf 
for further clarification. Frequency is provided based on 798 patients. Below is the CAEPR for SGN-35 
(brentuximab vedotin).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses next to the 
AE in the SPEER.  If this CAEPR is part of a combination protocol using multiple investigational 
agents and has an AE listed on different SPEERs, use the lower of the grades to determine if 
expedited reporting is required. 
      Version 2.5, February 13, 20191 
 
 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
 
 Colitis2 
  

  
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 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
 
 Enterocolitis 
  
 
 
Gastrointestinal hemorrhage3 
  
 
 
Gastrointestinal obstruction4 
  
 
 
Gastrointestinal perforation5 
  
 
 
Gastrointestinal ulcer6 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatotoxicity)7 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
  
  
Upper respiratory infection 
 
 Upper respiratory infection (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
Neutrophil count 
decreased 
 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Muscle cramp 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 
 
Pain in extremity 
 
  

  
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 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
 
 
Nervous system disorders - 
Other (progressive multifocal 
leukoencephalopathy) 
  
 
Paresthesia 
 
  
 
Peripheral motor neuropathy 
 
 Peripheral motor neuropathy (Gr 2) 
Peripheral sensory 
neuropathy 
 
 
 Peripheral sensory neuropathy (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
Oropharyngeal pain 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(pulmonary toxicity)8 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Hyperhidrosis 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to all 
Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent should 
be included in the e-mail. 
 
2Colitis may also include the term neutropenic colitis. 
 
3Fatal and/or serious gastrointestinal hemorrhages have been observed in SGN-35 (brentuximab vedotin) 
treated patients. Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, Colonic 
hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices hemorrhage, Gastric 
hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal hemorrhage, Jejunal 
hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under the 
GASTROINTESTINAL DISORDERS SOC. 
 
4Fatal and/or serious gastrointestinal obstructions have been observed in SGN-35 (brentuximab vedotin) 
treated patients. Gastrointestinal obstruction includes Colonic obstruction, Duodenal obstruction, 
Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal obstruction, 
Small intestinal obstruction, and other sites under the GASTROINTESTINAL DISORDERS SOC. 
 

  
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5Fatal and/or serious gastrointestinal perforations have been observed in SGN-35 (brentuximab vedotin) 
treated patients.  Gastrointestinal perforation includes Colonic perforation, Duodenal perforation, 
Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal perforation, and 
Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  Lymphoma with 
preexisting GI involvement may increase the risk of perforation. 
 
6Fatal and/or serious gastrointestinal ulcers have been observed in SGN-35 (brentuximab vedotin) treated 
patients.  Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, Esophageal ulcer, 
Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under the 
GASTROINTESTINAL DISORDERS SOC. 
 
7Hepatotoxicity may manifest as increased ALT/AST, bilirubin, alkaline phosphatase, and/or GGT. 
 
8Pulmonary toxicity, which may manifest as pneumonitis, interstitial lung disease, or adult respiratory 
distress syndrome (ARDS), has been observed in patients treated in brentuximab vedotin monotherapy 
trials as well as in combination with bleomycin. 
 
 
Adverse events reported on SGN-35 (brentuximab vedotin) trials, but for which there is 
insufficient evidence to suggest that there was a reasonable possibility that SGN-35 (brentuximab 
vedotin) caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system disorders - Other 
(lymphadenopathy) 
CARDIAC DISORDERS - Myocardial infarction; Pericardial effusion; Sinus tachycardia 
GASTROINTESTINAL DISORDERS - Dyspepsia; Esophagitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Non-cardiac chest pain 
INFECTIONS AND INFESTATIONS - Meningitis; Pharyngitis; Sepsis; Shingles; Sinusitis; Skin infection; 
Soft tissue infection; Thrush; Urinary tract infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; Carbon monoxide diffusing capacity 
decreased; Creatinine increased; Lipase increased; Lymphocyte count decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; Hyperkalemia; 
Hypertriglyceridemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; Hypokalemia; Hypomagnesemia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; Generalized muscle 
weakness; Myositis; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) - 
Myelodysplastic syndrome 
NERVOUS SYSTEM DISORDERS - Dysesthesia; Encephalopathy; Nervous system disorders - Other 
(demyelinating polyneuropathy); Seizure; Syncope 
PSYCHIATRIC DISORDERS - Depression 
RENAL AND URINARY DISORDERS - Acute kidney injury; Renal and urinary disorders - Other 
(pyelonephritis) 
REPRODUCTIVE SYSTEM AND BREAST DISORDERS - Irregular menstruation; Reproductive system 
and breast disorders - Other (groin pain) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - Adult respiratory distress syndrome8; 
Pleural effusion8; Pneumothorax8; Productive cough; Respiratory failure; Respiratory, thoracic and 
mediastinal disorders - Other (bronchitis) 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Dry skin 
VASCULAR DISORDERS - Hot flashes; Hypertension; Hypotension; Thromboembolic event 
 
 
Note: SGN-35 (brentuximab vedotin) in combination with other agents could cause an exacerbation of 
any adverse event currently known to be caused by the other agent, or the combination may result in 
events never previously associated with either agent. 

  
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6.1.3 
Formulation and Stability  
Brentuximab vedotin is supplied as a sterile, white to off-white preservative-free 
lyophilized cake or powder in individually-boxed single-use vials containing 
50 mg brentuximab vedotin per vial. Store vial dry under refrigeration at 2-8°C 
(36-46°F) in the original carton to protect from light until reconstitution and use. 
The stability testing of the intact vials is ongoing. Reconstituted agent must be 
diluted and administered within 24 hours. 
 
CAUTION: The single-use lyophilized dosage form contains no antibacterial 
preservatives. Therefore, the reconstituted product (from Step 1) should be 
discarded within 8 hours after initial entry/puncture. Use appropriate aseptic 
technique for reconstitution and preparation of dosing solutions. 
 
Preparation consists of 2 steps: dilution of the stock solution and dilution of the final 
solution. 
 
Step 1: Make a 5 mg/mL concentration. Use vials from the same Lot number 
for each dose. 
1. Reconstitute the 50 mg lyophilized powder brentuximab vedotin with 10.5 mL 
Sterile Water for Injection, USP. Final concentration is 5 mg/mL (Note: total 
volume is 11 mL). 
2. Swirl the vial gently. Do not shake. 
3. Let the reconstituted vial settle for one minute to eliminate bubbles. The 
reconstituted solution should be colorless, clear to slightly opalescent and should 
NOT have visible particulates. 
4. Store the reconstituted vial under refrigeration (2° – 8° C) and protect from light 
if not used immediately. Discard after 8 hours. 
 
Step 2: Further dilute the IV solution. 
1. Withdraw the calculated amount of drug from the 5 mg/mL reconstituted vial in 
step 1. 
2. Inject the required amount of drug into 0.9% NS, Lactated Ringer’s Solution, 
USP, or dextrose 5% in Water (D5W), USP to a final concentration between 
0.4 – 1.8 mg/mL.  
3. Brentuximab vedotin solution is compatible in polyvinylchloride (PVC), 
ethylene vinyl acetate (EVA), polyolefin, or polyethylene. 
4. Do not shake. Gently invert the bag (or syringe) to mix. 
5. The prepared IV bag (or syringe) is to be stored at refrigeration (2° – 8° C) and 
must be used within 24 hours of initial product reconstitution (or sooner per 
institutional practice for agents without a preservative). Protect the prepared IV 
solution from direct sunlight if not used immediately. 
6. Prior to administration, inspect the IV bag (or syringe) for discoloration or 
floating particulates. Do not use the IV solution if the solution is discolored or/and 
have particulates. 
 
6.1.4 
Guidelines for Administration  
See Treatment and Dose Modifications sections of the protocol.  
 

  
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Infuse the prepared IV solution over 30 minutes. Do not mix with other 
medications. Do not administer as an IV push or bolus. Do not use an in-line filter 
for the IV administration. The IV bag (or syringe) does NOT need light protection 
during the IV administration. 
 
6.1.5 
Supplier  
Supplied by Seattle Genetics, Inc. and the Division of Cancer Treatment and 
Diagnosis (DCTD), NCI. Do NOT use commercial supply. 
 
6.1.6  Obtaining the Agent 
Agent Ordering  
NCI supplied agents may be requested by the eligible participating investigator (or 
their authorized designee) at each participating institution. The CTEP assigned 
protocol number must be used for ordering all CTEP supplied investigational 
agents. The responsible investigator at each participating institution must be 
registered with CTEP, DCTD through an annual submission of FDA form 1572 
(Statement of Investigator), NIH Biosketch, Agent Shipment Form, and Financial 
Disclosure Form (FDF). If there are several participating investigators at one 
institution, CTEP supplied investigational agents for the study should be ordered 
under the name of one lead participating investigator at that institution. 
 
6.1.7  Clinical Drug Request 
Submit agent requests through the PMB Online Agent Order Processing (OAOP) 
application. Access to OAOP requires the establishment of a CTEP Identity and 
Access Management (IAM) account and the maintenance of an “active” account 
status and a “current” password, and active person registration status. For questions 
about drug orders, transfers, returns, or accountability call or email PMB any time. 
Refer to the PMB’s website for specific policies and guidelines related to agent 
management. 
 
6.1.8  Agent Accountability 
Agent Inventory Records 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the receipt, dispensing and final disposition of all 
agents received from the PMB using the appropriate NCI Investigational Agent 
(Drug) Accountability Record (DARF) available on the CTEP forms page. Store 
and maintain separate NCI Investigational Agent Accountability Records for each 
agent, strength, formulation and ordering investigator on this protocol. 
 
6.1.9 
Investigator Brochure Availability 
The current version(s) of the IB(s) for the agent will be accessible to site 
investigators and research staff through the PMB Online Agent Order Processing 
(OAOP) application. Access to OAOP requires the establishment of a CTEP IAM 
account and the maintenance of an “active” account status, a “current” password, 
and active person registration status. Questions about IB access may be directed to 
the PMB IB coordinator via email. 
 
6.1.10 Useful Links and Contacts 
• 
CTEP Forms, Templates, Documents: http://ctep.cancer.gov/forms/ 

  
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• 
NCI CTEP Investigator Registration: RCRHelpDesk@nih.gov 
• 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm 
• 
PMB Online Agent Order Processing (OAOP) application: 
https://ctepcore.nci.nih.gov/OAOP   
• 
CTEP Identity and Access Management (IAM) account: 
https://ctepcore.nci.nih.gov/iam/   
• 
CTEP IAM account help: ctepreghelp@ctep.nci.nih.gov  
• 
PMB email: PMBAfterHours@mail.nih.gov  
• 
IB Coordinator: IBCoordinator@mail.nih.gov   
• 
PMB phone and hours of service: (240) 276-6575 Monday through Friday 
between 8:30 am and 4:30 pm (ET) 
 
6.2 
BLEOMYCIN  
 
 
 
 
 
 
(05/06/11) 
(Bleomycin Sulfate, Blenoxane® Bleocin®, Bleocris®, Bleolem®, Bleomicina®, 
Cytorich®) NSC #125066 
 
6.2.1 
Source and Pharmacology 
Bleomycin is a mixture of cytotoxic glycopeptide antibiotics isolated from a strain 
of Streptomyces verticillus. Of the thirteen identifiable fractions, the main 
components are bleomycin A2 and B2. A DNA-binding region and an iron-binding 
region are present at opposite ends of the molecule. The cytotoxic effects of 
bleomycin result from the formation of oxygen free radicals, which then cause 
single- and double-strand DNA breaks. Bleomycin-mediated DNA damage 
requires the presence of a redox-active Fe2+ metal ion in the presence of oxygen to 
generate the activated free radical species. Recently it has also become apparent 
that bleomycin mediates the oxidative degradation of all major classes of cellular 
RNAs. The effects of bleomycin are cell cycle specific, as its major effects are 
mediated in the G2 and M phases of the cell cycle.  
 
In animal studies, high concentrations of bleomycin are found in the skin, lungs, 
kidneys, peritoneum, and lymphatics. Tumor cells of the skin and lungs have also 
been found to have high concentrations of bleomycin in contrast to the low 
concentrations found in hematopoietic tissue. The low concentrations of 
bleomycin found in bone marrow may be related to high levels of bleomycin 
degradative enzymes found in that tissue. After IV administration of 15 units/m2 
bleomycin, there is a rapid biphasic disappearance from the circulation. The initial 
distribution half-life is on the order of 10 to 20 minutes, whereas the terminal half-
life is in the range of 2 to 3 hours. Bleomycin is absorbed rapidly after IM injection, 
and peak blood levels approximately one-third to one-half those achieved after an 
IV dose are usually reached in 30 to 60 minutes. In patients with normal renal 
function, 60% to 70% of an administered dose is recovered in the urine as active 
bleomycin. In patients with a creatinine clearance of < 35 mL/min, the plasma or 
serum terminal elimination half-life increases exponentially as the creatinine 
clearance decreases. It was reported that patients with moderately severe renal 
failure excreted less than 20% of the dose in the urine.  

  
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Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
High fever (L), chills 
Rash (usually in pressure 
points) (L) 
Idiosyncratic reaction similar to 
anaphylaxis (hypotension, mental 
confusion, fever, chills, and wheezing), 
angioedema, nausea, vomiting, phlebitis, 
pain at tumor site, malaise 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Raynaud’s phenomenon, 
hyperpigmentation (with 
pruritus and scratching), 
mucositis 
Taste impairment, 
anorexia, weight loss 
Alopecia, onycholysis (dystrophy, 
shedding, thickening of the nail bed, and 
darkening of the nail cuticle), 
thrombocytopenia 
Delayed: 
Any time later 
during therapy, 
excluding the above 
conditions 
 
Pneumonitis (dose 
dependent) (L) 
Dyspnea, fine rales, pulmonary fibrosis 
(dose dependent – increased in 
combination with XRT and/or O2 resulting 
rarely in death) (L), scleroderma-like skin 
changes, in combination with other 
chemotherapy agents: coronary artery 
disease, myocardial infarction, arterial 
thrombosis, cerebrovascular accidents  
Unknown 
Frequency and 
Timing 
Fetal toxicities and teratogenic effects of bleomycin have been noted in animals. Administration 
of intraperitoneal doses of 1.5 mg/kg/day to rats (about 1.6 times the recommended human dose 
on a unit/m² basis) on Days 6-15 of gestation caused skeletal malformations, shortened 
innominate artery and hydroureter. Bleomycin is abortifacient but not teratogenic in rabbits, at IV 
doses of 1.2 mg/kg/day (about 2.4 times the recommended human dose on a unit/m² basis) given 
on gestation Days 6-18. It is unknown whether the drug is excreted in breast milk. 
(L) Toxicity may also occur later. 
 
6.2.2 
Formulation and Stability 
Available in 15 and 30 unit vials as bleomycin sulfate, a white or yellowish lyophilized 
powder. The sterile powder is stable under refrigeration, 2°-8°C (36°-46°F). 
 
Note: Bleomycin vials in the US are labeled as containing 15 or 30 units (also called 
USP units). Some countries outside of the US use bleomycin products that are 
labeled with international units (IU). Each USP unit is equivalent to 
1000 international units (i.e., 15 USP units=15,000 international units). Therefore, it 
is important to check the labeling of the product before compounding the dose. 
 
6.2.3 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 
 
For IV administration: reconstitute to a concentration of ≤ 3 units/mL with NS. 
For SubQ administration: reconstitute to a concentration of 3-15 units/mL with NS. 
 
Bleomycin should not be reconstituted or diluted with D5W or other dextrose 
containing diluents. When reconstituted in D5W and analyzed by HPLC, 
bleomycin demonstrates a loss of A2 and B2 potency that does not occur when 
reconstituted in NS. When reconstituted with solutions, bleomycin is stable for 
24 hours at room temperature. 
 

  
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6.2.4 
Special Precautions 
Test dose: it is recommended by the manufacturer because of the possibility of an 
idiosyncratic reaction similar to anaphylaxis that occurred in approximately 1% of 
lymphoma patients. Lymphoma patients may receive a test dose of 2 units or less 
IV or subcutaneously for the first 2 doses. Following administration of the test 
dose, consider monitoring of vital signs every 15 minutes for at least 1 hour and if 
no acute reaction occurs, the full dose may be given. Note: test doses may produce 
a false negative result. Sites are allowed to use their own policies in regards to 
using the test dose (See Section 5.2.10 for hypersensitivity reaction to Bleomycin). 
 
6.2.5 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information. 
 
6.3 
CYCLOPHOSPHAMIDE INJECTION 
 
 
 
 (03/13/13) 
(Cytoxan) NSC #26271 
 
6.3.1 
Source and Pharmacology 
Cyclophosphamide is an alkylating agent related to nitrogen mustard. 
Cyclophosphamide is inactive until it is metabolized by P450 isoenzymes (CYP2B6, 
CYP2C9, and CYP3A4) in the liver to active compounds. The initial product is 4-
hydroxycyclophosphamide (4-HC) that is in equilibrium with aldophosphamide that 
spontaneously releases acrolein to produce phosphoramide mustard. Phosphoramide 
mustard, which is an active bifunctional alkylating species, is 10 times more potent in 
vitro than is 4-HC and has been shown to produce interstrand DNA cross-link 
analogous to those produced by mechlorethamine. Approximately 70% of a dose of 
cyclophosphamide is excreted in the urine as the inactive carboxyphosphamide and 
5-25% as unchanged drug. The plasma half-life ranges from 4.1 to 16 hours after IV 
administration.  
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Anorexia, nausea & vomiting 
(acute and delayed) 
Abdominal discomfort, 
diarrhea 
Transient blurred vision, nasal 
stuffiness with rapid administration, 
arrhythmias (rapid infusion), skin 
rash, anaphylaxis, SIADH 
Prompt: 
Within 2-3 
weeks, prior to 
the next course 
Leukopenia, alopecia, immune 
suppression 
Thrombocytopenia, 
anemia, hemorrhagic 
cystitis (L) 
Cardiac toxicity with high dose (acute 
– CHF hemorrhagic myocarditis, 
myocardial necrosis) (L), 
hyperpigmentation, nail changes, 
impaired wound healing, infection 
secondary to immune suppression 
Delayed: 
Any time later 
during therapy 
Gonadal dysfunction: 
azoospermia or oligospermia 
(prolonged or permanent)1 (L) 
Amenorrhea1 
Gonadal dysfunction: ovarian 
failure1 (L), interstitial pneumonitis, 
pulmonary fibrosis2 (L)  
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy (ALL, ANLL, 
AML), bladder carcinoma (long term 
use > 2 years), bladder fibrosis  

  
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Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of cyclophosphamide (alone or in combination with other 
antineoplastic agents) have been noted in humans. Toxicities include: chromosomal abnormalities, 
multiple anomalies, pancytopenia, and low birth weight. Cyclophosphamide is excreted into breast milk. 
Cyclophosphamide is contraindicated during breast feeding because of reported cases of neutropenia in 
breast fed infants and the potential for serious adverse effects. 
1 Dependent on dose, age, gender, and degree of pubertal development at time of treatment. 
2 Risk increased with pulmonary chest irradiation and higher doses. 
(L) Toxicity may also occur later. 
 
6.3.2 
Formulation and Stability 
Cyclophosphamide for injection is available as powder for injection or lyophilized 
powder for injection in 500 mg, 1 g, and 2 g vials. The powder for injection contains 
82 mg sodium bicarbonate/100 mg cyclophosphamide and the lyophilized powder for 
injection contains 75 mg mannitol/100 mg cyclophosphamide. Storage at or below 
25ºC (77ºF) is recommended. The product will withstand brief exposures to 
temperatures up to 30ºC (86ºF). 
 
6.3.3 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 
 
6.3.4 
Cyclophosphamide for Injection 
If the drug will be administered as undiluted drug at the 20 mg/mL concentration, 
then reconstitute to 20 mg/mL with NS ONLY to avoid a hypotonic solution. If 
the drug will be further diluted prior to administration, then first reconstitute with 
NS, SWFI, or Bacteriostatic Water for Injection (paraben preserved only) to a 
concentration of 20 mg/mL. Following reconstitution further dilute in dextrose or 
saline containing solutions for IV use.  
 
6.3.5 
Supplier 
Commercially available from various manufacturers. See package insert for further 
information. 
 
6.4 
DOXORUBICIN 
 
 
 
 
 
 
(05/09/11) 
(Adriamycin®) NSC #123127  
 
6.4.1 
Source and Pharmacology 
An anthracycline antibiotic isolated from cultures of Streptomyces peucetius. The 
cytotoxic effect of doxorubicin on malignant cells and its toxic effects on various 
organs are thought to be related to nucleotide base intercalation and cell membrane 
lipid binding activities of doxorubicin. Intercalation inhibits nucleotide replication 
and action of DNA and RNA polymerases. The interaction of doxorubicin with 
topoisomerase II to form DNA-cleavable complexes appears to be an important 
mechanism of doxorubicin cytocidal activity. Doxorubicin cellular membrane 
binding may affect a variety of cellular functions. Enzymatic electron reduction of 
doxorubicin by a variety of oxidases, reductases, and dehydrogenases generate 
highly reactive species including the hydroxyl free radical (OH•). Free radical 
formation has been implicated in doxorubicin cardiotoxicity by means of Cu (II) 
and Fe (III) reduction at the cellular level. Cells treated with doxorubicin have been 
shown to manifest the characteristic morphologic changes associated with 
apoptosis or programmed cell death. Doxorubicin-induced apoptosis may be an 

  
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integral component of the cellular mechanism of action relating to therapeutic 
effects, toxicities, or both. 
 
Doxorubicin serum decay pattern is multiphasic. The initial distributive t½ is 
approximately 5 minutes suggesting rapid tissue uptake of doxorubicin. The 
terminal t½ of 20 to 48 hours reflects a slow elimination from tissues. Steady-state 
distribution volumes exceed 20 to 30 L/kg and are indicative of extensive drug 
uptake into tissues. Plasma clearance is in the range of 8 to 20 mL/min/kg and is 
predominately by metabolism and biliary excretion. The P450 cytochromes that 
appear to be involved with doxorubicin metabolism are CYP2D6 and CYP3A4. 
Approximately 40% of the dose appears in the bile in 5 days, while only 5 to 12% 
of the drug and its metabolites appear in the urine during the same time period. 
Binding of doxorubicin and its major metabolite, doxorubicinol, to plasma proteins 
is about 74 to 76% and is independent of plasma concentration of doxorubicin. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting, pink or 
red color to urine, sweat, 
tears, and saliva 
Hyperuricemia, facial 
flushing, sclerosis of the 
vein 
Diarrhea, anorexia, 
erythematous streaking of the 
vein (flare reaction), 
extravasation (rare) but if 
occurs = local ulceration, 
anaphylaxis, fever, chills, 
urticaria, acute arrhythmias 
Prompt: 
Within 2-3 weeks, 
prior to the next course 
Myelosuppression 
(leukopenia, 
thrombocytopenia, 
anemia), alopecia  
Mucositis (stomatitis and 
esophagitis), 
hepatotoxicity  
Radiation recall reactions, 
conjunctivitis and lacrimation 
Delayed: 
Any time later during 
therapy 
 
Cardiomyopathy1 (CHF 
occurs in 5-20% at 
cumulative doses 
≥ 450 mg/m²) (L) 
 
Cardiomyopathy1 (CHF occurs 
in < 5% at cumulative doses 
≤ 400 mg/m²) (L), ulceration 
and necrosis of colon, 
hyper-pigmentation of nail bed 
and dermal crease, onycholysis 
Late: 
Any time after 
completion of 
treatment 
Subclinical cardiac 
dysfunction 
CHF (on long term 
follow up in pediatric 
patients) 
Secondary malignancy (in 
combination regimens) 
Unknown Frequency 
and Timing: 
Fetal and teratogenic toxicities. Carcinogenic and mutagenic effects of doxorubicin 
have been noted in animal models. Doxorubicin is excreted into breast milk in humans 
1 Risk increases with cardiac irradiation, exposure at a young or advanced age. 
(L) Toxicity may also occur later. 
 
6.4.2 
Formulation and Stability 
Doxorubicin is available as red-orange lyophilized powder for injection in 10 mg¹, 
20 mg¹, 50 mg¹vials and a preservative-free 2 mg/mL solution in 10 mg¹, 20 mg¹, 
50 mg¹, 200 mg² vials. 
¹.Contains lactose monohydrate, 0.9 NS, HCl to adjust pH to 3. The Adriamycin 
RDF (rapid dissolution formula) also contains methylparaben, 1 mg per each 
10 mg of doxorubicin, to enhance dissolution. 
² Multiple dose vial contains lactose, 0.9% NS, HCl to adjust pH to 3. 

  
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Aqueous Solution Store refrigerated 2°-8°C, (36°-46°F). Protect from light. Retain 
in carton until contents are used. 
 
Powder for Injection Store unreconstituted vial at room temperature, 15°-30°C 
(59°-86°F). Retain in carton until contents are used. Reconstitute with preservative-
free NS to a final concentration of 2 mg/mL. After adding the diluent, the vial should 
be shaken and the contents allowed to dissolve. The reconstituted solution is stable for 
7 days at room temperature and 15 days under refrigeration, 2°-8°C (36°-46°F) when 
protected from light. Doxorubicin further diluted in 50 – 1000 mL of NS or D5W is 
stable for up to 48 hours at room temperature (25°C) when protected from light. 
 
6.4.3 
Guidelines for Administration  
See Treatment and Dose Modifications sections of the protocol. Administer IV 
through the tubing of rapidly infusing solution of D5W or 0.9% NaCl preferably 
into a large vein. Protect the diluted solution from sunlight. To avoid extravasation, 
the use of a central line is suggested. 
 
6.4.4 
Special Precautions 
Medication errors have occurred due to confusion between DAUNOrubicin and 
DOXOrubicin. DOXOrubicin is available in a liposomal formulation. The 
conventional and liposomal formulations are NOT interchangeable. Only 
conventional DOXOrubicin is used in this protocol. 
 
6.4.5 
Supplier  
Commercially available from various manufacturers. See package insert for further 
information. 
 
6.5 
ETOPOSIDE – INJECTION  
 
 
 
 
(11/15/16) 
(Toposar ®, Etopophos®,VP-16) NSC #141540  
 
 
 
 
 
 
6.5.1 
Source and Pharmacology  
A semisynthetic derivative of podophyllotoxin that forms a complex with 
topoisomerase II and DNA that results in single and double strand DNA breaks. 
Its main effect appears to be in the S and G2 phase of the cell cycle. The initial t½ 
is 1.5 hours and the mean terminal half-life is 4 to 11 hours. It is primarily excreted 
in the urine. In children, approximately 55% of the dose is excreted in the urine as 
etoposide in 24 hours. The mean renal clearance of etoposide is 7 to 10 mL/min/m² 
or about 35% of the total body clearance over a dose range of 80 to 600 mg/m². 
Etoposide, therefore, is cleared by both renal and non-renal processes, e.g., 
metabolism and biliary excretion. The effect of renal disease on plasma etoposide 
clearance is not known. Biliary excretion appears to be a minor route of etoposide 
elimination. Only 6% or less of an intravenous dose is recovered in the bile as 
etoposide. Metabolism accounts for most of the non-renal clearance of etoposide. 
 
The maximum plasma concentration and area under the concentration time curve 
(AUC) exhibit a high degree of patient variability. Etoposide is highly bound to 
plasma proteins (~94%), primarily serum albumin. Pharmacodynamics’ studies 
have shown that etoposide systemic exposure is related to toxicity. Preliminary 

  
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data suggests that systemic exposure for unbound etoposide correlates better than 
total (bound and unbound) etoposide. There is poor diffusion into the CSF < 5%. 
 
Etoposide phosphate is a water soluble ester of etoposide that is rapidly and 
completely 
converted 
to 
etoposide 
in 
plasma. 
Pharmacokinetic 
and 
pharmacodynamics data indicate that etoposide phosphate is bioequivalent to 
etoposide when it is administered in molar equivalent doses. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
Nausea, vomiting 
Anorexia 
Transient hypotension during 
infusion; anaphylaxis (chills, fever, 
tachycardia, dyspnea, 
bronchospasm, hypotension) 
Prompt: 
Within 2-3 weeks, 
prior to next course 
Myelosuppression 
(anemia, 
leukopenia), alopecia 
Thrombocytopenia, 
diarrhea, abdominal pain, 
asthenia, malaise, rashes 
and urticaria 
Peripheral neuropathy, mucositis, 
hepatotoxicity, chest pain, 
thrombophlebitis, congestive heart 
failure, Stevens-Johnson 
Syndrome, exfoliative dermatitis 
Delayed: 
Any time later during 
therapy 
 
 
Dystonia, ovarian failure, 
amenorrhea, anovulatory cycles, 
hypomenorrhea, onycholysis of 
nails 
Late: 
Any time after 
completion of 
treatment 
 
 
Secondary malignancy 
(preleukemic or leukemic 
syndromes) 
 
Unknown Frequency 
and Timing:  
Fetal toxicities and teratogenic effects of etoposide have been noted in animals at 1/20th 
of the human dose. It is unknown whether the drug is excreted in breast milk. 
 
6.5.2 
Formulation and Stability 
Etoposide for injection is available as a 20 mg/mL solution in sterile multiple dose 
vials (5 mL, 25 mL, or 50 mL each). The pH of the clear, nearly colorless to yellow 
liquid is 3 to 4. Each mL contains 20 mg etoposide, 2 mg citric acid, 30 mg benzyl 
alcohol, 80 mg modified polysorbate 80/tween 80, 650 mg polyethylene glycol 
300, and 30.5 percent (v/v) alcohol. Vial headspace contains nitrogen. Unopened 
vials of etoposide are stable until expiration date on package at controlled room 
temperature (20˚-25˚C or 68˚-77˚F). 
 
Etoposide phosphate for injection is available for intravenous infusion as a sterile 
lyophilized powder in single-dose vials containing etoposide phosphate equivalent to 
100 mg etoposide, 32.7 mg sodium citrate USP, and 300 mg dextran 40. Etoposide 
phosphate must be stored under refrigeration (2°-8°C or 36°-46°F). Unopened vials 
of etoposide phosphate are stable until the expiration date on the package. 
 
6.5.3 
Guidelines for Administration:  
See Treatment and Dose Modifications sections of the protocol. 
 

  
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Etoposide 
Dilute etoposide to a final concentration ≤ 0.4 mg/mL in D5W or NS. Etoposide 
infusions are stable at room temperature for 96 hours when diluted to concentrations 
of 0.2 mg/mL; stability is 24 hours at room temperature with concentrations of 
0.4 mg/mL. The time to precipitation is highly unpredictable at concentrations 
> 0.4 mg/mL. Use in-line filter during infusion secondary to the risk of precipitate 
formation. However, the use of an in-line filter is not mandatory since etoposide 
precipitation is unlikely at concentrations of 0.1-0.4 mg/mL. Do not administer 
etoposide by rapid intravenous injection. Slow rate of administration if hypotension 
occurs.  
 
Leaching of diethylhexyl phthalate (DEHP) from polyvinyl chloride (PVC) bags 
occurred with etoposide 0.4 mg/mL in NS. To avoid leaching, prepare the 
etoposide solution as close as possible, preferably within 4 hours, to the time of 
administration or alternatively as per institutional policy; glass or polyethylene-
lined (non-PVC) containers and polyethylene-lined tubing may be used to 
minimize exposure to DEHP. 
 
Etoposide Phosphate 
Reconstitute the 100 mg vial with 5 or 10 mL of Sterile Water for Injection, D5W, 
NS, Bacteriostatic Water for Injection with Benzyl Alcohol, or Bacteriostatic 
Sodium Chloride for Injection with Benzyl Alcohol for a concentration equivalent 
to 20 mg/mL or 10 mg/mL etoposide equivalent (22.7 mg/mL or 11.4 mg/mL 
etoposide phosphate), respectively. Use diluents without benzyl alcohol for 
patients with hypersensitivity to benzyl alcohol.  
 
When reconstituted as directed, etoposide phosphate solutions can be stored in 
glass or plastic containers under refrigeration for 7 days. When reconstituted with 
a diluent containing a bacteriostat, store at controlled room temperature for up to 
48 hours. Following reconstitution with SWFI, D5W, or NS store at controlled 
room temperature for up to 24 hours. 
 
Following reconstitution, etoposide phosphate may be further diluted to a 
concentration as low as 0.1 mg/mL of etoposide with D5W or NS. The diluted solution 
can be stored under refrigeration or at controlled room temperature for 24 hours. 
 
6.5.4 
Special Precautions 
Etoposide can be mixed in 0.9% NaCl or D5W. Avoid use of large volumes of D5W 
due to potential development of hyponatremia (see Section 5.2.9 for 
hypersensitivity reaction to Etoposide). 
 
6.5.5 
Supplier  
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
CANADIAN SITES 
Etoposide for Injection is available as a 20 mg/mL solution. 
 
Etopophos® (etoposide phosphate) is not commercially available in Canada. Sites 
may purchase and import the USA commercial supply from Bristol Laboratories 

  
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via an International Distributor (Pharma Exports LLC, phone: 1-412-885-3700, 
fax: 1-412-885-8022, email: pharexp@aol.com) under the authority of the 
protocol’s No Objection Letter (NOL). Drug Accountability Log (DAL) must 
record Lot #’s and expiry dates of shipments received and doses dispensed. Sites 
may use their own DAL as long as it complies with all elements of ICH GCP and 
Division 5 of the Food and Drugs Act. Each site is responsible for the procurement 
(import +/- purchase) of Etoposide Phosphate (Etopophos). Sites may import and 
manage a single clinical trial supply for multiple protocols as long as each protocol 
has an NOL and the protocol the patient is registered on is recorded on the DAL. 
 
6.6 
FILGRASTIM , TBO-FILGRASTIM, FILGRASTIM-SNDZ  
(11/15/16) 
(Granulocyte Colony-Stimulating Factor, r-metHuG-CSF, G-CSF, Neupogen®, Granix®, 
Zarxio®) NSC #614629 
 
6.6.1 
Source and Pharmacology  
Filgrastim is a human granulocyte colony-stimulating factor (G-CSF), produced 
by recombinant DNA technology. Filgrastim is a 175 amino acid protein with a 
molecular weight of 18,800 daltons manufactured by recombinant DNA 
technology utilizing E coli bacteria into which has been inserted the human 
granulocyte colony stimulating factor gene. It differs from the natural protein in that 
the N- amino acid is methionine and the protein is not glycosylated. G-CSF is a 
lineage specific colony-stimulating factor, which regulates the production of 
neutrophils within the bone marrow and affects neutrophil progenitor proliferation, 
differentiation, and selected end-cell functional activation (including enhanced 
phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated 
with 
cell 
surface 
antigens). 
Filgrastim 
exhibits 
nonlinear 
pharmacokinetics with clearance dependent on filgrastim concentration and 
neutrophil count. Filgrastim is cleared by the kidney. The elimination half-life is 
similar for subcutaneous and intravenous administration, approximately 3.5 hours. 
The time to peak concentration when administered subcutaneously is 2-8 hours. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children 
 out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Local irritation at the 
injection site, headache 
Allergic reactions (more common 
with IV administration than subq): 
skin (rash, urticaria, facial edema), 
respiratory (wheezing, dyspnea) and 
cardiovascular (hypotension, 
tachycardia), low grade fever  
Prompt: 
Within 2-3 weeks, prior to 
the next course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic rupture, rash 
or exacerbation of pre-existing skin 
rashes, sickle cell crises in patients 
with SCD, excessive leukocytosis, 
Sweet’s syndrome (acute febrile 
neutrophilic dermatosis) 
Delayed: 
Anytime later during 
therapy 
 
 
Cutaneous vasculitis, ARDS 

  
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Late: 
Anytime after completion 
of treatment 
 
 
MDS or AML (confined to patients 
with severe chronic neutropenia and 
long term administration) 
Unknown Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of filgrastim in humans are unknown. Conflicting 
data exist in animal studies and filgrastim is known to pass the placental barrier. It is 
unknown whether the drug is excreted in breast milk. 
 
6.6.2 
Formulation and Stability  
Neupogen® is supplied as a clear solution of 300 mcg/mL in 1 mL or 1.6 mL vials. 
Neupogen® vials are preservative free single use vials. Discard unused portions of open 
vials.  
 
Neupogen®, Granix®, and Zarxio® are also available as single use prefilled syringes 
containing 300 mcg/0.5 mL or 480 mcg/0.8 mL of filgrastim for subcutaneous 
administration. Store refrigerated at 2º-8ºC (36º-46ºF). Protect from light. Do not 
shake. Prior to injection, filgrastim and filgrastim-sndz may be allowed to reach 
room temperature for a maximum of 24 hours (infusion must be completed within 
24 hours of preparation). TBO-filgrastim may be removed from 2°C-8°C 
(36°F-46°F) storage for a single period of up to 5 days between 23°C to 27°C (73°F 
to 81°F). Avoid freezing and temperatures > 30ºC.  
 
For IV use, dilute filgrastim (Neupogen®) and tbo-filgrastim (Granix®) in D5W 
only to concentrations >15 mcg/mL. Filgrastim-sndz (Zarxio®) may be diluted in 
D5W to concentrations between 5 and 15 mcg/mL. At concentrations below 
15 mcg/mL, human serum albumin should be added to make a final albumin 
concentration of 0.2% (2 mg/mL) in order to minimize the adsorption of filgrastim 
to plastic infusion containers and equipment for all 3 products (communication on 
file from Teva Pharmaceuticals USA). Filgrastim or Filgrastim-sndz dilutions of 
5 mcg/mL or less are not recommended. Tbo-filgrastim dilutions below 2 mcg/mL 
are not recommended. Diluted filgrastim biosimilar products should be stored at 
2º-8ºC (36º- 46ºF) and used within 24 hours. Do not shake.  
 
Do not dilute with saline-containing solutions at any time; precipitation will occur. 
 
6.6.3 
Guidelines for Administration  
See Treatment and Dose Modifications sections of the protocol. 
Filgrastim biosimilar products should not be administered within 24 hours of 
(before AND after) chemotherapy.  
 
6.6.4 
Supplier  
Commercially available from various manufacturers. See package insert for further 
information  
 
6.7 
PEGFILGRASTIM 
 
 
 
 
 
 
(02/10/16) 
(pegylated filgrastim, PEG filgrastim, SD/01, Neulasta®) NSC #725961 
 
6.7.1 
Source and Pharmacology 
Pegfilgrastim is the pegylated form of recombinant methionyl human G-CSF 
(filgrastim). Pegfilgrastim is produced by covalently binding a 20-kilodalton (kD) 
monomethoxypolyethylene glycol molecule to the N-terminal methionyl residue 
of filgrastim. The molecular weight of pegfilgrastim is 39 kD. G-CSF is a lineage 

  
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specific colony-stimulating factor which regulates the production of neutrophils 
within the bone marrow and affects neutrophil progenitor proliferation, 
differentiation, and selected end-cell functional activation (including enhanced 
phagocytic ability, priming of the cellular metabolism associated with respiratory 
burst, antibody dependent killing, and the increased expression of some functions 
associated with cell surface antigens). 
 
After subcutaneous injection the elimination half-life of pegfilgrastim ranges from 15 
to 80 hours and the time to peak concentration ranges from 24 to 72 hours. Serum 
levels are sustained in most patients during the neutropenic period post chemotherapy, 
and begin to decline after the start of neutrophil recovery, consistent with neutrophil-
dependent elimination. After subcutaneous administration at 100 mcg/kg in 
37 pediatric patients with sarcoma, the terminal elimination half-life was 30.1 (+/- 
38.2) hours in patients 0 to 5 years-old, 20.2 (+/- 11.3) hours in patients 6 to 11 years 
old, and 21.2 (+/- 16) hours in children 12 to 21 years old. 
 
Toxicity: 
 
Common 
Happens to 21-100 
children out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of 
every 100 
Immediate: 
Within 1-2 days 
of receiving 
drug 
 
Local irritation at the 
injection site (pain, 
induration, and local 
erythema), headache 
Low grade fever, allergic reactions 
(anaphylaxis, angioedema, or 
urticaria), generalized erythema and 
flushing,  
Prompt: 
Within 2-
3 weeks, prior to 
the next course 
Mild to moderate 
medullary bone pain 
Increased: alkaline 
phosphatase, lactate 
dehydrogenase and uric 
acid, thrombocytopenia 
Splenomegaly, splenic rupture, 
sickle cell crises in patients with 
sickle cell disease (SCD), excessive 
leukocytosis, Sweet's syndrome 
(acute febrile neutrophilic 
dermatosis) 
Delayed: 
Anytime later 
during therapy 
 
 
ARDS 
Unknown 
frequency and 
timing: 
Fetal toxicities and teratogenic effects of pegfilgrastim in humans are unknown. 
Conflicting data exist in animal studies. It is unknown whether the drug is excreted in breast 
milk. 
 
6.7.2 
Formulation and Stability 
Supplied as a preservative-free solution containing 6 mg (0.6 mL) of pegfilgrastim 
(10 mg/mL) in a single-dose syringe with 27 g, ½ inch needle with an UltraSafe® 
Needle Guard. The needle cover of the prefilled syringe contains drug natural rubber 
(a derivative of latex). Store refrigerated at 2º-8ºC (36º-46ºF) and in the carton to 
protect from light. Prior to injection, pegfilgrastim may be allowed to reach room 
temperature protected from light for a maximum of 48 hours. Avoid freezing. 
 
6.7.3 
Guidelines for Administration  
See Treatment and Dose Modifications sections of the protocol. 
 
Pegfilgrastim should not be administered in the period between 2 weeks before and 
24 hours after chemotherapy. Do not shake. The manufacturer does not 
recommend use of the 6-milligram (mg) fixed-dose formulation of pegfilgrastim 
in infants, children, or adolescents under 45 kilograms.  

  
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6.7.4 
Supplier 
Commercially available. See package insert for further information. 
 
6.8 
PREDNISO(LO)NE 
 
 
 
 
 
 
(11/16/17) 
(Deltasone®, PredniSONE Intensol®, Rayos®, Meticorten®, Liquid Pred®, Pediapred®, 
Millipred®, OraPred ODT®) NSC #10023 (prednisone), NSC# 9151 (prednisolone) 
 
6.8.1 
Source and Pharmacology 
Prednisone and prednisolone are synthetic compounds closely related to 
hydrocortisone. Glucocorticoids produce widespread and diverse physiologic effects 
on carbohydrate, protein, and lipid metabolism, electrolyte and water balance, 
functions of the cardiovascular system, kidney, skeletal muscle, and the nervous 
systems. Glucocorticoids reduce the concentration of thymus-dependent 
lymphocytes (T-lymphocytes), monocytes, and eosinophils. Glucocorticoids 
selectively bind to the cortisol receptors on human lymphoid cells that are found 
in larger numbers on leukemic lymphoblasts. They also decrease binding of 
immunoglobulin to cell surface receptors and inhibit the synthesis and/or release 
of interleukins, thereby decreasing T-lymphocyte blastogenesis and reducing 
expansion of the primary immune response. The specific cellular mechanisms that 
act to halt DNA synthesis are thought to be related to inhibition of glucose transport 
or phosphorylation, retardation of mitosis, and inhibition of protein synthesis. Peak 
blood levels occur within 2 hours of oral intake. Prednisone is approximately 75% 
protein bound with a plasma t½ of 3.2 to 4 hours. (Biologic half-life is 12-36 hours.)  
 
Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children out of every 100 
Immediate: 
Within 1-2 days 
of receiving drug 
Insomnia, hyperphagia 
Gastritis 
Hyperuricemia 
Prompt: 
Within 2-
3 weeks, prior to 
the next course 
Immunosuppression, 
personality changes (mood 
swings, euphoria, anxiety, 
depression), pituitary-adrenal 
axis suppression, acne (L) 
Hyperglycemia, facial 
erythema, poor wound 
healing, infections 
(bacterial, fungal, 
parasitic, viral), edema 
Pancreatitis (L), electrolyte imbalance 
(Na retention, hypokalemia, 
hypocalcemia) (L), increased 
intraocular pressure (L), hypertension, 
psychosis, vertigo, headache 
Delayed: 
Any time later 
during therapy 
Cushing’s syndrome (moon 
facies, truncal obesity) 
Striae and thinning of the 
skin, easy bruising, 
muscle weakness, 
osteopenia  
Spontaneous fractures (L), growth 
suppression, peptic ulcer and GI 
bleeding, pseudotumor cerebri (increased 
intracranial pressure with papilledema, 
headache), aseptic necrosis of the 
femoral and humeral heads (L), 
urolithiasis1 (L) 
Late: 
Any time after 
completion of 
treatment 
 
Cataracts (that may be 
reversible on 
discontinuation of 
prednisone in children) 
 
Unknown 
Frequency and 
Timing:  
Fetal and teratogenic toxicities: Corticosteroids cross the placenta (prednisone has the poorest transport). 
In animal studies, large doses of cortisol administered early in pregnancy produced cleft palate, stillborn 
fetuses, and decreased fetal size. Chronic maternal ingestion during the first trimester has shown a 1% 

  
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60
incidence of cleft palate in humans. Prednisone is excreted into breast milk in humans; however, several 
studies suggest that amounts excreted in breast milk are negligible with prednisone doses ≤ 20 mg/day.  
1 Mainly reported in pediatric patients with ALL. Howard SC et al. Urolithiasis in pediatric 
patients with acute lymphoblastic leukemia. Leukemia 2003; 17: 541-6. 
(L) Toxicity may also occur later. 
 
6.8.2 
Formulation and Stability 
Prednisone is available in 1 mg, 2.5 mg, 5 mg, 10 mg, 20 mg, and 50 mg tablets. 
Also available as a solution in 1 mg/1 mL or 5 mg/mL concentrations. Inactive 
ingredients vary depending on manufacturer but tablet formulations may include 
calcium or magnesium stearate, corn starch, lactose, erythrosine sodium, mineral oil, 
sorbic acid, sucrose, talc and various dyes. The solution may include 5-30% alcohol, 
fructose, sucrose, saccharin, and sorbitol. 
 
Prednisolone is available as 5 mg scored tablets (base) and 10 mg, 15 mg, and 30 mg 
orally disintegrating tablets (ODT; sodium phosphate [strength expressed as base]). 
Liquid formulations of prednisolone are available as 15 mg/5 mL oral solution (base); 
5 mg/5 mL, 10 mg/5 mL, 15 mg/5 mL, 20 mg/5 mL oral solution (sodium phosphate 
[strength expressed as base]; and 15 mg/5 mL oral syrup (base). Inactive ingredients 
vary depending on manufacturer. Tablet formulations may contain dyes and liquid 
formulations may contain edetate disodium, methylparaben, saccharin sodium. 
 
6.8.3 
Guidelines for Administration  
See Treatment and Dose Modifications sections of the protocol. 
 
PredniSONE and prednisoLONE are equipotent corticosteroids. 
 
6.8.4 
Supplier 
Commercially available from various sources. See package insert for further 
information. 
 
6.9 
VINCRISTINE SULFATE 
 
 
 
 
 
(08/16/12) 
(Oncovin®, VCR, LCR) NSC #67574 
 
6.9.1 
Source and Pharmacology  
Vincristine is an alkaloid isolated from Vinca rosea Linn (periwinkle). It binds to 
tubulin, disrupting microtubules and inducing metaphase arrest. Its serum decay 
pattern is triphasic. The initial, middle, and terminal half-lives are 5 minutes, 
2.3 hours, and 85 hours respectively; however, the range of the terminal half-life 
in humans is from 19 to 155 hours. The liver is the major excretory organ in 
humans and animals; about 80% of an injected dose of vincristine sulfate appears 
in the feces and 10% to 20% can be found in the urine. The p450 cytochrome 
involved with vincristine metabolism is CYP3A4. Within 15 to 30 minutes after 
injection, over 90% of the drug is distributed from the blood into tissue, where it 
remains tightly, but not irreversibly bound. It is excreted in the bile and feces. There 
is poor CSF penetration.  
 
 

  
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Toxicity: 
 
Common 
Happens to 21-100 children 
out of every 100 
Occasional 
Happens to 5-20 children 
out of every 100 
Rare 
Happens to < 5 children  
out of every 100 
Immediate: 
Within 1-2 days of 
receiving drug 
 
Jaw pain, headache 
Extravasation (rare) but if occurs = 
local ulceration, shortness of breath, 
and bronchospasm 
Prompt: 
Within 2-3 weeks, 
prior to the next 
course 
Alopecia, constipation 
Weakness, abdominal pain, 
mild brief 
myelosuppression 
(leukopenia, 
thrombocytopenia, anemia) 
Paralytic ileus, ptosis, diplopia, night 
blindness, hoarseness, vocal cord 
paralysis, SIADH, seizure, defective 
sweating 
Delayed: 
Any time later 
during therapy 
Loss of deep tendon 
reflexes 
Peripheral paresthesias 
including numbness, 
tingling and pain; 
clumsiness; wrist drop, foot 
drop, abnormal gait  
Difficulty walking or inability to 
walk; sinusoidal obstruction 
syndrome (SOS, formerly VOD) (in 
combination); blindness, optic 
atrophy; urinary tract disorders 
(including bladder atony, dysuria, 
polyuria, nocturia, and urinary 
retention); autonomic neuropathy 
with postural hypotension; 8th 
cranial nerve damage with dizziness, 
nystagmus, vertigo and hearing loss 
Unknown 
Frequency and 
Timing: 
Fetal toxicities and teratogenic effects of vincristine (either alone or in combination with other 
antineoplastic agents) have been noted in humans. The toxicities include: chromosome 
abnormalities, malformation, pancytopenia, and low birth weight. It is unknown whether the 
drug is excreted in breast milk. 
 
6.9.2 
Formulation and Stability 
Vincristine is supplied in 1 mL and 2 mL vials that each mL contains vincristine 
sulfate 1 mg (1.08 µmol), mannitol 100 mg, SWFI; acetic acid and sodium acetate 
are added for pH control. The pH of vincristine sulfate injection, USP ranges from 
3.5 to 5.5. This product is a sterile, preservative free solution. Store refrigerated at 
2˚-8˚C or 36˚-46˚F. Protect from light and retain in carton until time of use. 
 
Do not mix with any IV solutions other than those containing dextrose or saline. 
 
6.9.3 
Guidelines for Administration 
See Treatment and Dose Modifications sections of the protocol. 
 
The World Health Organization, the Institute of Safe Medicine Practices (United 
States) and the Safety and Quality Council (Australia) all support the use of minibag 
rather than syringe for the infusion of vincristine. The delivery of vincristine via either 
IV slow push or minibag is acceptable for COG protocols. Vincristine should NOT be 
delivered to the patient at the same time with any medications intended for central 
nervous system administration. Vincristine is fatal if given intrathecally. 
 
Injection of vincristine sulfate should be accomplished as per institutional policy. 
Vincristine sulfate must be administered via an intact, free-flowing intravenous needle 
or catheter. Care should be taken to ensure that the needle or catheter is securely within 
the vein to avoid extravasation during administration. The solution may be injected 
either directly into a vein or into the tubing of a running intravenous infusion. 

  
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6.9.4 
Special Precautions  
FOR INTRAVENOUS USE ONLY. 
The container or the syringe containing vinCRIStine must be enclosed in an 
overwrap bearing the statement “Do not remove covering until moment of 
injection. For intravenous use only - Fatal if given by other routes.”  
 
VinCRIStine is available in a liposomal formulation (vinCRIStine sulfate liposomal 
injection, VSLI, Marqibo®). Use conventional vincristine only; the conventional and 
liposomal formulations are NOT interchangeable. 
 
6.9.5 
Supplier 
Commercially available from various manufacturers. See package insert for more 
detailed information. 
 
 
7.0 
EVALUATIONS/MATERIAL AND DATA TO BE ACCESSIONED 
Timing of protocol therapy administration, response assessment studies, and surgical interventions 
are based on schedules derived from the experimental design or on established standards of care. 
Minor unavoidable departures (up to 72 hours) from protocol directed therapy and/or disease 
evaluations (and up to 1 week for surgery) for valid clinical, patient and family logistical, or facility, 
procedure and/or anesthesia scheduling issues are acceptable (except where explicitly prohibited 
within the protocol). 
 
For biology specimens, every effort should be made to obtain the time points that occur before 
chemotherapy starts (i.e. diagnosis or Cycle 1, Day 1). During therapy, missed time points should 
be omitted. Once therapy is complete and the patient is in follow up, if biology specimens are not 
obtained at any requested time point, please send specimens at the next requested time point or at 
the next clinic visit, whichever is sooner.  
 
If CEA/CIPN measures are missed at any requested time point (including the baseline*), please 
obtain and submit at the next requested time point or at the next clinic visit, whichever is sooner.  
 
*Note: the CEA and CIPN sub-studies reached accrual and were closed to further patient entry as 
of September 8, 2017. Subjects already enrolled on these studies should continue to submit all 
required measures through Time Point #6 as indicated in Appendix VII and Appendix VIII. 
 
 

  
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7.1 
Required Clinical, Laboratory and Disease Evaluations  
Obtain prior to start of cycle unless otherwise indicated. For PK sampling, see Section 7.4. 
Baseline: obtain studies prior to therapy. See additional timing requirements in Section 3.2.  
Prior to Cycle 3: obtain studies between Days 18-22 of Cycle 2. 
End of Cycle 5 If NO RT: obtain studies 4-6 weeks from Day 8/last dose of Cycle 5. 
End of Cycle 5 If RT: obtain studies 3-4 weeks from start of Cycle 5.  
End of RT: obtain studies 6-9 weeks from last day of RT. 
STUDIES TO BE OBTAINED 
Baseline 
Prior to 
each 
cycle 
Day 8 
Cycle 2 
Prior to 
Cycle 3 
Prior to 
Cycle 4 
Day 8 
Cycle 5 
End of 
Cycle 5  
(If NO RT) 
End of 
Cycle 5 
 (If RT) 
End of 
RT 
History and physical, including nodal exam  
Day 1 of cycle unless otherwise indicated 
X 
X 
 
 
 
 
X 
 
X 
CBC/differential, electrolytes, BUN, creatinine, 
AST or ALT, and bili. 
X 
X 
 
 
 
 
X 
X 
X 
Albumin  
X 
 
 
 
 
 
 
 
 
ESR (Erythrocyte Sedimentation Rate) 
X 
 
 
 
 
 
 
 
 
Tumor biopsy/Pathology Report  
X 
 
 
 
 
 
XA 
XA 
 
Bilateral bone marrow biopsyB 
XB 
 
 
XB 
 
 
XB 
XB 
 
ECG 
X 
 
 
 
 
 
 
 
 
ECHO or MUGA 
X 
 
 
 
X 
 
 
 
 
PFTsC, DLCO if > 5 years 
XC 
 
 
 
XC 
 
 
 
 
CXR (PA lateral)L 
X 
 
 
 
 
 
 
 
 
CT with IV contrast L 
X 
 
 
XD 
 
 
XD 
XD 
XD 
18Flurodeoxyglocose Imaging L (FDG-PET) 
X (PET0) 
 
 
X (PET2) 
 
 
XE (PET5) XE (PET5) XF (PET6) 
Pregnancy test G 
X 
 
 
 
 
 
 
 
 
Tissue for Correlative Biology M
 (See Table 7.2) 
X 
 
 
 
 
 
 
 
 
Patient demographics H (CIPN study) 
XParent XYA 
 
 
 
 
 
 
 
 
FACT-GOG-Ntx H (CIPN study) 
XParent XY 
XYA  
 
XParent XY 
XYA  
 
 
XParent XY 
XYA 
XParent XY 
XYA 
 
XParent XY 
XYA 
CHRIS-Global H (CIPN study) 
XParent XY 
XYA  
 
XParent XY 
XYA  
 
 
XParent XY 
XYA  
XParent XY 
XYA 
 
XParent XY 
XYA 
Health Utility Index 2/3 K (CEA) 
XParent XY 
XYA 
 
XParent XY 
XYA 
 
 
XParent XY 
XYA 
XParent XY 
XYA 
 
XParent XY 
XYA 
Stanford Healthcare Utilization K (CEA) 
XParent  XYA 
 
XParent XYA 
 
 
XParent XYA XParent XYA 
 
XParent XYA 
Caregiver Work Limitation(CEA) K 
XParent 
 
 
 
 
 
XParent 
 
XParent 
A Recommended (not required): consider biopsy in the absence of alternative explanation for increased metabolic activity. Submission of pathology report is 
highly recommended. 
B Baseline required for children < 18 years old; recommended (not required) in adults ≥ 18. After Cycles 2, 5: in any age patient if positive at previous biopsy.  
C Pulmonary Function Tests (PFTs) to include Forced Vital Capacity (FVC); Total Lung Capacity (TLC); Functional Residual Capacity (FRC); Carbon 
Monoxide Diffusing Capacity (DLCO) corrected for anemia, Residual Volume (RV) and Peak Flows (PIF, PEF). 
D CT with IV contrast to include all areas involved at diagnosis. Perform between days 18-22 for Cycle 2. 
E PET5: post-chemotherapy FDG-PET/CT performed only if PET2 was Deauville 4 or 5 (See Section 10.3.1). Perform with patient off filgrastim at least 10 days, 
or 3 weeks after pegfilgrastim. 
F PET6: performed after external-beam (or proton) RT only if previous PET5 was positive (Deauville 5 point scale 3, 4 or 5- see Section 10.3.1). 
G Women of childbearing potential require a negative pregnancy test prior to starting treatment; males or females of reproductive potential may not participate 
unless they have agreed to use an effective contraceptive method during protocol therapy and for at least 30 days after the last dose of chemotherapy. Abstinence 
is an acceptable method of birth control. 
H Required for patients enrolled before CIPN reached accrual on 9/8/2017. See Appendix VII for CIPN and Quality of Life study Parent or patient reported 
outcomes (CIPN): XParent refers to parent proxy ratings of CIPNs for all minors 5-17.9 years; XY refers to youth ages 11 – 17.9 and XYA to young adult self-
report of CIPNs.  
K Required for patients enrolled before CEA reached accrual on 9/8/2017. See Appendix VIII for Cost Effective Analysis (CEA) study. The Caregiver WLQ is 
collected from parents of patients ages 5-17.9 and is not collected for patients who are 18 and older. For youth ages 11-17.9 the Stanford HCU measure is 
collected from parents; for young adults 18 and over, the appropriate version of this form is collected directly from the patient.  
L Baseline chest radiograph must be upright CXR with a PA view (portable AP is not acceptable). See Section 14.4 for imaging central review requirements. 
See Section 15.13 for quality assurance documentation that must be submitted prior to start of RT.  
M Tissue for patients who Consent to the Biology Studies should be submitted as per Section 13.0. Also see Section 7.2: if no block is available, 10 unstained 
slides and 2 H&E slides should be obtained for the Correlative Biology studies.  
NOTE: This table only includes evaluations necessary to answer the primary and secondary aims. Obtain 
other studies as indicated for good clinical care. 
 

  
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7.2 
Specimen Submission Schedule for Patients who Consent to the Biology Studies 
Time point 
Sample 
type 
Specimen Volume 
Total for tests listed at time point 
Immune 
studies 
EBV* 
TARC* TMA/GEP* Cytokine* 
Mailing 
Location 
Diagnosis 
Tissue 
biopsy 
1 block or 
10 unstained and 2 H&E 
stained slides 
----------------------------------------- 
0.5 g frozen tumor 
X 
 
 
X 
 
BPC1 
Blood 
> 12 kg: 2 mL/kg 
(max 20 mL)  
in heparin tubes2 
X 
 
 
 
 
Bollard 
lab1 
Cycle 1 Day 1# 
Blood 
20 mL in heparin 
 
X 
X 
 
X 
BPC 
Cycle 1 Day 8# 
Blood 
5 mL in heparin 
 
X 
 
 
 
BPC 
Cycle 2 Day 1# 
Blood 
15 mL in heparin 
 
X 
X 
 
 
BPC 
Cycle 3 Day 1# 
Blood 
15 mL in heparin 
 
X 
X 
 
 
BPC 
Last day of Cycle 5 
± 30 days  
Blood 
5 mL in heparin 
 
X 
 
 
 
BPC 
END OF CHEMOTHERAPY (Collect ONLY IF NO RT) -- Time points are flexible ± 30 days. 
Last day of 
Cycle 5  
Blood 
>12 kg: 2 mL/kg 
(max 40 mL) in heparin 2,3 
X 
 
 
 
 
Bollard 
lab 
4-6 weeks after  
last dose of Cycle 5 Blood 
5 mL in heparin 
 
X 
 
 
 
BPC 
END OF RT (SKIP to Follow-up IF NO RT) -- Time points are flexible ± 30 days. 
Last day of RT 
Blood 
7-10 mL in heparin 
 
X 
 
 
 
BPC 
>12 kg: 2 mL/kg 
(max 40 mL) in heparin 2 
X 
 
 
 
 
Bollard 
lab 
6-9 weeks after 
last day of RT 
Blood 
5 mL in heparin 
 
X 
 
 
 
BPC 
FOLLOW-UP -- Time points are flexible ± 30 days unless otherwise indicated. 
3 months 
6 months 
9 months 
12 months  
24 ± 3 months  
 
Time since end of 
all therapy 
Blood 
5 mL in heparin 
 
X 
 
 
 
BPC 
Relapse 
(prior to salvage 
chemotherapy) 
Blood 
20 mL in heparin 
 
 
 
 
 
BPC 
Tissue  
If Available 
1 block or 
10 unstained and 2 H&E 
stained slides 
0.5 g frozen tumor 
 
 
 
X 
 
 
1. Refer to Appendix VI for complete sample collection, processing and shipping details, including guidance for packaging samples for 
temperature stability during non-winter months. 
2. For patients weighing < 12 kg collect 1 mL/kg. For all patients: samples for immune studies should be collected in green top heparin tubes 
(either sodium heparin or lithium heparin are acceptable). Do NOT use plasma separator tubes (PST).  
3. For patients weighing < 21 kg who are participating in PK sampling, deduct 2.5 mL from volume to be sent to Bollard lab in order to send 
2.5 mL for ATA testing (See Table 7.4). 
* Planned studies that will be assessed at the completion of the protocol. Brief descriptions are provided in Appendix VI. 
# Prior to therapy. 
Note: Details for collection, processing and shipping of blood samples are provided in Appendix VI, along with details for 
shipment of tissue samples. Rationale and details of planned correlative studies are also described in Appendix VI. 

  
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7.3 
Follow-up 
Patients should be followed closely off therapy for evidence of recurrent disease. It is 
recommended that patients also be monitored for the development of long-term toxicity 
from this therapy. The off-therapy procedures for toxicity monitoring below are based on 
the therapy in this protocol. However, they should be individualized as clinically indicated. 
Some patients may require more or less frequent evaluations. See COG Late Effects 
Guidelines for recommended post treatment follow-up: 
http://www.survivorshipguidelines.org/   
TIME 
(months since end 
of all therapy) 
Physical 
Exams1 
Lab 
Tests2 
Labs for subjects 
that consented to 
biology study3 
CIPN and 
CEA 
measures4 
CT5 
3 ± 1 month 
X 
X 
X 
 
 
6 ± 1 month 
X 
X 
X 
 
X 
9 ± 1 month 
X 
 
X 
 
 
12 ± 1 month 
X 
X 
X 
X4 
X 
18 ± 3 months 
X 
X 
 
 
 
24 ± 3 months 
X 
X 
X 
 
 
30 ± 3 months 
X 
X 
 
 
 
36 ± 6 months 
X 
X 
 
X4 
 
48 ± 6 months 
X 
X 
 
 
 
1 All PE to include assessment of nodal areas (required). Discuss potential late effects 
and preventive measures (recommended). 
2 CBC every visit recommended until marrow recovery; then per institutional discretion. 
ALT or AST, BUN, creatinine, bilirubin at baseline into long term follow up - usually 
at 2 years post completion of therapy (recommended), after that, as clinically indicated. 
3 Labs to be collected in participants who consented to biology studies. Follow up 
specimens are to be submitted to BPC. Refer to Table 7.2 and Appendix VI for sample 
collection, processing and shipping details,  
4 Required for patients enrolled before CIPN/CEA reached accrual on 9/8/2017. CIPN 
and CEA time points are 12 ± 3 months and 36 ± 6 months off therapy. See Appendix VII 
and Appendix VIII for details. CEA measures are for US institutions only. 
5 CT with IV contrast to include all areas involved at diagnosis. CT of the neck, chest, 
abdomen and pelvis. MRI neck, chest, abdomen and/or pelvis may be substituted for 
the CT scan (required) at designated times after completion of therapy. Ultrasound may 
be substituted, but is limited for visualizing celiac or mesenteric nodes. PET/CT is not 
recommended for routine surveillance if prior PET is negative.   
 
Note: Follow-up data are expected to be submitted per the Case Report Forms (CRFs) 
schedule. 
 
7.3.1 
At Time of Relapse Sites Must Submit: 
1. All imaging and reports documenting first relapse. 
2. Blood and tissue (if available) samples for biology studies (See Section 7.2 and 
Appendix VI) if patient consented to the biology study. 
 
 
 

  
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7.4  
Pharmacokinetics (PK) Studies  
Limited to patients who are < 13 years of age who consent to PK sampling and receive 
treatment on the Experimental Arm (Bv-AVEPC).  
 
Sampling for the PK can be via the same line through which the infusion is administered. 
 
Blood draws will be conducted during Cycles 4-5 for the following assays: 
1. Antibody drug conjugate (ADC): serum from 2.5 mL whole blood (per time point) 
collected in a serum separation tube. 
2. Anti-therapeutic antibody (ATA): serum from 2.5 mL whole blood (per time point) 
collected in a serum separation tube. 
3. Monomethymuriamine (MMAE): plasma from 2.7 mL whole blood (per time point) 
collected in a 3 mL Na Citrate (blue top) tube. 
 
Table 7.4: PK Assessment Time Points and Blood Draw Volumes 
Volumes listed are the minimum necessary for a requested sample. 
ASSAY 
and specimen 
type 
Cycle 4 
Cycle 5 
Day 1  
Pre-dose* 
Day 1  
End of Infusion** Day 2  
Day 3 
Day 8 
Day 15 
±2 days 
Day 1  
Pre-dose* 
Day 22  
Flexible up to 
+30 days 
ADC 
serum  
2.5 mL 
2.5 mL 
2.5 mL 2.5 mL 2.5 mL 2.5 mL 
2.5 mL 
  
MMAE 
plasma 
2.7 mL 
2.7 mL 
2.7 mL 2.7 mL 2.7 mL 2.7 mL 
2.7 mL 
  
ATA 
serum  
2.5 mL 
  
  
  
  
  
2.5 mL 
2.5 mL 
 
 
Total volume 
7.7 mL 
5.2 mL 
5.2 mL 5.2 mL 5.2 mL 5.2 mL 
7.7 mL 
2.5 mL 
  * Pre-dose: obtain sample ≤ 30 minutes prior to initiating infusion. 
** End of Infusion: obtain sample ≤ 30 minutes after the end of infusion. 
 
7.4.1 
Order PK Sampling Kits before Cycle 2  
For each patient consenting to PK sampling, order required PK sampling kits 
before the patient begins Cycle 2 to allow adequate time for registration, order 
processing and shipment of the kits. Detailed instructions for ordering the kits are 
provided in the PK Guide to Registering and Ordering Kits available on the study 
web page. 
 
7.4.2 
Brief Overview of PK Sample Processing  
Consult the current version of the PK Lab Manual available on the study web 
page for the technical specifics. Blood samples collected in the serum separation 
tubes will be allowed to clot at room temperature for a specified length of time, 
centrifuged, and then the serum component aliquoted and frozen without delay. 
Blood samples collected in the blue top (Na Citrate) tubes will be mixed and 
immediately cooled, centrifuged, and then the plasma component aliquoted and 
frozen without delay. 
 
 

  
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8.0 
CRITERIA FOR REMOVAL FROM PROTOCOL THERAPY AND OFF STUDY 
CRITERIA 
8.1 
Criteria for Removal from Protocol Therapy 
a) Progressive disease.  
b) Refusal of further protocol therapy by patient/parent/guardian. 
c) Completion of planned therapy. 
d) Physician determines it is in patient’s best interest. 
e) Development of a second malignancy. 
f) Repeat eligibility studies are outside the parameters required for eligibility (if applicable, 
see Section 3.2). 
g) Study is terminated by Sponsor. 
h) Pregnancy. 
 
Patients who are off protocol therapy are to be followed until they meet the criteria for Off 
Study (see below). Follow-up data will be required unless patient is taken off study.  
 
8.2 
Off Study Criteria 
a) Death. 
b) Lost to follow-up. 
c) Patient enrollment onto another COG study with tumor therapeutic intent (e.g., recurrence). 
d) Withdrawal of consent for any further data submission. 
e) Tenth anniversary of the date the patient was enrolled on this study. 
 
 
9.0 
STATISTICAL CONSIDERATIONS 
9.1 
Statistical Design 
This is a randomized study that aims to examine the treatment efficacy of Bv in pediatric 
patients with high-risk classical HL. Primary outcome of interest is event-free-survival 
where events include disease relapse/progression, second malignancy, or death. Eligible 
patients are those age 21 or younger with classical HL at Stage IIB with bulk/IIIB/IVA/IVB 
disease, and will be randomized 1:1 between the standard arm of ABVE-PC and the 
experimental arm of Bv-AVEPC. After initial 2 cycles of chemotherapy, early response 
will be assessed by PET to determine slow responding lesions (SRL). At the end of 5 cycles 
of chemotherapy, patients with SRL at the post 2 cycle assessment will receive involved 
site radiation (ISRT) to SRL, and all patients with large mediastinal mass (LMA) at initial 
diagnosis will receive ISRT to LMA.  
 
9.2 
Patient Accrual and Expected Duration of Trial 
The study will accrue 580 eligible patients with IIB bulk/IIIB/IVA/IVB cHL disease at age 
21 or younger, with a maximum accrual of 600 patients. Enrolled patients who are found 
to not meet study eligibility staging criteria at the time of central review for early response 
assessment (after 2 cycles of chemotherapy) will be considered ineligible. Patients eligible 
for this study would have been eligible for and enrolled previously AHOD0031 or 
AHOD0831. Average annual accrual on AHOD0031 after 6 months from study activation 
for Stage IIB with bulk/IVA cHL patients age 18 or younger was about 69; average annual 
accrual on AHOD0831 after 6 months from activation for Stage IIIB/IVB cHL patients age 
18 or younger was about 77. Therefore, the estimated accrual rate for patients with cHL at 

  
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IIB bulk/IIIB/IVA/IVB and 21 years old or younger is around 146 patients per year. The 
expected accrual duration for 580-600 patients is about 4 years.  
 
Ineligibility rate on AHOD0031/AHOD00831 was less than 2%, suggesting up to 12 
ineligible patients among 600 enrollments. We expect few patients to be ineligible due to 
incorrect staging criteria found by central review after 2 cycles. On previous COG studies 
(AHOD0431/AHOD0031/AHOD0831), which enrolled over 2100 patients, approximately 
2.5% of patients were found by central reviews to have incorrect bulk disease or stage 
designation. On this study, even if the presence/absence of bulk disease was incorrectly 
specified by the institution, the majority of the patients will be eligible regardless. This is 
because IIIB/IVA/IVB patients are eligible with/without bulk disease and only IIB patients 
need to have bulk disease to be eligible. IIB bulk patients are projected to account for close 
to 25% of the total enrollment; given the prior misclassification rate of 2.5%, up to 4 IIB 
patients may be found ineligible due to incorrect bulk disease designation.  
 
9.3 
Statistical Analysis Methods 
Statistical analyses methods for aims 1.3.2 - 1.3.3 and 1.3.7 - 1.3.9 are included under the 
respective sections in the Appendices. 
 
9.3.1 
Analysis Methods for Aim 1.1.1 
9.3.1.1 
Analysis Plan 
Primary endpoint is event-free-survival (EFS), where events include 
disease progression or relapse, second malignancy, or death. Patients 
without any of these events will be censored at last contact. Primary 
analysis will be based 1-sided log rank test comparison of EFS curves 
between the 2 randomized arms per intention-to-treat principle. All 
eligible randomized patients will be included in the analysis. At final 
analysis, the significance level required to establish efficacy will take 
into account interim efficacy monitoring performed per Lan Demets 
method (see Section 9.3.7). 
 
9.3.1.2. Power estimation 
In power estimation, we assume a cure model for EFS curve in which a 
fraction of the patients will be cured and the failures for the rest of the 
patients follow an exponential distribution. In such cure model, we 
expect three quarters of the failures occur within the first 3 years. For 
standard arm, the projected 3-year EFS rate is 82%; assuming three 
quarters of failures within the first 3 years, the long-term EFS (cure 
fraction) for standard arm is 76% and the entire EFS curve is specified 
by the cure model described above.  
 
The estimate of 82% for 3-year EFS is based on historical data from prior 
COG studies with similar ABVE-PC chemotherapy backbone, but not 
with exact same chemotherapy dose/schedule and radiation, because no 
prior high-risk patients were treated exactly the same as the standard arm 
of ABVE-PC. On AHOD0031, patients < 18 years of age with Stage IIB 
bulk/IVA cHL who were treated with 4 cycles of ABVE-PC 
with/without DECA and with/without involved field radiation (IFRT) 
had 3-year EFS of 78% and 5-year EFS of 77%. Long-term EFS on 

  
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AHOD0831 for IIIB/IVB patients treated with 4-cycles of ABVE-PC 
with/without IV/RT is not yet available. On POG9425 (3 or 5 cycles of 
ABVE-PC with radiation), IIB/IIIB/IVA/IVB patients had 3-year EFS of 
86% and 5-year EFS of 84%, but this number includes IIB without bulk 
disease patients who are not included in the current study, due to 
observations from AHOD0031 that they had 3-year EFS of 90% 
compared to 3-year EFS of 75% for those with IIB bulk disease. Based 
on these prior data, we expect the 3-year EFS for control arm to be in 
low 80% and use 82% as our projected baseline.  
 
Assuming a 3-year EFS of 82% (5-year EFS of 78.4%, long term EFS of 
76%) for standard arm, the study will have approximately 86% power 
for detecting an 8% improvement in 3-year EFS in the Bv-AVEPC arm 
(3-year EFS of 90%, 5-year EFS of 88.0%, long term EFS of 86.7%) in 
log rank test when the EFS curves follow cure model as described earlier. 
Hazard ratio is approximately 0.53. Power estimation is based on 
290 eligible patients per arm and 1-sided log rank test with alpha level 
of 0.05. One-sided test is used since there is no interest in establishing 
treatment difference in the other direction. The power estimation 
assumes 4 years of accrual and 1 year of additional follow up after last 
patient accrual. The number of expected events from 580 eligible 
patients under the null hypothesis is 99; the number of expected events 
under the alternative hypothesis is 77. 
 
9.3.2 
Analysis Methods for Aim 1.2.1 
9.3.2.1 
Analysis Plan 
Endpoints for this aim include the proportion of patients with early 
response (i.e. no SRL nor PD at PET2) and the proportion of patients 
needing response-directed RT. 
 
We are not utilizing the term rapid early response (RER) in the current 
protocol, as clinical treatment will be based on the response of individual 
nodal sites/lesions (RRL or SRL). For the purpose of analysis, patients 
achieving early response are those with no slow responding lesions 
(SRL) and no PD at all sites (including LMA) after 2 cycles of 
chemotherapy (Bv-AVEPC or ABVE-PC) determined by PET per 
Deauville criteria through central review.  
 
Patients on each arm will receive RT to LMA and to any SRL after 
2 cycles of chemotherapy. Patients with PD after 2 cycles of 
chemotherapy on each arm will be taken off protocol therapy but will be 
considered as needing RT for analysis purpose. RT to LMA is the same 
on both arms and depends only on baseline characteristics not on 
chemotherapy. To compare RT between the 2 arms, patients needing 
response-directed RT (regardless of whether the patient actually receives 
it) are those with any SRL at sites other than LMA after 2 cycles of 
chemotherapy and those with PD after 2 cycles of chemotherapy. For 
patients without LMA, any response-directed RT is the same as any 
protocol-directed RT (i.e., any SRL) or any PD. For patients with LMA, 

  
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response-directed RT is any RT to sites other than mediastinum (i.e., any 
SRL at sites other than mediastinum) or any PD. As the study does not 
include Stage I patients, all patients with LMA should have other site(s) 
of disease. By excluding RT to LMA, response-directed RT removes the 
“background” RT to LMA which is the same on both arms by design, 
and directly compares the effect of chemotherapy on RT administration. 
All randomized patients can either receive or not receive response-
directed RT. 
 
The proportion of patients achieving early response (i.e., with no SRL 
and no PD at all sites including LMA) will be compared between the two 
randomized arms to see if Bv-AVEPC arm has a higher rate of early 
response compared to ABVE-PC arm. The proportion of patients 
needing response-directed RT (including PD) will be compared between 
the two arms to see if Bv-AVEPC arm has a lower rate for response-
directed RT compared to ABVE-PC arm. Two-sample Z test of 
proportions at 1-sided alpha level of 0.05 will be used for these 
comparisons. 
 
9.3.2.2 
Power estimation for early response rate comparison 
For ABVE-PC arm, we project a 70%-80% rate of early response, and 
we hypothesize that the rate of early response will be at least 9% higher 
in Bv-AVEPC arm than in ABVE-PC arm. With 290 eligible patients per 
arm, the power for detecting a 9% increase in early response rate for Bv-
AVEPC compared to ABVE-PC is at least 0.80 in two-sample test of 
proportions with 1-sided alpha of 0.05 when the rate of early response is 
at least 70% for ABVE-PC. The power is 0.91 when the rate of early 
response is 80% for ABVE-PC. 
 
The baseline early response rate of 70%-80% in ABVE-PC arm was 
estimated from prior studies with similar but slightly different 
chemotherapy and slightly different PET criteria. Patients eligible for 
this high-risk study (IIB bulk/IIIB/IVA/IVB) were previously treated 
with ABVE-PC type of regimen on either AHOD0031 or AHOD0831. 
There were 22 Stage IIB with bulk/IVA patients from AHOD0031 with 
retrospectively reviewed 2-cycle PET by 5-point criteria; the rate of early 
response by 5-point criteria was 82% (18/22), and the rate of rapid early 
response as defined by traditional PET assessment utilized on 
AHOD0031 was 64% (14/22). Of all Stage IIB bulk and IVB cHL 
patients on AHOD0031, the rate of rapid early response by PET per 
traditional PET assessment was 71%, slightly higher than the number of 
64% in this small cohort of 22 patients. For Stage IIIB/IVB patients, on 
AHOD0831 66% of them were rapid responder by PET after 2 cycles 
per traditional PET assessment utilized on AHOD0831; 5-point criteria 
PET assessments for these IIIB/IVB patients is not available at this time. 
Combining those historical high-risk patients, the rate of rapid early 
response by PET per traditional PET assessment is about 68%. We 
expect the rate of early response by PET 5-point criteria be slightly 
higher than that, and therefore project an early response rate of 70%-80% 
by PET 5-point criteria for ABVE-PC arm. 

  
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9.3.2.3  Power estimation for RT rate comparison 
With 290 patients per arm, assuming a baseline rate of 25-30% (see 
below) for response-directed RT in the standard (ABVE-PC) arm, we 
will have at least 85% power for detecting a reduction of 9-10% (25% 
vs. 16%, 30% vs. 20%) in the proportion of patients getting response-
directed protocol-RT in the experimental (Bv-AVEPC) arm. Power 
estimation is based on 2-sample test of proportions at 1-sided alpha level 
of 0.05. 
 
Approximately half of the IIB bulk/IVA patients from AHOD0031 and 
half of the IIIB/IVB patients from P9425 did not have LMA; thus we 
project that half of the patients on this study will not have LMA. For IIB 
bulk/IVA patients on AHOD0031 who did not have LMA, 
approximately 25% were PET2 positive per the prior traditional PET 
assessment, slightly lower than 33% PET2 positive for IIB bulk/IV 
patients with LMA on AHOD0031. For IIIB/IVB patients on 
AHOD0831 (unfortunately LMA data not available), approximately 
34% overall were PET2 positive per the traditional PET assessment. 
Based on these data, we project 25-30% PET2 positive rate for patients 
without LMA on the standard arm. This suggests 25-30% of patients 
without LMA will receive response-directed RT”. For patients with 
LMA, we project a slightly higher rate of positive PET2 than patients 
without LMA, at 30-40% based on data from AHOD0031 and 
AHOD0831. For patients with LMA and other sites of disease, a positive 
PET2 at patient level reported in prior studies can mean a positive PET 
(i.e., SRL) at either mediastinum and/or other site(s) of disease; therefore 
the positive-PET2/SRL rate for disease site(s) other than mediastinum 
will be lower than the overall patient-level PET2 positive rate unless 
there is perfect correlation of PET2 responses between mediastinum and 
other sites. Since we expect a high correlation of PET2 outcome for 
mediastinum and other disease sites, for patients with LMA we project 
25-30% for positive PET2/SRL rate at site(s) other than mediastinum. 
This corresponds to a projection of 25-30% patients with LMA will 
receive response-directed RT. Combining patients without LMA and 
patients with LMA, the rate of response-directed RT in the standard arm 
is estimated to be 25-30%.  
 
9.3.3 
Analysis Methods for Aim 1.2.2 
9.3.3.1  Analysis Plan 
The proportion of patients experiencing Grade 3+ peripheral neuropathy 
(assessed by modified Balis scale) after the first 2 cycles and after all 
5 cycles of chemotherapy will be estimated for Bv-AVEPC arm and for 
ABVE-PC arm along with the corresponding 95% confidence intervals. 
For this analysis, all patients that received some protocol chemotherapy 
will be included. The proportion will be compared between the 2 arms 
by two-sample Z test of proportions at 1-sided alpha level of 0.05. 
 

  
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9.3.3.2 
Power estimation 
With 290 eligible patients per arm, we will have > 80% power for 
detecting a peripheral neuropathy rate increase from 3% to 8%, or from 
2% to 7%, or from 1% to 5% for Bv-AVEPC arm compared to ABVE-
PC arm at 1-sided alpha of 0.05.  
 
On AHOD0031 and AHOD0831, the rate of Grade 3+ peripheral 
neuropathy (accessed by CTCAE which is expected to produce data 
similar to the modified Balis scale) was no more than 3%, and most of 
such toxicities were reported during the later cycles. On AHOD0031, the 
rate was < 1% during the first 2 cycles and altogether < 2% of patients 
reported such toxicities during treatment. On AHOD0831, all 5 patients 
with such toxicity (3% of total enrollments) reported such events during 
cycles 3-4. 
 
9.3.4 
Analysis Methods for Aim 1.3.1 
9.3.4.1 
Analysis Plan 
For CHIPS, patients are assigned one score for each of the 4 factors: 
Stage IV disease, fever (≥38°C), LMA (> 1/3 thoracic diameter), and low 
albumin (< 3.5 g/dL). The total score is the sum over these 4 factors, 
which can range from 0 to 4. 
 
CHIPS will be computed for all patients and summarized by descriptive 
statistics. Estimates for the distribution of CHIPS in this study population 
is lacking, since the only prior COG study that collected all the CHIPS 
factors is AHOD0031, which did not include Stage IIIB/IVB patients 
who are expected to make up slightly over half of the patients on this 
study. Among approximately 260 AHOD0031 Stage IIB bulk/Stage IVA 
patients with all CHIPS variables available, the distribution was 2% 
score 0, 40% score 1, 41% score 2, and 17% score 3; score of 4 was not 
possible on AHOD0031 due to Stage IV patients with any B symptom 
(including fever) not eligible for AHOD0031. Those high-risk patients 
with CHIPS 0-1 (42%) had 3-year EFS of 85%, compared to 3-year EFS 
of 71% for the CHIPS 2-3 (58%) patients. The early response rate by CT 
as assessed on AHOD0031 for those CHIPS 0-1 high-risk patients was 
86%, compared to 74% for those with CHIPS 2-3; PET negativity as 
assessed on AHOD0031 by the traditional criteria was 76% for CHIPS 
0-1 vs. 69% for CHIPS 2-3.  
 
Since this study is limited to high-risk patients defined by the Stage and 
B symptoms, the population does not include the complete range of cHL 
patients, even though patients can be any CHIPS score. Patients with the 
same CHIPS will also be treated differently (Bv-AVEPC vs. ABVE-PC 
and +/- ISRT) with chemotherapy being randomly assigned while ISRT 
being non-randomly assigned. We will examine the association between 
CHIPS and early response by cross-tabulations and Chi-square tests 
within each arm separately, as well as logistic regression model where 
early response is the outcome variable and CHIPS the predictor variable 
combining the 2 arms with adjustment for randomized chemotherapy. 

  
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Early response has been shown to correlate with EFS so it can serve as a 
surrogate for examining the association between CHIPS and EFS.  
 
Response and LMA-adapted RT introduces a complication in estimating 
and interpreting the association of CHIPS with EFS, as comparisons 
between CHIPS will be confounded by the non-random administration 
of RT. It is expected that patients with higher CHIPS (expect higher risk 
for EFS failures) will more likely be have SRL and thus receive RT 
which may reduce their risk for failures. Moreover, LMA is both a factor 
in CHIPS and part of the criteria for RT, which also introduces 
confounding effect in examining the association between CHIPS and 
EFS. For patients with otherwise similar CHIPS factors, those with LMA 
not only have 1 higher CHIPS score but also get RT, compared to those 
without LMA who may or may not get RT. These confounding effects 
are expected to attenuate the degree of association between CHIPS and 
EFS, which means the observed association would potentially 
conservative and be under-estimated. Despite these complications, we 
still anticipate observing overall association between CHIPS and EFS, 
as in the prior COG study AHOD0031 with response-adapted RT where 
CHIPS identified a cohort of patients with lower EFS who were not 
identified by early response to therapy. Overall, EFS by CHIPS within 
each arm and combining both arms will be estimated by Kaplan-Meier 
curves, and compared by log rank test. Subset analyses and Cox 
proportional hazards models will also be used to examine the correlation 
between CHIPS and EFS; interpretation of these subset analyses and 
adjusted analyses needs to be done carefully. For example, a comparison 
of CHIPS=1 ABVE-PC no-RT patients to CHIPS=2 ABVE-PC no-RT 
patients is not a direct comparison for all CHIPS 1 to 2 (treated with 
ABVE-PC and no-RT), it is comparing the subset of CHIPS 1 or 2 who 
have no initial LMA and no SRL after 2 cycles. Similarly analyses will 
be performed to examine the association between the groups defined by 
the traditional clinical factors (IIB with bulk, IIIB, IVA, and IVB) and 
clinical outcomes (early response and EFS). Here the groups are 
categories rather than ordered categories as defined by CHIPS. 
 
9.3.4.2 
Power estimation 
As described earlier, the projected early response rate for the ABVE-PC 
arm is 70%-80% and higher on the Bv-AVEPC arm. We also expect the 
early response rate to be higher in patients with lower CHIPS score, as 
seen from AHOD0031. The power for detecting a difference in the rate 
of early response between 2 groups defined by CHIPS (such as 0-1 vs. 
2-4) is shown in the table below. These analyses combine patients from 
both randomized patients. Power estimation is based on a two-sample 
test of proportions at 1-sided alpha of 0.05. 

  
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Table 1. Power for comparing rate of early response (no SRL) between 2 groups 
defined by CHIPS 
% patients with 
lower CHIPS 
% patients with 
higher CHIPS 
% early response 
in patients with 
lower CHIPS 
% early response 
in patients with 
higher CHIPS 
Power 
40% (n=232) 
60% (n=348) 
85% 
76% 
0.85 
40% (n=232) 
60% (n=348) 
80% 
70% 
0.86 
30% (n=174) 
70% (n=406) 
85% 
76% 
0.80 
30% (n=174) 
70% (n=406) 
80% 
70% 
0.81 
20% (n=116) 
80% (n=464) 
85% 
74% 
0.83 
20% (n=116) 
80% (n=464) 
80% 
68% 
0.84 
 
We project lower EFS for patients with higher CHIPS, as seen on AHOD0031. 
Power for comparing EFS between 2 groups defined by CHIPS is shown below. 
These analyses combine patients from both randomized arms. Power estimation is 
based on 1-sided log rank test at alpha of 0.05. EFS curves are assumed to follow 
cure model as specified for the primary aim, with accrual duration and follow-up 
the same as the primary aim. 
 
Table 2. Power for comparing EFS between 2 groups defined by CHIPS 
% patients with 
lower CHIPS 
% patients with 
higher CHIPS 
3-year EFS in 
patients with 
lower CHIPS 
3-year EFS in 
patients with 
higher CHIPS 
Power 
40% (n=232) 
60% (n=348) 
90% 
82% 
0.83 
40% (n=232) 
60% (n=348) 
85% 
76% 
0.82 
30% (n=174) 
70% (n=406) 
90% 
81% 
0.83 
30% (n=174) 
70% (n=406) 
85% 
75% 
0.82 
20% (n=116) 
80% (n=464) 
90% 
79% 
0.83 
20% (n=116) 
80% (n=464) 
85% 
73% 
0.82 
 
9.3.5 
Analysis Methods for Aim 1.3.4 
9.3.5.1 
Analysis Plan 
For this aim, our hypothesis is that the use of involved site RT (ISRT) 
will significantly reduce the dose of radiation received by normal tissues 
compared to prior COG studies that employed involved-field RT (IFRT). 
We project that 50-60% of patients on ABVE-PC arm will receive ISRT 
(i.e. 145-174 patients), while a smaller percentage will receive RT on 
Bv-AVEPC arm. The dose of radiation received by normal tissues for 
ABVE-PC arm patients on this study will be compared to those for 
patients from prior studies with similar ABVE-PC chemotherapy 
backbone such as AHOD0031. Descriptive statistics will be used to 
summarize RT doses received by normal tissues on this study. Two-
sample t-test will be used to compare the doses received on this study to 
those on prior studies.  
 

  
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9.3.5.2 
Power estimation 
We have used evaluated radiation dosimetry on 36 patients treated on 
AHOD0031, which employed IFRT, and found mean organ doses as 
follows: heart =11.9 Gy, lung = 9.1 Gy, thyroid = 19.2 Gy, bilateral 
breast = 4.0 Gy. Assuming at least 145 patients on ABVE-PC arm 
receiving RT on the current protocol, we will have at least 80% power to 
detect a 20% reduction in thyroid doses and breast doses, and a 25% 
reduction in heart and lung doses, based on observed standard deviations 
of 6.2 Gy, 4.3 Gy, 6.3 Gy, and 1.5 Gy for heart, lung, thyroid and breast 
doses from AHOD0031. Power estimation is based on two-sample t test 
with 1-sided alpha of 0.05.  
 
9.3.6 
Analysis Methods for Aim 1.3.5 
9.3.6.1 
Analysis Plan 
For this aim, we will evaluate the efficacy of ISRT in two ways: 1) by 
analyzing the event-free survival of patients treated with response-
adapted ISRT; 2) by evaluating patterns of relapse following ISRT. The 
specific hypotheses for these exploratory analyses are: 1) EFS for each 
chemotherapy arm and for the subset needing ISRT or the subset of SER 
on each arm will not be significantly worse than 82%; 2) less than 10% 
of relapses in the proposed study will be isolated nodal relapses that are 
“marginal misses” resulting from the use of ISRT instead of IFRT. 
 
EFS for patients on each arm as well as those receiving ISRT or those 
with SER on each arm will be estimated. One-sample log rank test will 
be used to compare the observed EFS to the assumed baseline of 82% at 
3 years to see if the observed EFS is significantly lower than the 
projection in these subsets. We recognize that the transition to ISRT is 
not the only change made to the standard therapy compared to prior COG 
trials, so it will not necessarily be possible to isolate ISRT as the cause 
if EFS falls significantly below the benchmark. Subset analyses will also 
be conducted to identify sites of failure and clinical factors associated 
with relapse. If the observed EFS is not significantly worse than the 82% 
benchmark, acknowledging that statistical power is limited in some of 
the subset analyses, this will provide some evidence that, in combination 
with the chemotherapy regimens used on this trial, ISRT is not associated 
with an unacceptably high relapse rate. 
 
We will conduct an analysis of the patterns of failure of study patients to 
evaluate the incidence of isolated failures in nodal regions that would 
have been treated with IFRT but are not included in ISRT volumes. 
Patterns of failure analyses of AHOD0031 and AHOD0831 are ongoing 
and relapse data are currently too sparse to establish a definitive baseline 
expectation for the occurrence of such marginal failures. Among relapses 
currently reported in AHOD0831, 4% were isolated Stage I nodal 
failures. The large majority (81%) of relapses were in multiple nodal ± 
visceral sites. In the proposed study, we anticipate approximately 
80 failures if the experimental arm is better than the standard arm as 
projected. Three isolated nodal failures in sites marginal to the RT 

  
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volume (4% of all relapses, 95% CI = 1%-11%) would be compatible 
with our current experience with IFRT. A proportion of marginal 
relapses ≥ 10% (e.g. 8/80 = 10%, 95% CI = 5%-19%) would be 
considered evidence that ISRT was not appropriate for the high-risk 
patients treated in this study. 
 
9.3.6.2 
Power estimation  
For each arm (n=290), the study has at least 80% power to detect a 
decrease in EFS from the assumed baseline of 82% to 76% in one-sample 
log rank test with 1-sided alpha of 0.05. Among the subset of patients 
needing ISRT (patients with LMA or SRL), which is projected to be 
50%-60% of the ABVE-PC arm (n=160 for 55%), the study will have at 
least 80% power for detecting a 3-year EFS of 74% in a similar 1-sample 
log rank test. Among the subset of SER patients (all needing ISRT), 
which is projected be about 20-30% on the ABVE-PC arm (n=72 for 
25%), the study will have at least 80% power to detect a 3-year EFS of 
70%. The proportion of patients getting RT and the proportion with SER 
are projected to be lower for the experimental arm than the standard arm, 
which will lead to smaller sample size and reduced power for these same 
analyses on experimental arm.  
 
9.3.7 
Interim Monitoring 
9.3.7.1 
Interim monitoring on EFS 
Final analysis will be performed after the expected number of events 
under the alternative hypothesis (77 events) are observed. One interim 
efficacy monitoring will be performed after approximately 50% of the 
expected events (39 events), to avoid concerns for premature efficacy 
monitoring from a regulatory standpoint and too much alpha spending on 
interim analysis. Interim inefficacy/futility analysis will be performed 
after approximately 25%, 50%, and 75% of the expected events, i.e., after 
20, 39, and 58 events. Interim analysis will be based on official data 
cutoff for COG DSMC review, which occurs every six months. The first 
inefficacy/futility analysis was performed in October 2017. 
 
Interim efficacy monitoring boundary will be based on Lan-Demets 
method with spending function αt2.38 Information fraction (t) is 
calculated as the sum of observed events from both arms at the time of 
analysis divided by the sum of expected events from both arms under 
the alternative hypothesis (77 events). The interim efficacy monitoring 
bound will be based on the actual information fraction observed at the 
time of monitoring. The final analysis will be performed based on 
Lan-Demets method at the significance level, which maintains the 
overall alpha of 0.05. For example, if information fraction of exactly 
50% was observed at interim monitoring, the boundary nominal p value 
will be 0.0125 for interim analysis, and the final analysis will be at 
significance level of 0.0446.  
 
Interim inefficacy/futility analysis will be mostly based on Fleming-
Harrington-O’Brien (FHOB) repeated testing of the alternative 

  
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hypothesis. Since the commonly used significance level of 0.005 in such 
repeated testing is considered too conservative under the null 
hypothesis, the testing boundary will be based on the modified boundary 
proposed by Anderson and High,39 which crosses zero at 50% of the 
information. In this study, it corresponds to testing the alternative 
hypothesis at significance level of 0.027. Because such repeated testing 
of the alternative hypothesis can be too aggressive early in the study 
when the number of events is small, the inefficacy/futility monitoring 
based on testing of the alternative hypothesis will start at the 2nd 
monitoring after 39 events, which is also approximately the time 
inefficacy monitoring in this study should start according to the 
inefficacy monitoring approach proposed by Freidlin et al.40 At the first 
monitoring after 20 events, a “harm” look as proposed by Freidlin et al 
will be implemented. This “harm” look is based on 1-sided 0.05 test of 
the null hypothesis in the direction of harm. 
 
The table below shows simulation results (10000 iterations) for 
probability of rejecting the null hypothesis and early termination under 
the null hypothesis and the alternative hypothesis for 2 different 
inefficacy/futility monitoring approaches, both with one interim efficacy 
monitoring after 39 events based on Lan-Demets method with spending 
function αt2. The inefficacy/futility analyses are either based on the 
FHOB repeated testing at 0.005 significance level at all 3 time points 
(20, 39, and 58 events), or based on the proposed approach (modified 
FHOB bound at 2nd/3rd time points with 1st time point being a “harm” 
look). Accrual of 580 eligible patients is assumed to be uniformly 
distributed over 4 years. With Amendment #3, the minimum follow-up 
time for final analysis was changed from 5 years to 3 years. The rationale 
for this change is that the survival curves for the two predecessor studies 
(AHOD0031-intermediate risk disease and AHOD0831-high risk 
disease) plateaued at 3 years after diagnosis, with the majority (91%) of 
the relapse events occurring within the first 3 years of follow-up. Final 
analysis is performed after 77 events or 3 years after the last patient 
enrollment, whichever comes first. The proposed modified-FHOB and 
“harm-look” approach leads to <1% power loss compared to FHOB 
boundary at 0.005 level, but has over 20% increase in the chance of early 
stopping for inefficacy under the null hypothesis. 
 
Table 3. Probability of rejecting the null hypothesis and early termination 
with 2 different approaches 
Truth 
Inefficacy 
monitoring 
Chance of Rejecting the  
Null Hypothesis 
Chance of Early Stop with 
Interim Monitoring 
No Interim 
Monitoring 
With Interim 
Monitoring 
For 
Efficacy 
For 
Inefficacy 
Null 
Proposed 
4.82% 
4.67% 
1.05% 
71.8% 
FHOB 0.005 
4.72% 
1.05% 
48.0% 
Alternative 
Proposed 
85.8% 
84.6% 
36.9% 
4.6% 
FHOB 0.005 
85.1% 
36.9% 
1.3% 
 

  
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At the time of interim efficacy monitoring, observed EFS in each arm 
will be also be compared to the baseline EFS curve under the cure model 
with 3-year EFS of 82% via one-sample log rank test, as an informal 
monitoring to ensure that outcome on either arm is not significantly 
worse than projected. If the true EFS outcome in either arm is 76% at 
3 years under the cure model, the power to detect a decrease in EFS from 
the specified baseline curve in the one-sample log rank is 0.83 at 1-sided 
alpha level of 0.05. Same monitoring boundary as that for efficacy 
monitoring will be used for this monitoring. 
 
9.3.7.2 
Interim monitoring on peripheral neurotoxicity for Bv-AVEPC arm 
Rates of peripheral neuropathy will be monitored for Bv-AVEPC arm 
following Cycle 2 and Cycle 5 of therapy. Peripheral neurotoxicity 
(≥ Grade 3 on modified Balis score) rate will be examined for each 
DSMC report with official monitoring among the first 100 patients 
treated with Bv-AVEPC. The rate of reported Grade 3+ peripheral 
neurotoxicity was low (≤ 3%) with 4 or 5 cycles of ABVE-PC in prior 
POG/COG trials. Monitoring will be done via a Bayesian rule. The prior 
distribution for the rate of toxicity p is assumed a Beta distribution with 
parameters α=1 and β=19. This Beta distribution for the rate of toxicity 
p has a mean of 5%; the support for p≤ 10% is 86%. If given the observed 
data at interim monitoring, the posterior probability of p > 5% is 0.9 or 
higher, it will be considered compelling evidence that the peripheral 
neurotoxicity rate is unacceptable and the study will be referred to 
DSMC for review and for amendment to eliminating Day 8 vincristine. 
Operationally, it will require, for example, ≥ 4/25, ≥ 6/50, ≥ 8/75, or 
≥ 10/100 patients with neurotoxicity for the rule to be met. The exact rule 
will depend on the number of patients in the denominator at the time of 
the interim monitoring. If the true rate of toxicity is 5%, 10%, or 15%, 
the chance of observing ≥ 6/50 patients with toxicity are 4%, 38%, and 
78% respectively; similarly, the chance of observing ≥ 10/100 patients 
with toxicity are 3%, 55%, and 95% respectively. 
 
9.3.8 
Analysis Methods for Aim 1.3.10  
For the population that is Deauville 3 at PET2 (confirmed by central imaging 
review), the frequency of patients with persistent Deauville score of 3 at PET5 will 
be calculated with corresponding standard deviation. 
 
For patients with at least one lesion that is Deauville 3 at PET2 (confirmed by 
central imaging review), the event time and the cause (death or relapse) will be 
recorded during follow-up. The cause-specific cumulative hazard of relapse will 
be calculated to evaluate the risk of relapse among these patients. 
 
EFS and risk of relapse for cases that are RRL, but have Deauville 3 lesions, will 
be compared to those that are classified as complete metabolic response at PET2 
with solely Deauville 1 or 2 lesions. The natural history of Deauville 3 lesions and 
the appropriateness of this Deauville cutoff at PET2 for determination of need for 
radiation therapy remains unknown. We will therefore compare the EFS and risk 
of relapse of patients with or without radiation at same Deauville score level 

  
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(2 or 3) and perform Cox multivariate models to include other possible covariates 
besides of the Deauville score. 
 
9.3.9 
Analysis Methods for Aim 1.3.11 
Pharmacokinetic analyses will be performed by Seattle Genetics. 
 
Pharmacokinetic concentration time-profile data of BV and MMAE will be 
evaluated using a population pharmacokinetic (PopPK) approach whereby the PK 
data from the AHOD1331 trial will be integrated with the brentuximab vedotin 
population PK models from other datasets. These integrated analyses will extend 
the understanding of the covariate effect of weight and/or other demographic 
covariates on the pharmacokinetic properties of brentuximab vedotin and MMAE, 
and would support an evaluation of what (if any) demographic profiles may require 
a dose adjustment in order to maximize an individual’s benefit/risk.  
 
Initial enrollment data indicates that an age cut-off of < 13 years will be expected 
to capture approximately 10.3% (22 of 214) of subjects that weigh < 40 kg; and 
5.6% (12 of 214) of subjects that weigh below 30 kg. Assuming by the point of 
amendment there are 300 subjects remaining to enroll (1:1 experimental to 
standard arm); it is expected that intensive brentuximab vedotin PK data from 
15 subjects (10% of 150) will be obtained to further inform our understanding of 
brentuximab vedotin PK. Of these 15 subjects, half (~8) will be below 30 kg and 
half (~7) will be between 30-40 kg. 
 
It is also worth pointing out that, with an age cut-off entry criterion into the PK 
sub-study, there will naturally be subjects who are under the age of 13 and that 
weigh > 40 kg who will also undergo these additional PK assessments. These 
predictions are summarized in the following table. 
 
Predicted Enrollment in PK Sub-study with Age < 13 years Entry Criteria. 
Weight 
Number of Subjects Enrolled* 
<30 kg 
8 
30 to 40 kg 
7 
>40 kg 
15 
*Assuming 1:1 experimental to standard arm randomization and 300 subjects 
remaining to enroll in study at the time of Amendment 2B activation. 
 
We expect a sample size of 7-8 in each of the under 30 and 30 to 40 kg weight 
ranges to be sufficient to provide PK data to explore and characterize the 
demographic effects of weight and/or other covariate factors on the PK of 
brentuximab vedotin in these pediatric subjects. Additionally, we expect the 
15 subjects in the >40 kg group to provide valuable PK information that may assess 
in exploring the impact of other important factors such as age and sex on 
brentuximab vedotin PK. Note, in typical first-in-human studies, a sample size of 
6 to 8 subjects per cohort is considered sufficient to characterize the PK properties 
of a drug at a given dose-level. 
 

  
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In summary, the addition of this aim to AHOD1331 will provide additional needed 
pediatric data for every-21-day dosing and evaluate the PK of brentuximab vedotin 
in combination with the AVE-PC backbone of chemotherapy. 
 
9.4 
Gender and Minority Accrual Estimates 
 
The gender and minority distribution of the study population is expected to be: 
 
 
Accrual Targets 
 
Ethnic Category 
Sex/Gender 
Females 
Males 
Total 
Hispanic or Latino 
58 
47 
105 
Not Hispanic or Latino 
205 
290 
495 
Ethnic Category: Total of all subjects 
263 
337 
*600 
Racial Category 
 
American Indian or Alaskan Native 
1 
4 
5 
Asian 
6 
17 
23 
Black or African American 
37 
45 
82 
Native Hawaiian or other Pacific Islander 
1 
1 
2 
White 
218 
270 
488 
Racial Category: Total of all subjects 
263 
337 
*600 
* These totals must agree 
 
This distribution was derived from combining patients younger than 18 years of age with Stage IIB 
bulk and IVA disease on AHOD0031 and those younger than 18 years of age on AHOD0831 
according to their projected proportion on this study. 
 
 

  
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10.0 
EVALUATION CRITERIA  
10.1 
Common Terminology Criteria for Adverse Events (CTCAE)  
This study will utilize version 5.0 of the CTCAE of the National Cancer Institute (NCI) for 
toxicity and performance reporting, except for the grading of neuropathy, which will use 
the modified Balis Scale. A copy of the CTCAE version 5.0 can be downloaded from the 
CTEP website  
(http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm). 
Additionally, toxicities are to be reported on the appropriate case report forms. 
 
Please note: ‘CTCAE v5.0’ is understood to represent the most current version of CTCAE 
v5.0 as referenced on the CTEP website (i.e., version 5.02 and all subsequent iterations 
prior to version 6.0). 
 
10.2 
Baseline Imaging Lesion Evaluation at Diagnosis 
Imaging guidelines and response criteria have been revised from previous COG protocols, 
including AHOD0031, AHOD0431, AHOD0831, CCG 5942, CCG 59704, POG 9425, and 
POG 9426 and incorporate International Lymphoma Working Group’s revised 
recommendations and the Euro net consortium guidelines for malignant lymphoma.41,42  
 
Note: The determination of RRL or SRL and CR will be based on interim and end-
of-therapy FDG-PET response, and will not be based on size change on CT, with the 
exception of macronodular splenic involvement. CT-based size criteria will still be used 
in the determination of PD and in cases of macronodular splenic involvement. As such, 
diagnostic quality contrast-enhanced CT imaging will still be required for staging and at 
the time of interim and end of therapy response assessment. This will also facilitate 
comparison with prior COG studies, and allow the importance of CT imaging to be 
prospectively assessed within the context of the proposed PET response criteria. 
 
10.2.1 Staging Considerations  
Measurable disease indicates the presence of at least one measurable lesion. 
Superficial lesions (e.g., palpable lymphadenopathy) measurable only by clinical 
exam or ultrasound are operator dependent and are not admissible as target lesions. 
A measurable lesion by CT is a lesion that can be accurately measured in 
2 orthogonal dimensions. For extranodal sites, this typically involves lesions of at 
least 1 cm diameter. Lymph nodes are considered abnormal if the long axis 
is > 2.0 cm, regardless of the short axis. Lymph nodes with a long axis measuring 
between 1.0-2.0 cm are only considered abnormal if they are part of a 
conglomerate of nodes and are FDG-PET positive. 
 
10.2.1.1 Evaluable disease 
Non-measurable evaluable lesions include permeative bone lesions, 
malignant ascites, malignant pleural/pericardial effusions, pulmonary or 
cutaneous lymphangitic spread, and lesions too small to accurately 
measure in 2 dimensions by CT. All non-target and non-measurable 
assessable lesions will be recorded at baseline and noted on follow-up. 
 
 

  
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10.2.1.2 Lymph node involvement 
Any lymph node is considered involved if and only if it is FDG-PET 
positive. 
 
FDG-PET positive is defined as: 
a. For moderately sized ( ≥ 2 cm in greatest transverse diameter by 
CT) regardless of their location, mild and diffusely increased 
FDG uptake with intensity higher than that of mediastinal blood 
pool structures should be considered positive. When possible use 
the ascending aorta or aortic arch for reference mediastinal blood 
pool. (See Section 10.3.1) 
b. For smaller masses or normal sized lymph nodes (< 2 cm in 
greatest transverse diameter by CT), any FDG uptake more than 
that of surrounding background activity should be considered 
positive.  
 
10.2.1.3 Bulk Disease (See Appendix I) 
 
10.2.1.4 Extra nodal involvement 
o Extra-lymphatic structures contiguous with sites of lymph node 
involvement are considered E-lesions (particularly lung). Exception: 
liver and/or bone marrow involvement is considered Stage 4. 
 
o Pleural and pericardial effusions alone are not considered E-lesions. 
 
o Pleural, pericardial, or chest wall infiltration by an adjacent nodal 
lesion that is PET positive is considered an E-lesion. 
 
10.2.1.5 Organ involvement 
 
10.2.1.5.1 
Lung 
Lung involvement is assumed if there is at least one 
intrapulmonary focus that is >1 cm and is PET positive or 
3 or more lesions between 0.5 and 1 cm regardless of 
FDG-PET activity. Solitary lung nodules that are < 1 cm 
in transverse diameter, but are FDG avid, are also 
considered disease. 
 
10.2.1.5.1.1 
FDG-PET positive is defined as: 
a. For lung nodules that are ≥ 1 cm in 
greatest transverse diameter by CT, 
FDG 
uptake 
exceeding 
that 
of 
mediastinal blood pool structures should 
be considered positive. When possible 
use the ascending aorta or aortic arch for 
reference mediastinal blood pool. 
b. For lung nodules < 1 cm in greatest 
transverse diameter by CT, due to 
partial volume averaging effects, any 
uptake is considered positive. 

  
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10.2.1.5.2 
Visceral organs (liver, spleen, kidney) 
Any focal mass lesion large enough to characterize is 
considered due to lymphomatous involvement unless the 
imaging characteristics indicate an alternative nature 
(e.g., cyst, hemangioma, abscess, etc.). Ultrasound or 
MRI may be utilized if clarification is necessary. Focal 
splenic lesions seen on an appropriately timed IV contrast 
enhanced CT scan can be considered positive if they are 
PET positive; small lesions below limits of detection by 
PET/CT must be confirmed by ultrasound or MRI. 
Splenomegaly without focal lesions does not indicate 
splenic involvement with disease. 
10.2.1.5.2.1 
Hepatic and Splenic Lesions: 
FDG-PET positive is defined as: 
a. For hepatic or splenic lesions 
≥ 1.5 cm on CT, FDG uptake greater 
than or equal to that of normal liver 
or spleen parenchyma, respectively, 
should be considered positive. 
b. For hepatic or splenic lesions 
< 1.5 cm on CT, FDG uptake greater 
than that of normal liver or spleen 
parenchyma, respectively, should be 
considered positive. 
c. In the absence of focal splenic 
involvement at diagnosis, diffusely 
increased splenic FDG uptake greater 
than normal liver parenchymal FDG 
uptake but in the absence of lesions 
seen on CT will not be considered 
evidence of involvement.  
 
10.2.1.5.3 
Bone and bone marrow involvement  
Focal bone lesions that are permeative, sclerotic, or both 
and are PET positive are considered involved. A bone 
focus of PET positivity outside the regions included in 
pre-study diagnostic CT evaluation should be assessed on 
the attenuation correction CT. Alternatively this can be 
evaluated individually by dedicated regional CT or 
preferably MRI. If there are three or more PET positive 
bony foci with no CT or MRI correlate these likely 
represent bone marrow involvement and are sufficient to 
establish Stage IV disease. As part of the Imaging aim, 
these will be recorded and will be correlated with bone 
marrow biopsy results at a later time. For this reason bone 
marrow biopsy results (required in children < 18 years of 
age; optional in patients who are ≥ 18 years of age) should 
be recorded on all patients when they are performed. 
 

  
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10.2.1.5.3.1 
Bone Marrow FDG Uptake: 
FDG-PET positive is defined as: 
a. Three or more FDG-PET positive 
lesions in bone marrow. Suggest 
MRI correlation for confirmation of 
these FDG-PET positive marrow 
foci if possible. Diffusely increased 
bone 
marrow 
FDG 
uptake, 
regardless of level of uptake – 
including more intense than liver, is 
not considered positive.  
b. A negative bone marrow FDG-PET 
does not exclude bone marrow 
involvement or preclude a bone 
marrow biopsy/aspirate assessment. 
 
10.3 
Response Criteria 
Guidelines for standardization using visual FDG-PET for interim response assessment are 
still developing with improved outcome on interim PET in Hodgkin Lymphoma when 
applying a higher visual PET threshold compared to current IWG thresholds.43,44 The level 
of tumor uptake on FDG-PET imaging was assessed in the prior COG high-risk protocol, 
AHOD0831, subjectively by visual inspection, in concordance with the International 
Working Group criteria adapted to the pediatric oncology population.25 Incorporation of 
FDG-PET for lymphoma interim response assessment however is critically dependent on 
the visual threshold used to determine a positive PET scan (slow responding lesion, SRL) 
versus a negative PET scan (rapid responding lesion, RRL). A recent study demonstrated 
that visual 5-point score or Deauville criteria can improve prediction of outcome and are 
reproducible enough in advanced-stage Hodgkin Lymphoma for recommendation as a 
standard reporting criterion in clinical practice and for clinical trials.44,45 Note: Semi-
quantitative assessment of response by determination of standardized uptake values (SUV) 
is not utilized for treatment decisions in this study. However, SUV measurements will be 
available for all PET scans and can be incorporated into reports as per routine clinical 
practice. 
 
The COG AHOD1331 high-risk HL initial therapeutics clinical protocol will 
incorporate interim FDG-PET assessment as an integral part of its risk-adapted 
treatment stratification scheme. This assessment will consist of central review of the 
baseline PET (PET0) and post-Cycle 2 PET (PET2) utilizing a 5-point visual scale or 
Deauville criteria, which has been validated in other HL studies and our own COG 
retrospective study. 
 
For the purposes of this protocol, FDG-PET response criteria for PET-positive and PET-
negative will be used at interim PET2 and at post-chemotherapy PET5. At PET2, individual 
lesion/nodal response (SRL or RRL) will be determined by FDG-PET. At PET5, for those 
subjects that have at least one SRL at PET2, overall response (IMR or CMR) will be 
determined by FDG-PET. CT based size criteria are used in conjunction with FDG-PET to 
determine progressive disease (PD) at any time point. Note that the definition of PET 
positive/negative varies depending on the time point of therapy (See Sections 10.3.1 and 
10.3.2 and Tables 10.3.1.and 10.3.2). 
 

  
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PET/CT scans using an IV-contrast CT as the attenuation-correction CT component of the 
PET/CT will be permitted for this study. However, PET/MRI will not be permitted. 
 
10.3.1 Definition of PET Response of Lymph Node or Nodal Masses 
Visual PET criteria are scored according to uptake involved by lymphoma from 
the Deauville 5-point scale from 1 to 5 as follows: 
1) No uptake. 
2) Uptake ≤ mediastinal blood pool. 
3) Uptake > mediastinal blood pool and ≤ normal liver. 
4) Moderately increased uptake > normal liver. 
5) Markedly increased uptake > normal liver. 
 
10.3.1.1 Baseline PET (PET0) response visual threshold utilizes mediastinal 
blood pool as the reference activity: 
• 
FDG-PET positive is defined as visual score 3, 4, 5. 
• 
FDG-PET negative is defined as visual score 1, 2. 
 
10.3.1.2 Interim post Cycle 2 PET (PET2) response visual threshold uses normal 
liver as the reference activity: 
• 
FDG-PET positive is defined as visual score 4, 5. 
• 
FDG-PET negative is defined as visual score 1, 2, 3. 
 
10.3.1.3 End of chemotherapy PET (PET5) response visual threshold also utilizes 
mediastinal blood pool as the reference activity: 
• 
FDG-PET positive is defined as visual score 3, 4, 5. 
• 
FDG-PET negative is defined as visual score 1, 2. 
 
10.3.2 Splenic Response 
In the instance where there is diffuse splenic uptake secondary to recent G-CSF 
administration the FDG-PET studies may not be of sufficient quality to adequately 
assess for response to therapy. In those circumstances CT criteria of macroscopic 
nodular should be used to assess for response to therapy. Decrease of all 
measurable splenic lesions by 50% in largest transverse diameter is considered a 
favorable response or < 1 cm is considered a favorable response. Alternative 
imaging with MRI or ultrasound may be used instead of or in addition to CT scan 
for assessment. 
 
 

  
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Table 10.3.1 - Interim FDG-PET/CT (PET2)  
Deauville score of 
PET at Baseline 
PET 2 result 
CT with contrast result* 
Interim Response 
Stratification 
Any PET Positive 
Lesions** 
Deauville 1, 2, 3 
Mass of any size  
Rapidly Responding 
Lesion (RRL)& 
 
 
 
 
Deauville 4, 5 
Deauville 4, 5 
< 50% increase in PPD (product of 
perpendicular diameter) of any of the 
nodal masses relative to baseline CT  
Slowly Responding 
Lesion (SRL)#, & 
Deauville 4, 5 
Deauville 4, 5 
≥ 50% increase in PPD of any of the 
nodal masses relative to prior 
measurement OR appearance of new 
lesion(s) > 1.5 cm in any axis. 
Progressive Disease 
(PD) 
Deauville 1, 2, 3 
Deauville 4, 5  
Any  
Progressive Disease 
(PD)@ 
 
 
 
 
N/A 
Deauville 3, 4, 5 
New Lesion(s) > 1.5 cm in any axis not 
seen on baseline CT 
Progressive Disease 
(PD)@ 
* CT with contrast will be used for radiation therapy planning purposes. 
** See Baseline Imaging Lesion Evaluation at Diagnosis criteria, Section 10.2 
# Nodal regions with SRL will be detailed for radiation therapy planning purposes 
& PET5 is limited to patients with Deauville ≥ 4 PET2 results. PET5 is required for any SRL 
(Deauville score 4, 5). 
@ In the absence of alternative explanation for increased metabolic activity. Consider biopsy if 
uncertain. 
Note: Visual PET criteria are scored according to uptake involved by lymphoma applying the 
Deauville 5-point scale of 1 to 5 as follows: 1) No uptake, 2) Uptake ≤ mediastinal blood pool, 
3) Uptake > mediastinal blood pool and ≤ normal liver, 4) Moderately increased uptake > normal liver, 
5) Markedly increased uptake > normal liver. 
 
Table 10.3.2 – End of Chemotherapy FDG-PET/CT (PET5) 
PET 2 result 
PET 5 result 
CT with contrast result 
End of therapy 
Response 
RRL and SRL 
Deauville 1, 2 
Mass of any size 
Complete Metabolic 
Response (CMR) 
Deauville 3 
Deauville 3 
< 50% increase in PPD of any of the nodal 
masses compared with baseline 
Complete Metabolic 
Response (CMR) 
 
 
 
 
SRL 
Deauville 3, 4, 5 
< 50% increase in PPD of any of the nodal 
masses compared to CT 2 
Incomplete Metabolic 
Response (IMR)^ 
RRL and SRL 
Deauville 3, 4, 5 
≥ 50% increase in PPD of any of the nodal 
masses compared to CT 2 
Progressive Disease 
(PD) 
RRL 
Deauville 4, 5 
Any 
Progressive Disease 
(PD)@ 
 
 
 
 
N/A 
Deauville 3, 4, 5 
New Lesion(s) > 1.5 cm in any axis 
compared to any previous CT 
Progressive Disease 
(PD) @ 
^ SRL with Incomplete metabolic response will require RT boost (see Section 15.3) 
@ In the absence of alternative explanation for increased metabolic activity, consider biopsy if 
uncertain. 
 

  
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10.3.3 Complete Metabolic Response (CMR) 
10.3.3.1 HL is typically an FDG-avid lymphoma. Pre-treatment PET scans are 
required. At sites where the PET scan was positive before therapy, a post-
treatment residual mass of any size is permitted as long as it is PET 
negative. 
10.3.3.2 See Section 10.3.2 for the situation where splenic response cannot be 
adequately assessed by PET. 
10.3.3.3 New FDG-PET positive lung nodules in patients without established 
pulmonary lymphoma at baseline prior to initiation of therapy and 
evidence of complete response at all previously known disease site 
should be considered negative for lymphoma regardless of size or uptake 
because these typically represent infectious or inflammatory lesions. 
Lesions that were Deauville 3 (and hence RRL by definition) at PET2 
will be considered as such regardless of PET5 findings; these lesions 
will not receive RT unless they demonstrate progression at PET5  
 
10.3.4 Incomplete Metabolic Response (IMR) 
10.3.4.1 At sites where the FDG-PET scan was positive before therapy, the post-
treatment PET is positive at one or more of the previously involved sites. 
See Section 10.3.1.3 for end of chemotherapy PET (PET5) response 
visual threshold which utilizes mediastinal blood pool as the reference 
activity. 
10.3.4.2 There should be no progressive disease, including new sites of disease, 
as defined in Tables 10.3.1.and 10.3.2 and Section 10.3.5. 
10.3.4.3 See Section 10.3.2 for the situation where splenic response cannot be 
adequately assessed by PET. 
 
10.3.5 Relapsed Disease (after CR) or Progressive Disease [PD] 
10.3.5.1 At least 50% increase in the product of the perpendicular diameters 
(PPD) of any of the involved nodes or nodal masses. To be considered 
progressive or relapsed disease, a lymph node with a short axis diameter 
of less than 1.0 cm must increase by  50%, i.e., to a size of 1.5 x 1.5 cm 
or to more than 1.5 cm in the long axis. 
10.3.5.2 At least 50% increase in the PPD of any of the focal organ lesions. 
10.3.5.3 Lesions should be FDG positive in order to be considered progressive or 
relapsed disease, provided they are sufficiently large to be detected by 
current PET systems (i.e.,  1.5 cm in longest diameter). New FDG-PET 
positive lung nodules in patients without established pulmonary 
lymphoma should be considered negative for lymphoma regardless of 
size or uptake because these typically represent infectious or 
inflammatory lesions. For enlarging lymph nodes or nodal aggregates 
that are FDG-negative, biopsy is required to establish progressive or 
relapsed disease. 
 

  
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10.3.5.4 Increase in Deauville score in previously PET positive lesions. See 
Table 10.3.1 and Table 10.3.2.  
10.3.5.5 Progression or relapse of non-measurable assessable disease at an 
extranodal site (e.g., pleural and/or pericardial effusions, bone lesions, 
bone marrow). Disease that is only assessable will still be considered 
positive for malignancy unless it is histologically negative (this includes 
bone marrow disease). 
10.3.5.6 Development of new measurable lesion(s) or new sites of assessable 
disease. These new lesions should be PET avid. 
 
 
11.0 
ADVERSE EVENT REPORTING REQUIREMENTS 
 
11.1 
Purpose 
Adverse event (AE) data collection and reporting, which are required as part of every 
clinical trial, are done to ensure the safety of patients enrolled in the studies as well as those 
who will enroll in future studies using similar agents. Certain adverse events must be 
reported in an expedited manner to allow for timely monitoring of patient safety and care. 
The following sections provide information about expedited reporting. 
 
11.2 
Determination of reporting requirements 
Reporting requirements may include the following considerations: 1) whether the patient 
has received an investigational or commercial agent; 2) the characteristics of the adverse 
event including the grade (severity), the relationship to the study therapy (attribution), and 
the prior experience (expectedness) of the adverse event; 3) the phase (1, 2, or 3) of the 
trial; and 4) whether or not hospitalization or prolongation of hospitalization was associated 
with the event.  
 
An investigational agent is a protocol drug administered under an Investigational New Drug 
Application (IND). In some instances, the investigational agent may be available commercially, 
but is actually being tested for indications not included in the approved package label. 
Brentuximab vedotin is the investigational agent in this study. 
 
Commercial agents are those agents not provided under an IND but obtained instead from 
a commercial source. The NCI, rather than a commercial distributor, may on some 
occasions distribute commercial agents for a trial. 
 
When a study includes both investigational and commercial agents, the following rules apply. 
• 
Concurrent administration: When an investigational agent is used in 
combination with a commercial agent, the combination is considered to be 
investigational and expedited reporting of adverse events would follow the 
guidelines for investigational agents. 
• 
Sequential administration: When a study includes an investigational agent 
and a commercial agent on the same study arm, but the commercial agent is 
given for a period of time prior to starting the investigational agent, 
expedited reporting of adverse events that occur prior to starting the 
investigational agent would follow the guidelines for commercial agents. 
Once therapy with the investigational agent is initiated, all expedited reporting 
of adverse events follow the investigational agent reporting guidelines. 

  
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11.3 
Expedited Reporting Requirements – Serious Adverse Events (SAEs) 
To ensure compliance with these regulations/this guidance, as IND/IDE sponsor, NCI 
requires that AEs be submitted according to the timeframes in the AE reporting tables 
assigned to the protocol, using the CTEP Adverse Event Reporting System (CTEP-AERS). 
 
Any AE that is serious qualifies for expedited reporting. An AE is defined as any 
untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug related. A Serious Adverse Event (SAE) is any adverse drug event 
(experience) occurring at any dose that results in ANY of the following outcomes: 
 
1) Death. 
2) A life-threatening adverse drug experience. 
3) An adverse event resulting in inpatient hospitalization or prolongation of existing 
hospitalization (for ≥ 24 hours). This does not include hospitalizations that are part 
of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
5) A congenital anomaly/birth defect. 
6) Important Medical Events (IME) that may not result in death, be life threatening, 
or require hospitalization may be considered a serious adverse drug experience 
when, based upon medical judgment, they may jeopardize the patient or subject 
and may require medical or surgical intervention to prevent one of the outcomes 
listed in this definition. 
 
11.4 
Special Situations for Expedited Reporting 
 
11.4.1 SAEs Occurring More than 30 Days After Last Dose of Study Drug 
Any Serious Adverse Event that occurs more than 30 days after the last 
administration of the investigational agent/intervention and has an attribution of a 
possible, probable, or definite relationship to the study therapy must be reported 
according to the CTEP-AERS reporting tables in this protocol. 
 
11.4.2 Persistent or Significant Disabilities/Incapacities 
Any AE that results in persistent or significant incapacity or substantial disruption 
of the ability to conduct normal life functions (formerly referred to as disabilities), 
congenital anomalies or birth defects, must be reported via CTEP-AERS if it 
occurs at any time following treatment with an agent under a NCI IND/IDE since 
these are considered to be serious AEs. 
 

  
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11.4.3 Death 
 
Reportable Categories of Death  
 
o Death attributable to a CTCAE term.  
o Death Neonatal: A disorder characterized by cessation of life during the first 
28 days of life.  
o Sudden Death NOS: A sudden (defined as instant or within one hour of the 
onset of symptoms) or an unobserved cessation of life that cannot be attributed 
to a CTCAE term associated with Grade 5.  
o Death NOS: A cessation of life that cannot be attributed to a CTCAE term 
associated with Grade 5.  
o Death due to progressive disease should be reported as Grade 5 “Disease 
progression” in the system organ class (SOC) “General disorders and 
administration site conditions.” Evidence that the death was a manifestation of 
underlying disease (e.g., radiological changes suggesting tumor growth or 
progression: clinical deterioration associated with a disease process) should be 
submitted. 
 
Any death occurring within 30 days of the last dose, regardless of attribution to 
the investigational agent/intervention requires expedited reporting within 24 hours.  
 
Any death occurring greater than 30 days after the last dose of the investigational 
agent/intervention requires expedited reporting within 24 hours only if it is 
possibly, probably, or definitely related to the investigational agent/intervention. 
 
11.4.4 Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, radiation or 
chemotherapy). A metastasis of the initial neoplasm is not considered a secondary 
malignancy.  
 
The NCI requires all secondary malignancies that occur following treatment with 
an agent under an NCI IND/IDE be reported via CTEP-AERS. Three options are 
available to describe the event:  
• 
Leukemia secondary to oncology chemotherapy  
• 
Myelodysplastic syndrome  
• 
Treatment related secondary malignancy  
Any malignancy possibly related to cancer treatment (including AML/MDS) must 
also be reported via the routine reporting mechanisms outlined in this protocol. 
 
11.4.5 Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and 
is NOT a metastasis from the initial malignancy). Second malignancies require 
ONLY routine reporting via CDUS unless otherwise specified 
 

  
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11.4.6 Pregnancy, Pregnancy Loss, and Death Neonatal 
NOTE: When submitting CTEP-AERS reports for “Pregnancy”, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form, available at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/Pregna
ncyReportForm.pdf, needs to be completed and faxed along with any additional 
medical information to (301) 230-0159. The potential risk of exposure of the fetus 
to the investigational agent(s) or chemotherapy agent(s) should be documented in 
the “Description of Event” section of the CTEP-AERS report. 
 
11.4.6.1 Pregnancy 
Patients who become pregnant on study risk intrauterine exposure of the 
fetus to agents that may be teratogenic. For this reason, pregnancy needs 
to be reported in an expedited manner via CTEP-AERS as Grade 3 
“Pregnancy, 
puerperium 
and 
perinatal 
conditions 
- 
Other 
(pregnancy)” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. 
 
Pregnancy needs to be followed until the outcome is known. If the baby 
is born with a birth defect or anomaly, then a second CTEP-AERS report 
is required. 
 
11.4.6.2 Pregnancy Loss (Fetal Death) 
Pregnancy loss is defined in CTCAE as “Death in utero.” Any 
Pregnancy loss should be reported expeditiously, as Grade 4 
“Pregnancy loss” under the “Pregnancy, puerperium and perinatal 
conditions” SOC. Do NOT report a pregnancy loss as a Grade 5 event 
since CTEP-AERS recognizes any Grade 5 event as a patient death. 
 
11.4.6.3 Death Neonatal  
Neonatal death, defined in CTCAE as “Newborn death occurring during 
the first 28 days after birth”, should be reported expeditiously, as 
Grade 4, “Death Neonatal” under the “General disorders and 
administration” SOC, when the death is the result of a patient 
pregnancy or pregnancy in partners of men on study. Do NOT report 
a neonatal death resulting from a patient pregnancy or pregnancy in 
partners of men on study as a Grade 5 event since CTEP-AERS 
recognizes any Grade 5 event as a patient death.  
 
11.5 
Reporting Requirements for Specialized Adverse Events 
 
11.5.1 Baseline AEs 
Although a pertinent positive finding identified on baseline assessment is not an 
AE, when possible it is to be documented as “Course Zero” using CTCAE 
terminology and grade. An expedited AE report is not required if a patient is 
entered on a protocol with a pre-existing condition (e.g., elevated laboratory value, 
diarrhea). The baseline AE must be re-assessed throughout the study and reported 
if it fulfills expedited AE reporting guidelines. 
 
a. If the pre-existing condition worsens in severity, the investigator must 
reassess the event to determine if an expedited report is required. 

  
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b. If the AE resolves and then recurs, the investigator must re-assess the event 
to determine if an expedited report is required. 
c. No modification in grading is to be made to account for abnormalities 
existing at baseline. 
 
11.5.2 Persistent AEs 
A persistent AE is one that extends continuously, without resolution between 
treatment cycles.  
 
ROUTINE reporting: The AE must be reported only once unless the grade 
becomes more severe in a subsequent cycle. If the grade becomes more severe the 
AE must be reported again with the new grade. 
EXPEDITED reporting: The AE must be reported only once unless the grade 
becomes more severe in the same or a subsequent cycle. 
 
11.5.3 Recurrent AEs 
A recurrent AE is one that occurs and resolves during a cycle/course of therapy 
and then reoccurs in a later cycle/course. 
ROUTINE reporting: An AE that resolves and then recurs during a subsequent 
cycle/course must be reported by the routine procedures. 
EXPEDITED reporting: An AE that resolves and then recurs during a subsequent 
cycle/course does not require CTEP-AERS reporting unless: 
1) The grade increases OR 
2) Hospitalization is associated with the recurring AE. 
 
11.5.4  Neuropathy reporting: 
All Grade ≥ 2 neuropathy by the Balis scale is to be noted on the CRF on either 
study arm.  
 
11.6 
Exceptions to Expedited Reporting 
 
11.6.1 Specific Protocol Exceptions to Expedited Reporting (SPEER) 
The SPEER for brentuximab vedotin is in Section 6.1.2. 
SPEER: Is a subset of AEs within the Comprehensive Adverse Events and 
Potential Risks (CAEPR) that contains a list of events that are considered expected 
for CTEP-AERS reporting purposes. (Formerly referred to as the Agent Specific 
Adverse Event List (ASAEL).)  
 
AEs listed on the SPEER should be reported expeditiously by investigators to the 
NCI via CTEP-AERS ONLY if they exceed the grade of the event listed in 
parentheses after the event. If the CAEPR is part of a combination IND using 
multiple investigational agents and has an SAE listed on different SPEERs, use the 
lower of the grades to determine if expedited reporting is required. 
 
11.6.2 Special Situations as Exceptions to Expedited Reporting 
An expedited report may not be required for a specific protocol where an AE is 
listed as expected. The exception or acceptable reporting procedures will be 
specified in the protocol. The protocol specific guidelines supersede the NCI 
Adverse Event Reporting Guidelines. These special situations are listed under the 
CTEP-AERS reporting Table A for this protocol. 

  
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11.7 
Reporting Requirements - Investigator Responsibility 
Clinical investigators in the treating institutions and ultimately the Study Chair have the 
primary responsibility for AE identification, documentation, grading, and assignment of 
attribution to the investigational agent/intervention. It is the responsibility of the treating 
physician to supply the medical documentation needed to support the expedited AE reports 
in a timely manner.  
 
Note: All expedited AEs (reported via CTEP-AERS) must also be reported via routine 
reporting. Routine reporting is accomplished via the Adverse Event (AE) Case Report 
Form (CRF) within the study database. 
 
11.8 
General Instructions for Expedited Reporting via CTEP-AERS  
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 will be utilized for AE reporting. All 
appropriate treatment areas should have access to a copy of the CTCAE version 5.0. A copy 
of the CTCAE version 5.0 can be downloaded from the CTEP website:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm.  
 
An expedited AE report for all studies utilizing agents under an NCI IND/IDE must be 
submitted electronically to NCI via CTEP-AERS at: https://eapps-ctep.nci.nih.gov/ctepaers.  
 
In the rare situation where Internet connectivity is disrupted, the 24-hour notification is to be 
made to the NCI for agents supplied under a CTEP IND by telephone call to (301)-897-7497.  
 
In addition, once Internet connectivity is restored, a 24-hour notification that was phoned 
in must be entered into the electronic CTEP-AERS system by the original submitter of the 
report at the site. 
 
• 
Expedited AE reporting timelines are defined as: 
o 24-Hour; 5 Calendar Days - The AE must initially be reported via CTEP-
AERS within 24 hours of learning of the event, followed by a complete 
expedited report within 5 calendar days of the initial 24-hour report. 
o 7 Calendar Days - A complete expedited report on the AE must be submitted 
within 7 calendar days of the investigator learning of the event.  
 
• 
Any event that results in a persistent or significant incapacity/substantial disruption of 
the ability to conduct normal life functions, or a congenital anomaly/birth defect, or is 
an IME, which based upon the medical judgment of the investigator may jeopardize 
the patient and require intervention to prevent a serious AE, must be reported via 
CTEP-AERS if the event occurs following investigational agent administration.  
 
• 
Any death occurring within 30 days of the last dose, regardless of attribution to an 
agent/intervention under an NCI IND/IDE requires expedited reporting within 
24 hours.  
• 
Any death occurring greater than 30 days of the last dose with an attribution of 
possible, probable, or definite to an agent/intervention under an NCI IND/IDE requires 
expedited reporting within 24 hours.  
 

  
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CTEP-AERS Medical Reporting includes the following requirements as part of the report: 
1) whether the patient has received at least one dose of an investigational agent on this 
study; 2) the characteristics of the adverse event including the grade (severity), the 
relationship to the study therapy (attribution), and the prior experience (expectedness) of 
the adverse event; 3) the Phase (1, 2, or 3) of the trial; and 4) whether or not hospitalization 
or prolongation of hospitalization was associated with the event.  
 
Any medical documentation supporting an expedited report (e.g., H & P, admission 
and/or notes, consultations, ECG results, etc.) MUST be faxed within 48-72 hours to 
the NCI. NOTE: English is required for supporting documentation submitted to the 
numbers listed below in order for the NCI to meet the regulatory reporting timelines.  
 
Fax supporting documentation for AEs related to investigational agents supplied under 
a CTEP IND to: (301) 230-0159 (back-up: (301) 897-7404).  
 
Also: Fax or email supporting documentation to COG for all IND studies 
(Fax # (310) 640-9193; email: COGAERS@childrensoncologygroup.org; Attention: COG 
AERS Coordinator).  
 
• 
ALWAYS include the ticket number on all faxed documents. 
 
• 
Use the NCI protocol number and the protocol-specific patient ID 
provided during trial registration on all reports. 
 
 

  
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11.9 
Reporting Table for Late Phase 2 and Phase 3 Studies – Table A 
Expedited Reporting Requirements for Adverse Events that Occur on Studies under an 
IND/IDE within 30 Days of the Last Administration of the Investigational 
Agent/Intervention 1 
 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312)  
NOTE: Investigators MUST immediately report to the sponsor (NCI) ANY Serious Adverse Events, 
whether or not they are considered related to the investigational agent(s)/intervention (21 CFR 312.64)  
An adverse event is considered serious if it results in ANY of the following outcomes:  
1) Death.  
2) A life-threatening adverse event.  
3) Any AE that results in inpatient hospitalization or prolongation of existing hospitalization for 
≥ 24 hours. This  does not include hospitalizations that are part of routine medical practice. 
4) A persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions.  
5) A congenital anomaly/birth defect.  
6) Important Medical Events (IME) that may not result in death, be life threatening, or require 
hospitalization may be considered serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR  312.32; ICH E2A and ICH E6.)  
 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting in 
Hospitalization 
≥ 24 hrs 
 
7 Calendar Days 
 
 
24-Hour Notification 
5 Calendar Days 
Not resulting in 
Hospitalization 
≥ 24 hrs 
 
Not Required 
 
7 Calendar Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. Additional 
Special Situations as Exceptions to Expedited Reporting are listed below.  
 
Expedited AE reporting timelines are defined as:  
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of 
learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour 
notification. 
“7 Calendar Days” - A complete expedited report on the AE must be submitted within 7 calendar days 
of learning of the AE.  
 
1SAEs that occur more than 30 days after the last administration of investigational agent/intervention 
and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for:  
• 
All Grade 4, and Grade 5 AEs  
Expedited 7 calendar day reports for:  
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
• 
Grade 3 adverse events  
 
 
 

  
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11.10 Protocol Specific Additional Instructions and Expedited Reporting Exceptions 
• 
Grades 1-4 myelosuppression (anemia, neutropenia, and thrombocytopenia) do 
not require expedited reporting.  
• 
Grades 1-2 AST/ALT elevations do not require expedited reporting. 
• 
Grade 3 AST/ALT elevations do not require expedited reporting if they recover 
to ≤ Grade 1 (< 2.5 X ULN) or baseline within 7 days of study drug interruption. 
• 
Grade 3 febrile neutropenia does not require expedited reporting. 
• 
Grade 1-2 pulmonary toxicity does not require expedited reporting. 
• 
Grade 3 infection does not require expedited reporting. 
• 
Grade 3 nausea and vomiting of < 3 days duration does not require expedited 
reporting. 
• 
Grade 3 hyponatremia, hypophosphatemia, hypokalemia, hypocalcemia or 
hypomagnesemia responsive to oral supplementation does not require expedited 
reporting. 
• 
Grade 3 GI toxicities – mucositis, stomatitis, diarrhea, gastritis does not require 
expedited reporting. 
• 
Grade 3 Hypersensitivity reactions not related to brentuximab vedotin (e.g. from 
bleomycin or etoposide) do not require expedited reporting. 
• 
Grade 3 anorexia; hyperglycemia; hypoalbuminemia; back pain; bone pain; 
pruritis do not require expedited reporting. 
• 
Constipation (Grade 1, 2, and 3) do not require expedited reporting. 
 
11.11 Reporting of Adverse Events for commercial agents – CTEP-AERS abbreviated 
pathway 
 
The following are expedited reporting requirements for adverse events experienced by 
patients on study who have not received any doses of an investigational agent on this study. 
Commercial reporting requirements are provided in Table B.  
 
COG requires the CTEP-AERS report to be submitted within 7 calendar days of learning 
of the event. 
 
Table B  
Reporting requirements for adverse events experienced by patients on study who 
have NOT received any doses of an investigational agent on this study. 
 
CTEP-AERS Reporting Requirements for Adverse Events That Occur During 
Therapy with a Commercial Agent or within 30 Days1 
 
Attribution 
Grade 4 
Grade 5 
 
Unexpected 
Expected 
 
Unrelated or Unlikely 
 
 
CTEP-AERS 
Possible, Probable, Definite 
CTEP-AERS 
 
CTEP-AERS 
1This includes all deaths within 30 days of the last dose of treatment with a commercial 
agent, regardless of attribution. Any death that occurs more than 30 days after the last 
dose of treatment with a commercial agent that can be attributed (possibly, probably, or 
definitely) to the agent and is not due to cancer recurrence must be reported via CTEP-
AERS. 

  
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11.12 Routine Adverse Event Reporting 
 
Note: The guidelines below are for routine reporting of study specific adverse events on 
the COG case report forms and do not affect the requirements for CTEP-AERS reporting. 
 
Routine reporting is accomplished via the Adverse Event (AE) Case Report Form (CRF) 
within the study database. For this study, during protocol treatment, routine reporting will 
include all toxicities reported via CTEP-AERS, all Grade ≥ 2 peripheral neuropathy (by 
the Balis scale) in either study arm, Grade 3 and higher Adverse Events, and all Grade 2 
Adverse Events that result in dose modifications listed in Section 5.0. During off-protocol 
therapy follow up period, routine reporting will include all toxicities reported via CTEP-
AERS, plus all Grade ≥ 2 peripheral neuropathy, all Grade ≥ 3 cardiac Adverse Events, 
and all Grade ≥ 3 pulmonary Adverse Events – but only for occurrence before the patient 
receives any post-protocol (i.e., non-AHOD1331) chemotherapy, radiation, or stem cell 
transplantation.  
 
 
12.0 
RECORDS AND REPORTING 
See the Case Report Forms posted on the COG web site with each protocol under “Data 
Collection”. A submission schedule is included. 
 
12.1 
CDUS 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31 and October 31. This is not a responsibility of institutions 
participating in this trial. 
 
12.2 
CRADA/CTA 
The agent(s) supplied by CTEP, DCTD, NCI used in this protocol is/are provided to the 
NCI under a Collaborative Agreement (CRADA, CTA, CSA) between the Pharmaceutical 
Company(ies) (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer 
Treatment and Diagnosis. Therefore, the following obligations/guidelines, in addition to 
the 
provisions 
in 
the 
“Intellectual 
Property 
Option 
to 
Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) 
contained 
within the terms of award, apply to the use of the Agent(s) in this study: 
 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can 
Agent(s) be transferred or licensed to any party not participating in the clinical study. 
Collaborator(s) data for Agent(s) are confidential and proprietary to Collaborator(s) 
and shall be maintained as such by the investigators. The protocol documents for 
studies utilizing Agents contain confidential information and should not be shared or 
distributed without the permission of the NCI. If a copy of this protocol is requested 
by a patient or patient’s family member participating on the study, the individual 
should sign a confidentiality agreement. A suitable model agreement can be 
downloaded from: http://ctep.cancer.gov. 
 

  
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2. For a clinical protocol where there is an investigational Agent used in combination 
with (an)other Agent(s), each the subject of different Collaborative Agreements, the 
access to and use of data by each Collaborator shall be as follows (data pertaining to 
such combination use shall hereinafter be referred to as "Multi-Party Data”): 
 
a. NCI will provide all Collaborators with prior written notice regarding the 
existence and nature of any agreements governing their collaboration with 
NCI, the design of the proposed combination protocol, and the existence of 
any obligations that would tend to restrict NCI's participation in the proposed 
combination protocol. 
 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the 
clinical trial by any other Collaborator solely to the extent necessary to allow 
said other Collaborator to develop, obtain regulatory approval or 
commercialize its own Agent. 
 
c. Any Collaborator having the right to use the Multi-Party Data from these trials 
must agree in writing prior to the commencement of the trials that it will use 
the Multi-Party Data solely for development, regulatory approval, and 
commercialization of its own Agent. 
 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative 
Agreement will be made available to Collaborator(s), the NCI, and the FDA, as 
appropriate and unless additional disclosure is required by law or court order as 
described 
in 
the 
IP 
Option 
to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and 
disclosed consistent with all applicable federal statutes and regulations for the 
protection of human subjects, including, if applicable, the Standards for Privacy of 
Individually Identifiable Health Information set forth in 45 C.F.R. Part 164. 
 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative 
Group studies, or PI for other studies) of Collaborator's wish to contact them. 
 
5. Any data provided to Collaborator(s) for phase 3 studies must be in accordance with 
the guidelines and policies of the responsible Data Monitoring Committee (DMC), if 
there is a DMC for this clinical trial. 
 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP 
by the Group office for Cooperative Group studies or by the principal investigator for 
non-Cooperative Group studies for immediate delivery to Collaborator(s) for advisory 
review and comment prior to submission for publication. Collaborator(s) will have 30 
days from the date of receipt for review. Collaborator shall have the right to request 
that publication be delayed for up to an additional 30 days in order to ensure that 
Collaborator’s confidential and proprietary data, in addition to Collaborator(s)’s 
intellectual property rights, are protected. Copies of abstracts must be provided to 
CTEP for forwarding to Collaborator(s) for courtesy review as soon as possible and 
preferably at least three (3) days prior to submission, but in any case, prior to 
presentation at the meeting or publication in the proceedings. Press releases and other 

  
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media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/media presentation should be sent to: 
 
Email: ncicteppubs@mail.nih.gov 
 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s 
confidential / proprietary information. 
 
 
13.0 
PATHOLOGY GUIDELINES  
 
13.1 
Pathology Guidelines and Specimen Procurement Requirements 
Please note: Patients may also be enrolled on the current COG Biology Banking study 
which includes pre-therapy specimens. If patients are enrolled on both AHOD1331 and a 
biology banking study, the priority is to submit the specimens requested for AHOD1331 
through AHOD1331 first. 
 
Please consult with the oncologist and pathologist prior to biopsy to ensure that adequate 
specimen is procured. Pathology classification is up to the institutional investigators as 
there is no central pathology review on this study. 
 
Tissue should preferentially be obtained fresh and delivered immediately to the Pathology 
Laboratory for optimal handling and distribution. Submit representative tissue slices for 
fixation including, whenever possible, at least one block with 10% buffered formalin using 
the preferred fixative of the institutional pathologist(s). The fixative utilized and length of 
time in fixative before processing should be indicated for each respective paraffin block. 
Fixation times should be appropriate for the fixative to allow optimal antigen preservation 
and immunophenotypic analysis.  
 
Morphologic evaluation and classification of Hodgkin lymphoma must employ the criteria 
and nomenclature of the World Health Organization 2008 Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. Histologic diagnosis is preferred, though cytologic 
diagnosis may be acceptable if the material is adequate and diagnostic.  
 
A panel of antibodies should be employed for immunophenotypic evaluation and support 
of the diagnosis per WHO criteria. Methodology may be by any standard technique, usually 
employing paraffin sections. A recommended minimum panel of antibodies should include 
CD45, CD3, CD20, CD15 (Leu-M1), CD30 (Ber-H2, Ki-1), and PAX-5. Other markers 
that may be helpful in some situations include other T-cell markers, B-cell markers, CD68, 
ALK-1, EMA and EBV-associated markers (LMP1 and EBER in-situ hybridization). If 
immunophenotyping studies are not available locally, appropriate immunophenotyping 
studies to establish/confirm the diagnosis may be performed by consulting pathologists 
and/or reference laboratories. 
 
13.2 
Tissue Specimen Submission for Correlative Biology Studies 
For those consenting to tissue biology studies, submit snap frozen tumor tissue and at least 
one paraffin block or 10 unstained slides and 2 H&E stained slides to the COG 
Biopathology Center.  
 

  
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See Appendix VI for additional information, including packaging instructions and the 
shipping address for the Biopathology Center. 
 
13.2.1 Blocks or Slides 
Fixative should be identified for each block. Fixation of tissue for over 24 hours 
should be avoided to allow optimal antigen preservation and immunophenotyping 
analysis. Sections should be placed on silanized slides (i.e. Fisher Superfrost Plus). 
If paraffin blocks cannot be submitted, then submit ten (10) unstained sections 
(4 microns thick) of unbaked slides air-dried at room temperature and 2 H&E 
stained slides from one representative block (see Table 7.2 and Appendix VI). 
 
If the patient was diagnosed by biopsy before referral to the treating institution, a 
good faith effort should be made to obtain a representative sample of the tissue 
block with 10 unstained slides and 2 H&E stained slides. 
 
Paraffin blocks will be retained at the COG Biopathology Center unless return is 
requested by the referring institution. For cases requiring urgent return of paraffin 
blocks to the primary institution, the referring institution should contact the COG 
Biopathology Center to request the blocks be returned immediately after removal 
of sample for biology samples for consenting patients. Please note that for patients 
who have consented to the Biology studies, representative cores may be obtained 
for GEP and tissue array development from the paraffin blocks prior to return. 
 
13.2.2 Snap Frozen Tumor 
Snap frozen tissue in foil is requested from the surgical biopsy. These samples will 
be used for biology correlative studies-molecular classification (Appendix VI). Snap 
freeze 0.5 gram of tumor in vapor phase liquid nitrogen (do not submerge the tissue 
in liquid nitrogen) or cold isopentane. Tip: label foil with the COG Patient ID Number 
prior to freezing. Place tissue in a bag labeled with the COG Patient ID Number, 
specimen type (primary or metastatic) and collection date. Anatomic site from which 
the tissue was collected must be documented on the transmittal form. If not shipped 
immediately, these samples can be kept adequately in a -70ºC freezer until shipped. 
 
 

  
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14.0 
IMAGING STUDIES REQUIRED  
 
See Appendix II for detailed guidelines for CT with contrast and PET imaging. 
 
14.1 
[18F]Fluorodeoxyglucose (FDG) PET 
Note: Since FDG-PET imaging plays a significant role in the management of patients, only 
dedicated PET scanners will be utilized and gamma camera co-incidence FDG imaging 
will NOT be included for this protocol. 
 
Exceptional circumstances may require emergent therapy and therapy should not be 
delayed in these cases. In this setting, baseline FDG-PET scans should be performed within 
3 days from initiation of corticosteroid therapy. If FDG-PET is obtained during the 
2nd cycle of chemotherapy (PET2 respectively), it should be performed between Day 18-22 
of Cycle 2. If FDG-PET is obtained at the end of chemotherapy and prior to RT, it should 
be performed at least 3-4 weeks from the start of the last cycle of chemotherapy and with 
patient off G-CSF at least 10 days, in order to minimize potential post-therapy 
inflammatory changes and bone marrow uptake.  
 
In cases of initial involvement of the spleen with lymphoma: If there was splenic 
involvement with focal activity initially, FDG-PET imaging too soon after filgrastim or 
peg-filgrastim shows diffuse splenic uptake that may not be due to disease.  
 
If FDG-PET/CT is obtained at the completion of radiation therapy, for patients not in CR 
prior to RT, it should be obtained at least 6 to 9 weeks after completion of RT to minimize 
inflammatory changes. FDG-PET/CT is not required at the end of chemotherapy or at end 
of radiotherapy for patients with a negative PET2. 
 
14.2 
Computed Tomography (CT) with contrast 
Most, if not all, COG institutions will be using multi-detector helical CT scanners. This is 
preferred in order to decrease scanning time compared to conventional CT, allow image 
acquisition at the time of peak contrast enhancement, reduce/eliminate the need for 
sedation, and reduce image degradation from motion artifact.  
 
The volumetric acquisition of helical/spiral CT and the reconstruction of overlapping 
images increases the conspicuity of small lesions and facilitates multi-planar reconstruction 
for better depiction of certain lesions. Sagittal and coronal reconstructed images, as well as 
images reconstructed using a lung algorithm should be submitted where feasible, along 
with the axial imaging data. CT imaging should be performed with intravenous and oral 
contrast using age and weight-based adjustments to kVp and mA, in accordance with 
institutional practice and ALARA/Image Gently guidelines. 
 
MRI may be used as an alternative modality after completion of treatment during the follow 
up phase only, provided the institution is able to acquire images using phased array surface 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 

  
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coils, cardiac gating and respiratory triggering, in order to minimize artifacts from cardiac 
motion, diaphragmatic motion and bowel peristalsis. Pulse sequences should include at a 
minimum axial and coronal T1, axial and coronal fat-saturated FRFSE-T2 and multi-planar 
post-gadolinium fat-saturated T1 weighted imaging. If MRI is used for imaging of the 
thorax, abdomen and/or pelvis, an unenhanced CT of the chest should still be obtained to 
evaluate the lungs. 
 
14.3 
CT during PET/CT 
Nearly all PET scanners in use today are integrated PET/CT scanners. However, low 
dose CT scans performed on integrated PET/CT scanners for the purpose of 
attenuation correction are of non-diagnostic quality, are usually performed without 
intravenous contrast, and will not be acceptable for staging or response assessment 
or for RT planning. As noted above, staging CT scans should include intravenous and 
oral contrast. In some instances – particularly for staging – a diagnostic quality CT will 
have been performed prior to the PET/CT. In these cases an additional low-dose CT will 
still be required for attenuation correction of the PET images. While all diagnostic imaging 
should be obtained within three weeks prior to start of protocol therapy, if the diagnostic 
quality CT scan has been performed within 28 days of the PET/CT, a repeat diagnostic CT 
examination is not necessary at the time of PET/CT. 
 
For post-therapy follow-up scans limited to the neck and/or thorax the use of IV contrast 
alone is sufficient, provided the scanning parameters are optimized to achieve diagnostic 
quality images. Some institutions perform the low dose attenuation correction CT with 
intravenous contrast. While this is acceptable for the FDG-PET imaging evaluation, for the 
purposes of this protocol, these contrast-enhanced attenuation correction CTs cannot be 
substituted for the required diagnostic quality CT.  
 
14.4 
Central Review of Imaging Studies 
Central review of images will be performed to confirm institutional reporting. 
14.4.1 Real-time central review 
Real time central review to assess response for all patients will be done after the 
second cycle of chemotherapy and at the completion of chemotherapy for patients 
who had PET positive disease at the end of 2 cycles of chemotherapy. Copies of 
all imaging studies at baseline and after 2 cycles of chemotherapy should be 
submitted (baseline PA upright chest radiograph, CT with contrast, FDG-PET 
imaging) as detailed below. Institutional imaging reports and the AHOD1331 
Staging and Response Worksheet should be submitted with these scans. Sites are 
encouraged to submit baseline scans directly after enrollment to confirm that 
all baseline scans required for the central imaging review are available and of 
adequate quality. Eligibility (including bulk and LMA) will be centrally 
confirmed using the baseline scans at the time of the Post 2 cycle review. 
 
In instances in which the central imaging review assessment of disease status 
differs from that of the institution, a web-based conference will be organized by 
IROC Rhode Island (previously known as QARC) to expedite resolution of any 
discrepancies in interpretation of the imaging data. Subjects found to not meet 
study eligibility specified stages at the time of central review for early response 
assessment (after 2 cycles of chemotherapy), will be deemed ineligible. Institutions 
will be notified and the patient will be taken off study. As a reminder, institutions 

  
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may seek input from IROC prior to study enrollment if there are questions 
regarding study eligibility based on imaging measurements regarding LMA or 
bulk. 
 
14.4.2 Time lines and submissions to IROC RI 
For all patients, in the last week of Cycle 2 of ABVE-PC or Bv-AVEPC, and no 
later than Day 22 of this cycle, the institution must send all scans (PET0 and PET2; 
CT with contrast; CXR) and institutional reports along with the AHOD1331 
Hodgkin Lymphoma Staging and Response Worksheets (done to that point) to 
IROC RI (see below). If PET/CT is done on day 1 of cycle 3, sites need to ensure 
that patients proceed to Cycle 3 therapy on schedule. Note that the institution is 
required to report Deauville score for the hottest lesions present at PET2 (See 
Appendix II). 
• 
For patients who had PET positive disease after 2 cycles of chemotherapy, the 
PET and CT with contrast scans done after 5 cycles of chemotherapy should 
be submitted for central review. The corresponding radiology reports and the 
AHOD1331 Staging and Response Worksheet should be submitted to IROC 
RI for central review of response. This response review will determine if an 
additional RT boost to slow responding areas is required.  
• 
For patients who had PET negative disease (Deauville 1, 2, 3) after 2 cycles of 
chemotherapy, CT scans with IV contrast should be submitted for a 
retrospective central imaging review after Cycle 5.  
• 
At time of relapse for any patient enrolled on the study, all imaging studies 
done at the time of the first relapse should be sent to IROC RI.  
• 
Timely submission of studies to IROC RI is required. ANY RADIATION 
THERAPY (POST CYCLE 5 OF CHEMOTHERAPY) DELIVERED 
THAT 
IS 
NOT 
CONSISTENT 
WITH 
THE 
RESPONSE 
CATEGORIZATION, AS DETERMINED BY CENTRAL REVIEW, 
WILL BE CONSIDERED A MAJOR PROTOCOL VIOLATION. The 
results of the central review will be entered into RAVE. 
• 
All radiotherapy treatment plans must be reviewed by IROC RI and approved 
prior to the start of radiotherapy. 
 
14.4.3 Studies to be submitted: 
• 
Pre-Study (Baseline): chest radiograph (must be upright CXR with a PA view; 
portable AP is not acceptable); CT with IV contrast; FDG-PET imaging 
• 
After Cycle 2 of chemotherapy: CT with IV contrast, FDG-PET  
• 
After Cycle 5 of chemotherapy (prior to RT, if RT is indicated): CT with IV 
contrast and FDG-PET if positive by central review after Cycle 2 (mandatory 
submission). 
• 
At first relapse: all imaging studies performed. 
• 
Additional studies obtained if used to determine response (MRI, ultrasound). 
 
14.4.4 Technical Details of Submission  
To ensure an adequate interpretation of FDG-PET and CT with contrast scans, 
scans transferred between the treating institutions and the Imaging and Radiation 
Oncology Core Group IROC RI must be submitted in Digital Imaging and 
Communications in Medicine (DICOM) format. BMP ﬁles, JPG ﬁles, or hard 
copies (ﬁlms) are unacceptable for adequate interpretation of PET and CT with 

  
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contrast scans. Imaging studies must be submitted electronically as outlined in the 
following paragraph. The images will be made available to study radiologists and 
nuclear medicine physicians for central review. 
 
Submission of Diagnostic Imaging data in digital format is required. Digital files 
must be in DICOM format. Due to the critical time constraints for submitting data 
for the central review of response the following methods should be used to submit 
imaging data, such as sFTP, Dicommunicator, or on CD (if sent by courier). Digital 
data submission instructions including instructions for obtaining a sFTP account, 
can be found at http://irocri.qarc.org. Follow the link labeled digital data. 
Alternatively, if submission via sFTP or Dicommunicator is not feasible, the 
imaging may be burned to a CD and mailed to IROC RI at the address below. 
Multiple studies for the same patient may be submitted on one CD; however, 
please submit only one patient per CD. Sites using Dicommunicator may submit 
imaging via that application. Contact IROC RI with questions or for additional 
information. 
 
For FDG-PET imaging, the transferred imaging data should include uncorrected 
and attenuation-corrected PET projection data, as well as the reconstructed PET or 
PET/CT images used by the institution to achieve a response assessment. If low-
dose CT was used for attenuation correction, the acquired CT images should also 
be submitted. The imaging data submitted for central review must allow the study 
to be reconstructed and displayed in transaxial, sagittal and coronal formats using 
standard reconstruction techniques. Reconstructed MPEG clips and similar types 
of reconstructions will not be accepted. CT and MRI images similarly should be 
submitted in a format that either includes properly reconstructed multi-planar 
viewing formats in soft tissue and bone windows, or includes the thin-section axial 
acquisition data from which multi-planar reconstructions can be re-created.  
 
Address for submission: 
IROC Rhode Island 
Building B, Suite 201 
640 George Washington Highway 
Lincoln, RI  02865-4207  
Phone: (401) 753-7600 
Fax: 
(401) 753-7601 
Web: 
http://irocri.qarc.org 
 
 
 

  
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15.0 
RADIOTHERAPY GUIDELINES 
Timing of protocol therapy administration, response assessment studies, and surgical 
interventions are based on schedules derived from the experimental design or on established 
standards of care. Minor unavoidable departures (up to 72 hours) from protocol directed therapy 
and/or disease evaluations (and up to 1 week for surgery) for valid clinical, patient and family 
logistical, or facility, procedure and/or anesthesia scheduling issues are acceptable (except where 
explicitly prohibited within the protocol). 
 
Radiotherapy (RT) for patients on COG protocols can only be delivered at approved COG 
RT facilities.  
 
Central Review of response is necessary prior to submission and initiation of the RT plan. 
Central review will also confirm sites of LMA which will require radiation. Any radiation 
therapy delivered not consistent with the central review response categorization will be 
considered a major protocol deviation. 
 
15.1 
General Principles – Risk-Adapted RT  
In advanced-stage or high-risk patients, involved field radiotherapy (IFRT) has 
traditionally encompassed a large volume of normal tissue due to anatomically widespread 
sites of multiple disease and extra-lymphatic spread. One of the aims of this study is to 
reduce the volume of radiotherapy in order to reduce potential acute and late toxicities, 
while maintaining disease control. This will be done in two ways: 1) omitting radiotherapy 
(RT) among patients without large mediastinal adenopathy (LMA) who also have an early 
response to systemic therapy (RRL as defined in Section 10.3.2) and 2) limiting the volume 
of RT among patients who receive this treatment by employing involved site RT (ISRT). 
 
15.2 
Indications for Radiotherapy  
The indications for RT include disease sites with the following characteristics: 
 
1. Initial large mediastinal adenopathy defined in Appendix I. All patients with LMA will 
receive ISRT regardless of RRL status. 
2. SRL as determined by FDG-PET scan residual avidity (Deauville score 4 or 5) after 
the first 2 cycles of chemotherapy (PET2) (See Section 10.3.2) 
 
With the exception of LMA, disease that reverts to being PET negative after 2 cycles of 
chemotherapy (RRL) will not be treated with RT. 
 
Based on these guidelines, a volume reduction over standard involved field radiotherapy is 
envisioned that will help reduce acute and late toxicity. Accordingly, the volume of lung, 
heart, breasts, salivary glands, and abdominal structures irradiated are likely to be reduced 
for this patient population. The long-term goal is to maintain high cure rates with lower 
toxicity. 
 
15.3 
Radiotherapy Dose and Schedule for SRL Lesions 
Note: Lesions which were Deauville 3 (and hence RRL by definition) at PET2 will be 
considered as such even if the lesions remain Deauville 3 on PET5; these lesions will not 
receive RT unless they demonstrate progression at PET5. 

  
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15.3.1 PET Negative After 5 Cycles of Systemic Therapy (PET score 1-2) 
Radiotherapy will consist of 2100 cGy in 14 fractions of 150 cGy per day. The 
treatment will be given 5 days per week. All fields should be treated once each 
day. The total elapsed treatment time will be approximately 2.8-3.0 weeks 
(14 sessions) for each site.  
15.3.2 PET Positive After 5 Cycles of Systemic Therapy (PET score 3-5) 
For patients receiving RT (who have not been removed from study due to PD) who 
have PET score 3-5 at the end of chemotherapy, a boost of an additional 900 cGy 
in 6 fractions is to be prescribed to bring the total dose to 3000 cGy to PET avid 
sites (i.e. to the post-chemotherapy GTVPET+ volume with an additional PTV 
margin). The post-chemotherapy CTV and PTV should receive 21 Gy as outlined 
in Section 15.7. The additional boost dose is only given to that component of the 
target volume that is PET-avid (defined as PET score 3-5). 
 
15.4 
Timing of Radiotherapy and Starting Criteria 
Treatment should begin no later than 6 weeks from the start of Cycle 5 of chemotherapy 
or when blood counts have recovered. Criteria include an ANC > 750/μL and 
platelets > 75,000/μL prior to treatment for each site. 
 
15.5 
Credentialing Requirements 
Patients may receive RT with photons or proton therapy. Intensity Modulated Radiation 
Therapy (IMRT) or protons are allowed in circumstances where the treating oncologist 
believes these provide significant clinical benefits compared to conventional anterior-
posterior parallel opposed pairs. Investigators may use proton therapy only if their 
institution has been appropriately credentialed by the IROC Houston QA Center. 
Credentialing requirements for proton therapy which include, but are not limited to, 
completion of a proton facility questionnaire, a successful IROC Houston site visit, which 
identifies the proton technique(s) which can be used, annual monitoring of the proton beam 
calibration, e.g. IROC Houston’s monitoring program, and successful digital phantom data 
submission to IROC Houston (details for data submission are available at 
http://rpc.mdanderson.org). Centers not previously credentialed for use of proton therapy 
treatment of thoracic tumors in COG trials must irradiate the Proton Lung Phantom 
available from IROC Houston. 
 
The credentialing requirements by treatment modality are summarized in the following 
table. 
 
 

  
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RT 
Credentialing 
Requirements 
Web Link for Credentialing Procedures and Instructions 
http://irochouston.mdanderson.org 
Treatment Modality 
 
3D-CRT 
Photon 
Proton 
Key Information 
Facility 
Questionnaire 
X 
X 
X 
The IROC Houston electronic facility questionnaire (FQ) 
should be completed or updated with the most recent 
information about your institution.  To access this FQ, email 
irochouston@mdanderson.org to receive your FQ link. 
Credentialing 
Status Inquiry 
Form 
X 
X 
X 
To determine if your institution has completed the 
requirements above, please complete a “Credentialing Status 
Inquiry Form” found under Credentialing on the IROC 
Houston QA Center website 
(http://irochouston.mdanderson.org). 
Phantom 
Irradiation 
 
X 
X 
Sites treating with IMRT and not previously credentialed for 
its use on COG trials must irradiate IROC Houston’s head 
and neck phantom. Proton centers must complete all 
required phantom irradiations for IROC Houston 
credentialing, including the proton lung phantom. 
Instructions for requesting and irradiating the phantoms are 
found on the IROC Houston web site. 
(http://irochouston.mdanderson.org).   
Motion 
Management 
(when used) 
 
X 
X 
If treating with IMRT and gating or tracking methods are 
used to compensate for respiratory motion, IROC Houston’s 
Lung Phantom must be irradiated with its accompanying 
reciprocating platform to simulate motion. Instructions for 
requesting and irradiating the phantom are found on the 
IROC Houston web site 
(http://irochouston.mdanderson.org) 
Credentialing Notification Issued to: 
Institution 
 
 
 
Institution will be credentialed for the treatment modality 
that they intend to use on all patients. IROC Houston QA 
Center will notify the institution that all desired 
credentialing requirements have been met. 
 
15.6 
Equipment 
15.6.1 Modality 
Photons with a nominal energy of ≥ 4 MV and ≤ 18 MV are preferred. In the 
unusual circumstance of an isolated superficial lesion, electron fields may be used. 
Conventional, conformal, and IMRT techniques are allowed in this study. Patients 
receiving IMRT should have this delivered with 6 MV photon beams, and 18 MV 
photon beams should not be used to deliver IMRT.  
 

  
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Proton therapy may be delivered using passively scattered proton or scanning 
beams provided that the specific beam line in use has been appropriately 
credentialed. Selected proton energies should be high enough to adequately 
provide target coverage. Range shifters may be used to make fine adjustment to 
the maximum proton range.  
 
IMRT or protons may be used in the thoracic region or for treatment of tumors 
affected by respiratory motion when the degree of motion can be limited to 0.5 cm 
relative to the mean position (end-to-end tumor motion is less than 10 mm) using 
motion management techniques if needed. Use of IMRT in conjunction with gating 
or tracking techniques requires credentialing by the IROC Houston (see 
Section 15.9 below). The Motion Management Reporting Form shall be submitted 
with the Quality Assurance Documentation materials whenever motion 
management techniques are used. 
 
15.6.2 Guidelines and Requirements for the Use of Proton Beam Therapy 
Investigators using proton beam therapy will be required to comply with current 
guidelines for the use of protons in National Cancer Institute sponsored 
cooperative group trials. These guidelines are available on the IROC Houston 
website at http://irochouston.mdanderson.org. These guidelines specify the 
following for the participating institution: dose reporting will be in Cobalt Gy 
equivalent (1 CGE = 1 proton Gy * 1.1) which is the same as ICRU 78 DRBE; 
radiation doses shall be prescribed to protocol specified definitions for gross 
(GTV) and clinical (CTV). For CT number to proton stopping power calibration 
uncertainties, set-up uncertainties and target motion, additional margin, smearing, 
range of modulation will be added on a per beam basis for passive scattering and 
uniform scanning. The proton institution is required to participate in on-site and 
remote review according to COG requirements. 
 
15.6.3 Treatment Planning 
CT (volumetric) based planning is required to optimize dose to the targeted volume 
while documenting dose to normal tissues. Slices ≤ 5 mm thick should be taken 
throughout the extent of the irradiated volume. In cases where the mediastinum is 
being treated, the entire lung volume should be scanned to create accurate 
estimates of whole lung dose. There are mandatory requirements for submission 
of the dose to selected normal tissues (see Sections 15.11 and 15.12). A Dose 
Volume Histogram (DVH) is necessary to determine target coverage and evaluate 
dose to normal tissues. 
 
15.6.4 In-Room Verification of Spatial Positioning 
Image guidance to verify patient position is an important standard feature of 
contemporary RT delivery. Institutional protocols should be in place common to verify 
patient position. Orthogonal pair (AP and lateral) portal images (MV or kV) or cone-
beam imaging are acceptable. There is no central review of verification imaging. 
 
15.7 
Target Volumes 
Recommendations of The International Commission on Radiation Units and 
Measurements (ICRU) for prescription methods and nomenclature will be utilized for this 
study (Reports 50, 62, and 78).  
 

  
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The indications for RT are outlined in Section 15.3 and should be the principal 
determinants in defining the gross tumor volume (GTV), the clinical target volume (CTV) 
and the planning target volume (PTV). It is important to note that the use of bony anatomy 
to define RT field borders is not employed in this protocol, as the intent is to utilize 
contemporary image-guided RT and volumetric definitions.  
 
Targets at non-contiguous sites need to be separately identified. Numerical or 
descriptive suffixes can be used such as GTV2, CTV2, PTV2; or GTV-pelvis, 
CTV-pelvis, PTV-pelvis, for instance. Generally, in cases for which two PTV targets 
are >5 cm apart, these should be treated separately unless there is a compelling reason 
to treat uninvolved tissue in between. 
 
Note: The following definitions apply only to sites of disease that meet the criteria for 
receiving RT. 
 
15.7.1 Pre-Chemotherapy (or Pre Surgery) GTV 
The pre-chemotherapy GTV includes nodal and non-nodal tissues that were 
involved with lymphoma prior to any treatment, and meet the criteria for requiring 
RT (LMA or SRL). Imaging criteria for defining whether a nodal or extra-nodal 
site is involved are described in Section 10.2. 
 
15.7.2 Post-Chemotherapy GTV 
The post-chemotherapy GTV includes imaging abnormalities persisting after all 
planned chemotherapy. For example, residual enlargement of anterior mediastinal 
tissue that has not returned to normal on anatomic or functional imaging following 
chemotherapy. Note that for RT planning purposes the residual abnormality seen 
on CT is considered part of the post-chemotherapy GTV, even when PET-negative. 
The GTV (and CTV) are not just the PET-avid sites. It is critical to note that the 
Deauville cutoffs used for PET response differ between PET2 and PET5. 
Following completion of 5 cycles of chemotherapy, the GTV is subdivided into: 
 
GTVPET+: An area of imaging abnormality demonstrating the lymph node(s) that 
remain PET avid (Deauville score > 2, uptake greater than mediastinal blood pool. 
See Table 10.3.2) following completion of all 5 chemotherapy cycles. 
 
GTVPET- : An area of imaging abnormality on CT demonstrating the lymph 
node(s) as no longer PET avid (Deauville score 1-2) after completion of all 
5 chemotherapy cycles. 
 
15.7.3 Post-Chemotherapy Clinical Target Volume (CTV)  
The CTV should include the lymph nodes/tissues originally involved with 
lymphoma (i.e. the pre-chemotherapy GTV), but must take into account the 
reduction in axial diameter that has occurred with chemotherapy. The concept is 
that all areas of lymphoma infiltration needs to be targeted, but the aspects of the 
lymphoma with a pushing border in the mediastinum that displaces normal lung 
(or para-aortic nodes displacing bowel) need not be targeted when that normal 
tissue relaxes back into a normal anatomic position as the lymphoma responds to 
systemic therapy. Anterior mediastinal disease will shrink in axial diameter away 
from the lung with chemotherapy, and the width of the post-chemotherapy CTV 
should reflect this change.  

  
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Delineation of the CTV requires consideration of the expected routes of disease 
spread, and the quality of pre-treatment imaging. For example, in some 
circumstances it can be difficult to clearly rule out disease (e.g. in the aorto-
pulmonary window) or not possible to exactly locate the abnormality within an 
exact location in an axial image of the involved nodal space. Consideration of other 
clinical and imaging factors (e.g. extent of involvement in nearby nodal regions, 
bulk of disease) should guide decisions regarding whether to include or exclude 
such areas from the CTV.  
 
The CTV expansion cannot be rigidly determined a priori as there can be 
considerable uncertainties inherent with GTV delineation due to inaccuracies in 
matching patient positioning and the variable internal anatomy shifts that change 
with disease volume and patient position between diagnostic and treatment 
positions. Typically, on a given axial cut, the whole nodal fossa/level that 
contained the initially abnormal node(s) will be contoured as the CTV. As a 
guideline, a margin of 1.5 cm above and below lymph nodes involving lymphoma 
is recommended.  
 
Uncommonly, normal nodal tissue may be included in the CTV if located between 
two anatomically close (i.e. within 5 cm) sites requiring RT that are going to be 
joined and treated as a single volume. 
 
15.7.4 Internal Target Volume (ITV)  
The ITV encompasses the CTV with an added margin to account for variation in 
shape and motion within the patient. Respiratory motion, for example, will produce 
movement of the mediastinal structures and spleen, and an additional margin 
around the CTV is required to account for this.  
 
15.7.5 Planning Target Volume (PTV)  
The PTV should encompass the CTV and ITV, and accounts for geometric 
variation in daily setup. It should take into account the reproducibility of the 
immobilization, and the accuracy of the daily setup imaging. 
 
Notably, an isometric 5 mm expansion around a CTV that includes inferior 
mediastinal structures will rarely provide adequate coverage. Typically ITV+PTV 
margins around CTVs in the neck will be 3-5 mm. 
 
ITV+PTV margins in the mediastinum should range from 8-15 mm and should not 
be as small as 5 mm. ITV+PTV margins around the spleen should be 10-15 mm, 
unless 4D simulation demonstrates the need for a larger margin. 
 
When proton therapy is used, the GTV and CTV are the same as for photons. 
 
In patients with moving tumors within the lung, the iGTV is required for 
calculation of dose for proton therapy. The iGTV includes the GTV with a margin 
for GTV respiratory motion. The PTV is defined differently for the purpose of dose 
reporting vs. treatment planning. For dose reporting purposes the PTV will include 
a margin which is added to the CTV in 3-dimensions. The margin should be 

  
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consistent with the motion control and setup accuracy for the particular type of 
treatment (scattered versus scanning) at the treating proton center.  
 
For treatment planning, the goal will be CTV coverage at 100% directly with 
specific measures taken for each specific uncertainty. The PTV will vary with each 
individual field and will require additional adjustment including (1) the lateral 
margins, (2) smearing of compensator, (3) range of beam (depth of penetration) 
and, (4) modulation (number of required Bragg peaks). Adjustments to any of the 
aforementioned parameters (usually 2-7 mm) will be based on the range 
uncertainty, CT number uncertainty, internal motion, and set up error determined 
for the particular body site at the individual proton institution. The following 
parameters must be explicitly reported for each beam when using passive 
scattering or uniform scanning: range, modulation, smearing radius of the 
compensator, set-up margin (SM) and PTV margin. The specifics of dose reporting 
for the proton PTV and recommendations regarding the PTV margin are discussed 
in Section 15.8.4. 
 
When there is extension within the lung with lymphoma with corresponding 
respiratory motion of the tumor, certain guidelines are required to ensure 
appropriate target coverage. For the iGTV approach, adequacy of coverage in both 
end-inhale and end-exhale phases must be reviewed.  
 
15.7.6 Special Circumstances 
15.7.6.1 No residual tissue seen on planning CT 
Patients with LMA typically have significant reduction in the 
mediastinal bulk with chemotherapy. The principle of creating the CTV 
is to include all nodal tissue originally involved, however this may be 
challenging to visualize and localize, particularly when a complete 
response has been achieved at the superior or inferior limits of the 
initially involved site. When possible, image fusion of the planning CT 
and the pre-treatment imaging should be employed to identify the 
superior-inferior extent of disease, and this extent should be included in 
the CTV. At times, this may require contouring of macroscopically 
normal anatomy (e.g. the anterior pericardium) in cases where at CR has 
been achieved. 
 
Similarly, a SRL that requires ISRT may have achieved a CR by the time 
chemotherapy is completed. In this case, fusion of pre-chemotherapy 
imaging may aid delineation of the appropriate CTV, recognizing that 
differences in the patient positioning may create uncertainty about the 
accuracy of the fusion. The nodal tissue/fossa at the level of the node(s) 
requiring RT should be contoured as the CTV with a patient-specific 
margin for uncertainty of target localization given the absence of 
macroscopic imaging abnormalities. 
 
15.7.6.2 Chest wall invasion 
On occasion, HL, at presentation, may involve or invade the chest wall, 
particularly at the anterior aspect. Despite chemotherapy response that 
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included in the CTV definition as an area of lymphoma infiltration that 
should be targeted. If the chest wall disease is extensive, 3D conformal 
techniques or IMRT may be used to avoid excess dose to the lungs or 
heart. Pleural or pericardial effusions are not included in determination 
of GTV/CTV. 
 
15.7.6.3 Sites of nodal disease adjacent to site of mediastinal bulk 
There may be sites of disease adjacent to a LMA mass. With the 
exceptions noted below, the field edge required to treat the LMA should 
not cut through initially involved sites of disease, even if the latter do not 
require RT based on response criteria. For example, involved 
supraclavicular or neck nodes adjacent to a site of LMA should be 
included unless they are sufficiently separate to allow the field edge to 
cover the LMA without cutting through the initially involved sites in the 
supraclavicular fossa/neck.  
 
This guideline does not apply, however, when the additional toxicity of 
extending the treatment volume would be potentially significant and 
avoidable. For example, the irradiation of the axillae in females, the high 
cervical nodes (and salivary structures, and cardiophrenic/diaphragmatic 
nodes (heart) should be avoided when these sites do not meet the response 
criteria for irradiation. In such situations it is permissible to cut through 
involved sites that do not meet the slow-response indication for RT. 
 
Uninvolved adjacent sites should never be included; with the exception 
of the linking of two closely approximated sites that each meet criteria 
for requiring RT (see below). Clinicians may contact IROC RI or one of 
the study radiation oncologists to discuss specific cases as necessary. 
 
15.7.6.4 Joining separate sites of disease receiving RT 
When two or more sites of disease meet criteria for receiving RT, these 
should typically be treated as separate targets if the PTV volumes are 
> 5 cm apart. Separate sites may be joined at the discretion of the treating 
oncologist in cases where the intervening nodal tissue was involved, or 
when issues of setup variability or concerns about the accuracy of 
dosimetry within small shielded areas between two treated sites may 
make linking two volumes preferable. When this is done, care should be 
taken to consider and treat the appropriate nodal anatomy in the 
intervening volume. 
 
15.7.7 Specific Anatomic Sites 
15.7.7.1 Spleen 
Splenic involvement per se is not an indication for splenic RT on this 
protocol. The spleen will be treated if it is a site of SRL. In such cases, 
the entire spleen should be targeted as the CTV, not just the slow-
responding nodule. The spleen will be treated if it contains a SRL. In 
such cases, the entire spleen should be targeted as the CTV, not just the 
slow-responding nodule. 
 

  
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NOTE: For patients with involvement of the spleen, vaccination against 
Pneumococcus, Haemophilus influenza and Meningococcus is strongly 
recommended prior to therapy. If not performed at this time, it should 
be administered prior to beginning radiation therapy. Waiting to 
immunize until after Cycle 5 may be affected by muted immune response 
at that time. 
 
15.7.7.2 Lung, heart, liver, bone or other parenchymal nodules 
There are explicit definitions of extranodal involvement in Section 10.2.1. 
These sites are treated only if they are sites of SRL. Whole organ 
irradiation is to be avoided. If lung parenchymal involvement is adjacent 
to other sites of GTV, the radiation oncologist may use their discretion 
about inclusion of such involved sites in the GTV definition with the 
guiding principal that this protocol aims to reduce the volume of 
radiotherapy in order to reduce long term toxicities, but irradiate those 
regions of initial mediastinal bulky involvement or slow response to 
chemotherapy. 
 
15.7.7.3 Unilateral neck 
Only the involved nodal site in the neck should be treated. It is not 
necessary on this protocol to treat the entire superior-to-inferior extent 
of the nodal compartment. In most cases fusion of pre-chemotherapy 
imaging to the planning CT scan can facilitate localization of the 
appropriate GTV and CTV. In many cases, where there is some 
uncertainty in exact location of the nodal mass, the entire axial extent of 
the nodal compartment may be contoured as the CTV, but it is not 
necessary to treat the entire unilateral neck. In particular, irradiation of 
the salivary glands should be avoided unless there was immediately 
adjacent slow responding disease making this necessary.  
 
15.7.7.4 Bilateral neck 
If necessary to treat both sides of the neck, the target volumes should be 
contoured independently. Some patients may have asymmetric 
irradiation of the neck if the levels of involvement are different. 
 
15.7.7.5  Unilateral axilla 
Arms should preferably be positioned akimbo (hands on hips). It is not 
necessary to treat the entire axillary nodal fossa based on bony 
landmarks, although in some cases ISRT target volume definitions may 
be equivalent to doing this. The superior and inferior edge of the ISRT 
volumes should be defined as per the volumetric definitions described 
above, not by bony landmarks. 
 
15.7.7.6 Mediastinum (including hila) 
In contrast to prior protocols, bony landmarks are not employed to 
delineate mediastinal volumes. In cases where the mediastinal disease is 
enmeshed within the major vessels, it is acceptable to contour the entire 
mediastinum as the CTV at levels above the heart. However, at the level 
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precisely as possible using the definitions above without including the 
heart in the CTV (unless there is direct pericardial/cardiac involvement). 
Hila should be considered independently and included in the GTV/CTV 
only when staging imaging showed them to be involved at diagnosis. 
Mediastinal involvement does not automatically require hilar nodes to 
be encompassed in the target volume. In cases with LMA with internal 
mammary node involvement, these nodes should be included in the 
CTV, as should areas of chest wall invasion. 
 
In circumstances when the mediastinum is being treated for protocol-
directed indications (mediastinal bulk or slow early response) and when 
the supraclavicular fossa(e) or neck nodes were involved but responded 
rapidly (RRL), the field may be extended at the discretion of the treating 
oncologist to include the involved neck nodes superiorly to avoid placing 
a field border through involved sites. This is not necessary, and will not 
be counted as a protocol deviation.  
 
15.7.7.7 Waldeyer’s ring 
Waldeyer’s ring will only be treated if it is a site of SRL. The extent of 
disease may be difficult to localize based on PET and CT alone. 
Pre-treatment MRI is preferable, if possible. It is not necessary to treat 
the entire Waldeyer’s ring however, unless there is evidence of bilateral 
involvement.  
 
15.7.7.8 Spleen only 
In those patients scheduled to receive RT to the spleen because of SRL, 
the entire spleen should be treated with a 1.0 -1.5 cm field margin to 
account for respiratory movement. The post-chemotherapy spleen volume 
should be used, as defined by CT scan. If the paraaortic lymph nodes are 
not part of the GTV, then they do not need to be specifically included. 
 
15.7.7.9 Paraaortic lymph nodes only 
Involved para-aortic lymph nodes may be treated in cases where there is 
a SRL. In cases where the lymph nodes are difficult to visualize 
following chemotherapy, the CTV should encompass a symmetric 
expansion around the para-aortic vessels of at least 12 mm. It is not 
necessary to include the spleen in the CTV unless it would otherwise 
meet criteria for requiring RT. 
 
15.7.7.10 Pelvic lymph nodes 
In cases where the lymph nodes are difficult to visualize following 
chemotherapy, the CTV should encompass a symmetric expansion 
around the major pelvic vessels of at least 10 mm. When possible, MRI 
simulation and/or fusion of pelvic MRI with planning CT should be 
performed to contour the ovaries and facilitate estimation of ovarian 
dosimetry. Females should have consideration for an oophoropexy 
moving the ovaries away from the PTV volume. The male gonads should 
also be shielded using a clam-shell type block, as appropriate. 
Positioning the legs apart may facilitate testicular shielding. 

  
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15.7.7.11 Pericardium 
The intent is to avoid whole heart irradiation. If the pericardium was 
extensively involved by gross lymphoma and part of the GTV definition, 
the mean dose to the heart should be limited to < 15 Gy. Where the 
superior or anterior aspect of the pericardium was involved requiring 
radiotherapy, that region should be targeted in continuity with the 
mediastinum where feasible. A shrinking field technique may be 
required to limit the mean heart dose to < 15 Gy. Pericardial effusions at 
diagnosis do not require whole heart irradiation. Isolated inferior 
pericardial or peri-diaphragmatic nodes may be treated separately from 
the main mediastinal volume when indicated. 
 
15.7.7.12 Sites of metastatic disease or isolated extranodal disease (lung, liver, bone) 
Sites of metastatic or isolated extranodal disease are treated only if they 
meet the definition of SRL. The intent, however, is to avoid whole organ 
irradiation. For lung nodules, when the SRL criterion applies, the 
involved portion of lung (or lungs) should be treated with at least a 
1.5 cm margin. Larger margins to account for respiratory movement are 
allowed. In cases of direct extension into the lung from mediastinal disease 
or limited central pulmonary involvement particularly in a pattern of 
lymphatic spread, the part of the lung to be irradiated should be in 
continuity with the mediastinal fields. Patients presenting with a pleural 
effusion need not receive treatment to the involved hemithorax. Similarly, 
isolated liver or bone lesions meeting criteria for SRL may be treated with 
GTV, CTV, and PTV definitions as described above. Whole liver or bone 
RT is rarely required. 
 
15.7.7.12.1 Solitary Bone or Bone Marrow Lesion 
If a solitary bone or focal region of marrow is found to be 
involved at the time of early response assessment, it should 
be treated to 2100 cGy with at least a 1 cm margin around 
the radiological abnormality. No more than 3 sites should 
be considered for radiation if multiple bony sites remain. 
Some residual metabolic activity in bone may reflect bony 
healing, and thus interpretation within the context of the 
response of other involved areas may be appropriate. In 
these situations WebEx conference between IROC, treating 
institutions and study committee chairs should be 
considered. The sites can be determined in evaluation and 
review with IROC. 
 
15.7.7.12.2 Multiple Sites of Bone or Bone Marrow Involvement 
These sites need not be irradiated as part of the treatment 
for Stage IV disease. 
 

  
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15.7.7.13 Supra and subdiaphragmatic disease 
Patients requiring RT both above and below the diaphragm can be treated 
with sequential or concurrent fields at the discretion of the treating 
oncologist. If the treatment volumes approach what was historically 
termed subtotal nodal irradiation, sequential RT treatment courses with 
a three week time interval may help avoid significant myelosuppression. 
 
15.7.7.14 Partial Response at the end of Chemotherapy (PET positive) 
Nodal masses that are undergoing RT and have PET score > 2 after 
5 cycles of chemotherapy should have received a boost with an 
additional of 900 cGy in 6 fractions to be delivered to the GTVPET+ 
plus an appropriate margin (total dose to PET avid sites = 3000 cGy) 
immediately after completion of 2100 cGy course to the initial PTV. 
 
15.8 
Target Dose 
The total dose will be 2100 cGy in 14 fractions of 150 cGy. In the case of a partial response 
with persistent FDG uptake at the end of chemotherapy, a small volume boost of an additional 
900 cGy in 6 fractions is to be prescribed to bring the total dose to 3000 cGy to such sites.  
 
15.8.1 Dose Definitions 
The absorbed dose is defined in centigray (cGy)-to-muscle. Proton dose will be 
reported in Gy (relative biological effectiveness, RBE), where 1 Gy (RBE) = 
proton dose Gy x RBE, and RBE = 1.1.  
 
15.8.2  Plan Normalization 
There are several ways in which plans cans be normalized, most commonly 
normalization to a point or to an isodose surface. In all cases the isodose coverage 
around GTV, CTV and PTV should be evaluated and the dose uniformity 
requirements in Section 15.8.4 shall be satisfied. If normalization is to a point, the 
point should be in solid tissue, not in lung. If the central axis falls beneath a block 
in any field, an appropriate off-axis point may be used for calculations. 
 
15.8.3  Heterogeneity corrections 
Calculations must take into account tissue heterogeneity and should be performed 
with CT-based treatment planning to generate dose distributions and treatment 
calculations from CT densities. When treatment beams traverse lung, planning 
must be performed using an approved dose calculation algorithm. Approved 
algorithms include: convolution superposition, collapsed cone convolution, and 
Monte Carlo. When protons are used, correlation between the institutional CT 
treatment planning system Hounsfield Units and “relative proton stopping power” 
must be established and documented. Proton therapy should be used with extreme 
caution when any of the treatment beams traverse normal lung parenchyma. 
 
15.8.4  Dose Uniformity 
For all treatments, 95% of the prescription dose must cover > 99% of the CTV and no 
more than 10% of the CTV or PTV should receive more than 110% of the protocol 
dose. In addition, 95% of the prescription dose should cover > 95% of the PTV. The 
maximum dose in the patient should not exceed 120% of the prescription dose.  
 

  
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No more than 0.03 cc of the PTV should receive less than 85% of the prescription dose. 
• If > 0.03 cc of the PTV receives 75-85% of the prescription dose, this will be 
a minor deviation. 
• If > 0.03 cc of the PTV receives <75% of the prescription dose, this will be a 
major deviation. 
 
15.8.4.1 Proton Specific Guidelines: 
For protons, treatment planning does not specifically use a traditionally 
defined PTV for treatment planning. All uncertainties are taken into 
account explicitly to create a robust plan that provides full dose coverage 
of the CTV, generally from each beam – proton plans should be 
evaluated for adequate coverage provided by each individual beam and 
for PTV coverage from the summation of all beams. For passive 
scattering and uniform scanning, the aperture margin must include the 
appropriate beam penumbra for the selected beam energy, and PTV 
margin. These margins depend on the patient setup techniques used at 
the treating proton center. The aperture margin may be expanded further 
if a cold spot occurs near the edge of CTV due to insufficient lateral 
scatter. The smearing radius for the range compensator must be equal to 
the PTV margin. The beam range should be equal to the maximum water 
equivalent depth of the CTV plus a range margin. The main part of the 
range margin comes from uncertainty in CT accuracy and the conversion 
of the Hounsfield units to proton stopping power ratios. Additional range 
margin should be applied if internal motion could increase the water 
equivalent depth of the CTV. The modulation width should be increased 
consistently to ensure proximal coverage of the target volume. The beam 
range may be adjusted at the discretion of the treating radiation 
oncologist based on normal tissue dose concerns. A PTV should be 
created by a uniform expansion from CTV for reporting purposes. A 
potential exception is when the range margin is smaller than the PTV 
expansion. As a result, the beam may not penetrate deep enough to 
sufficiently cover the distal portion of the PTV. This may occur for shallow 
target volumes where the maximum depth of the CTV is small and the range 
margin is small. This scenario is not expected for this protocol; however, 
such incomplete coverage of the PTV will not constitute a planning 
deviation because the plan should be sufficiently robust to cover the CTV 
with the protocol specified dose accounting for all uncertainties. 
 
15.8.5  Interruptions, Delays and Dose Modifications 
There will be no planned rests or breaks from treatment, and once RT has been 
initiated, treatment will not be interrupted except for any life threatening infection 
or severe hematologic toxicity defined as ANC < 300/ µL or platelets less than 
40,000/µL during the course of treatment. Under these circumstances, RT shall be 
delayed until the counts have recovered. Blood product support should be 
instituted according to institutional/protocol guidelines. The reason for any 
interruptions greater than 3 treatment days should be recorded in the patient’s 
treatment chart and submitted with the QA documentation. There should be no 
modifications in dose fractionation due to age or field size. If any area has been 
previously treated (emergently), care should be taken not to exceed normal tissue 
tolerance levels. 

  
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15.9 
Treatment Technique 
Treatment in most cases should be delivered through AP/PA parallel opposed fields. IMRT 
or protons may be used provided target coverage and homogeneity requirements are met. 
In certain circumstances, the use of electron beam RT to treat superficial sites is permitted. 
Methods of patient immobilization and organ motion can be undertaken as per institutional 
protocols. Patients receiving RT to the neck should be immobilized in a thermoplastic 
mask. 4-D simulation and breath-hold techniques are permitted to estimate organ motion 
and minimize PTV expansions. 
 
15.9.1 Selection of Proton Beam Arrangements 
There are uncertainties (1-3 mm) in the distal range of the proton beam in which 
the RBE may be greater than 1.1; therefore, single proton beam plans which stop 
in the spinal cord will not be allowed.  
 
15.9.2 Motion Management and Margins to Account for Target Volume and Organ Motion 
Considering motion of normal tissues and target volumes is important. The internal 
target volume (ITV) is defined as the CTV surrounded by the internal motion (IM) 
component of the PTV and is meant to account for potential motion of the CTV. 
If adequate clinical data do not exist to define the IM component of the PTV 
margin, the following suggestions are provided: 
 
• 
For a CTV susceptible to physiologic motion, a margin of at least 0.5 cm 
should be added to the CTV prior to PTV margin expansion or a PTV margin 
of 1 cm should be chosen, unless additional motion management (e.g. active 
breath hold and/or daily CT imaging) are employed. 
• 
For tumors of the thorax or abdomen, an assessment should be made to 
determine the extent of motion present. PTV margins should include this 
motion as a component. In the mediastinum the PTV margin around the CTV 
should be ≥8 mm. 
• 
IMRT or protons may be used for tumors of the thorax only if the degree of 
tumor motion is assessed and can be accounted for in an ITV. Motion of the 
target volume in three dimensions (cranial, caudal, anterior to posterior, and 
lateral) may be determined by 4-dimensional CT, respiratory gated CT, or 
other accepted techniques. 
• 
A description of the method used and evidence (i.e., observed motion during 
fluoroscopy, motion of surrogate markers using camera systems, or analysis 
of 4-D CT) of the remaining tumor motion should be submitted on the Motion 
Management Reporting Form with the Quality Assurance Documentation 
materials as noted in Section 15.13. 
 
NOTE: For patients treated with IMRT, use of gating or tracking methods to 
compensate for respiratory motion requires irradiation of IROC Houston’s 
Thorax-Lung Phantom with accompanying reciprocating platform to simulate 
motion. Contact IROC Houston (http://irochouston.mdanderson.org) for 
information about their phantoms. 
 

  
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15.10 Treatment Position 
The patient should be treated entirely in the supine position. Some institutions may incline 
female patients to reduce breast dose, and this is acceptable. Reproducible setups are 
critical, and the use of immobilization devices are strongly encouraged. Consideration 
should be given to implications for inter- and intra-fraction motion when using 
non-standard position approaches. Standard immobilization devices for the torso, 
extremities or head and neck are to be used. For IMRT delivery approaches, the methods 
used for localization and immobilization of both patient and tumor are critical. The imaging 
studies should provide a clear assessment of the target volume with the patient in the 
treatment position. Anesthesia or sedation may be required in certain patients, such as very 
young patients, to prevent movement during simulation and daily RT treatments. 
 
15.11 Organs at Risk 
 
15.11.1  Lungs 
No more than 35% of the entire lung volume (i.e. bilateral lung) shall receive a 
cumulative dose greater than 2000 cGy (i.e. V20 should be ≤ 35%). The bilateral 
mean lung dose must be less than 1500 cGy. 
 
15.11.2  Kidneys 
If the GTV encroaches on one of the kidneys, the mean dose to the designated 
ipsilateral kidney should not be greater than 1500 cGy. In that instance, 50% of the 
contralateral kidney should receive no more than 800 cGy and no more than 25% 
should receive a cumulative dose greater than 1200 cGy. If both kidneys require 
treatment (beyond standard APPA fields to the para-aortic region) both kidneys 
may receive a mean dose of 1200 cGy and no more than 50% of either kidney 
should receive 1500 cGy. 
 
15.11.3 Liver 
No more than 50% of the liver shall receive a cumulative dose greater than 
1500 cGy. No more than 25% of the liver may receive a dose greater than 
2100 cGy. 
 
15.11.4 Spinal Cord 
Whenever the spinal cord is included in adjacent treatment areas, the field borders 
will be separated by an appropriate gap. The gap dose to the spinal cord at that gap 
should be calculated and submitted as part of the Quality Assurance 
Documentation. The maximum dose to the spinal cord for all combined RT 
treatments must be less than 4500 cGy. 
 
15.11.5 Heart 
For a prescribed dose of 2100 cGy, the goal should be to limit the mean heart dose 
to less than 1500 cGy. If mean heart dose is anticipated to be greater than 
1500 cGy, then IMRT deep inspiration breath hold, or proton therapy should be 
considered. For a prescribed dose of 2100 cGy, a mean heart dose exceeding 
1800 cGy will be considered a protocol deviation unless reviewed with IROC and 
a study radiation oncologist and deemed unavoidable prior to treatment. If a 
900 cGy boost is required (i.e. 30 Gy total prescribed dose) the total (composite) 
mean heart dose should not exceed 2100 cGy. 
 

  
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15.11.6 Other Organs at Risk 
It is important that in addition to the OARs noted above, dose volume histograms 
(DVH) be submitted for the female breast (left, right and combined), and thyroid 
when any of these tissues are in the entrance or exit path of any beam. 
 
Also a DVH must be submitted for a category of tissue called “unspecified tissue,” 
which is defined as tissue contained within the skin and encompasses all tissues 
within a volume 2 cm above and below the PTV. 
 
15.12 Dose Calculations and Reporting 
 
15.12.1  Prescribed Dose 
The prescribed dose for each target volume and/or phase of treatment shall be 
submitted using the RT-1 Dosimetry Summary Form or Proton Reporting Form. 
If IMRT or proton therapy is used, the monitor units generated by the 
IMRT/ proton therapy planning system must be independently checked prior to the 
patient’s first treatment. Measurements in a QA phantom can suffice for a check 
as long as the patient’s plan can be directly applied to a phantom geometry. The 
total dose delivered shall be calculated and reported on the RT-2 Radiotherapy 
Total Dose Record.  
 
15.12.2  Scanning Limits 
The scanning limits must be adequate to produce whole organ estimates of normal 
tissue dosimetry as outlined below. Treatment of the mediastinum requires 
evaluation of the thyroid, female breasts, heart and lungs. Note that treatment of 
the spleen requires dose estimation to the heart (i.e. requiring scanning and 
contouring of the heart) in addition to the kidneys and liver. 
 
15.12.3  Normal Tissue Dosimetry 
Dose volume histograms (DVH) shall be submitted for the following organs at 
risk: female breast (left, right and combined), lungs (left, right and combined), 
thyroid, liver, kidney (right, left), and heart.  
 
These DVHs are required when the organ is in the entrance or exit path of any 
beam or beam segment. Where these organs are only exposed to “scatter dose” it 
is not necessary to scan the entire organ only for the purposes of creating a DVH. 
 
A DVH must be submitted for a category of tissue called “unspecified tissue,” 
which is defined as tissue contained within the skin and encompasses all tissues 
within a volume 2 cm above and below the PTV.  
 
15.13 Quality Assurance Documentation 
 
15.13.1 Digital Submission 
Submission of treatment plans as DICOM RT is required. Digital data must include 
treatment planning CT, structures, plan, and dose files.  
 
Submission may be by sFTP or CD. Due to the critical time constraints for 
submitting data for pre-treatment review, we encourage sites to submit data via 
sFTP to ensure that the pre-treatment reviews are completed in a timely manner. 

  
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Instructions for data submission by sFTP or CD are on the IROC RI web site at 
http://irocri.qarc.org/ under "Digital Data." Any items on the list below that are not 
part of the digital submission may be included with the transmission of the digital 
RT data or submitted separately. Screen captures are preferred to hard copy for 
items that are not part of the digital plan. 
 
Please submit the following items at least one week prior to the start of 
radiotherapy for pre-treatment review: 
 
15.13.1.1 Treatment Planning System Output 
• 
RT treatment plans including CT, structures, dose, and plan files. 
These items are included in the digital plan.  
• 
Dose volume histograms (DVH) for the composite treatment plan 
for all target volumes and required organs at risk. When using 
IMRT, a DVH shall be submitted for a category of tissue called 
“unspecified tissue.” This is defined as tissue contained within the 
skin, but which is not otherwise identified by containment within 
any other structure. DVHs are included in the digital plan. 
• 
Digitally reconstructed radiographs (DRR) for each treatment 
field with outlines of target volumes only. Submission of DRR’s 
is not required for IMRT. 
• 
Treatment planning system summary report that includes the 
monitor unit calculations, beam 
parameters, calculation 
algorithm, and volume of interest dose statistics. 
 
15.13.1.2 Supportive Data 
• 
All diagnostic imaging used to plan the target volume.  
• 
Copies of reports (radiology, operative, pathology, cytology) and 
any other information used in defining the target volumes. Note: 
Reports and imaging submitted for the central imaging review 
need not be resubmitted. 
• 
If the recommended doses to the organs at risk are exceeded, an 
explanation should be included for review by the IROC and the 
radiation oncology reviewers. 
• 
Documentation of any emergency RT administered prior to the 
protocol prescribed course of RT. Documentation should be 
provided in the form of the RT (treatment chart). 
 
15.13.1.3 Forms 
• 
RT-1 Dosimetry Summary Form 
• 
Proton Reporting Form (if applicable) 
• 
Motion Management Reporting Form (if motion management 
techniques are used) 
 
Submit the following items within 1 week following the completion 
of radiotherapy: 
• 
Radiotherapy record (treatment chart) including prescription and 
daily and cumulative doses to all required areas and organs at risk. 
• 
RT-2 Radiotherapy Total Dose Record Form. 

  
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Questions regarding the dose calculations or documentation should be 
directed to: 
 
Protocol Dosimetrist 
IROC Rhode Island  
640 George Washington Highway 
Building B, Suite 201 
Lincoln, RI 02865-4207 
Tel: 
(401) 753-7600 
Fax: 
(401) 753-7601 
Email: physics@qarc.org 
 
15.14 Definitions of Deviation in Protocol Performance 
 
 
Variation Acceptable 
Deviation Unacceptable 
Dose 
10% PTV receives > 110% of protocol 
dose but ≤ 115% 
or 
< 95% but ≥ 90% of the protocol dose 
covers 95% of PTV or 99% of CTV 
10% PTV receives > 115% of protocol dose 
or 
< 90% of the protocol dose covers 95% of 
PTV or 99% of CTV 
Volume 
Margins for CTV/PTV less than 
specified or excessively large 
A portion of the GTV or potentially tumor 
bearing area (CTV) is not included in the 
treated volume 
Organs 
at Risk 
Dose to any required OAR exceeds the 
goal stated in Section 15.11 
Will be assessed at the time of final 
review 
 
 

  
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APPENDIX I: CLINICAL AND STAGING CRITERIA FOR HODGKIN LYMPHOMA 
A. 
Stage  
 
(See the diagram below for definitions of regions). 
 
Stage I: 
Involvement of single lymph node region (I) or localized involvement of a single 
extralymphatic 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 extralymphatic 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 extralymphatic organ or site 
(IIIE), by involvement of the spleen (IIIS), or both (IIIE+S). 
 
Stage IV: 
Disseminated (multifocal) involvement of 1 or more extralymphatic organs or tissues, with 
or without associated lymph node involvement, or isolated extralymphatic 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 sweats in the preceding month. 
 
C. 
Bulk disease 
Each of the following presentations are considered "bulk" disease: 
 
• 
Large mediastinal Adenopathy (LMA):  
Mediastinal Bulk (LMA) = transverse tumor diameter > 1/3 the thoracic diameter at the 
dome of the diaphragm on a 6 foot PA upright CXR. A portable exam is not acceptable 
for measuring LMA and if this is the only exam available at the treating institution, a repeat 
exam must be performed prior to establishing bulk as it is a criterion for targeting 
subsequent radiotherapy.  
 
The hilum is technically not part of the anterior mediastinum, but if the hilar adenopathy 
is confluent with the anterior mediastinal adenopathy, it may be included in the transverse 
measurement. 
 
• 
Large extra-mediastinal nodal aggregate:  
Extra-mediastinal bulk is defined as a continuous aggregate of nodal tissue outside the 
mediastinum that measures > 6 cm in transverse dimension on axial CT or longest 
dimension on coronal or sagittal reformatted CT. This would not include a contiguous 
chain of small nodes. 
 
 

  
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D.  
Splenic lesions:  
Splenomegaly without focal lesions does not indicate splenic involvement with disease. Focal 
splenic lesions seen on an appropriately timed IV contrast enhanced CT scan can be considered 
positive if they are PET positive; small lesions below limits of detection by PET/CT must be 
confirmed by ultrasound or MRI, and are also considered positive. Diffusely increased splenic FDG 
uptake greater than normal liver parenchymal FDG uptake but in the absence of lesions seen on CT 
will not be considered evidence of involvement at diagnosis. 
 
E.  
E-Lesions Defined:  
Extra-lymphatic structures contiguous with sites of lymph node involvement are considered E-
lesions (particularly lung). Pleural, pericardial, or chest wall infiltration by an adjacent nodal lesion 
that is PET positive would be considered an E-lesion. Liver and/or bone marrow involvement is 
not considered an E lesion, but rather considered Stage IV. Pleural and pericardial effusions alone 
are not considered E-lesions. 
 
F. 
Regions of Nodal Involvement 
 
Peripheral Upper Regions (indicate laterality: right or left) 
 Neck: cervical (upper, lower/supraclavicular), occipital, and pre-auricular 
 Infraclavicular 
 Axilla 
 Pectoral 
 Epitrochlear   
 Brachial 
 
Central Regions 
 Waldeyer's ring (including base of tongue) 
 Mediastinum (anterior; hilar; cardiophrenic; subcarinal) 
 Hilar 
 Mesenteric 
 Paraaortic (including retrocrural, portal and celiac) 
 Splenic/splenic hilar 
 
Peripheral Lower Regions (indicate laterality: right or left) 
 Iliac 
 Inguinal 
 Femoral  
 Popliteal 
 
Other Non-Nodal Sites 
 Lung (right, left or bilateral) 
 Bone  
 Bone marrow 
 
 
 

  
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APPENDIX II: RECOMMENDED GUIDELINES FOR IMAGING 
CT Scan 
 
CT Image Acquisition 
Breath-hold technique should be used in cooperative older children to reduce motion artifact and spatial 
mis-registration from respiration. In very young children and in uncooperative older children sedation may 
be used when clinically feasible to minimize image degradation from patient motion.  
 
For staging examinations both intravenous and oral contrast should be used. For follow-up examinations 
limited to the neck/thorax, only IV contrast is necessary. Because of the difficulty of assessing mediastinal 
structures on non-contrast examinations, non-contrast scans are inadequate for response assessment. MRI 
study is not allowed for baseline or response assessments. Exceptions to this rule include the following 
special circumstances: patients with contrast allergies, renal failure, or other contraindications to the use of 
intravenous CT contrast media. In these cases MRI or non-contrast CT may be used as an alternative 
imaging modality. The study radiologist must be notified if only the use of non-contrast CT is available as 
an alternative imaging modality; central review at IROC RI should be notified with an explanation.  
 
For abdomen and pelvic CT scans, oral contrast should be administered at least 45 minutes prior to the 
exam to allow adequate opacification of the small bowel. The dose of oral contrast will vary with the type 
of contrast available at an institution and the patient age or size. Imaging during a single phase (i.e., portal 
venous) after injection usually suffices for intravenous contrast. A dose of 1.5-2.5 mL/kg of low osmolar 
intravenous contrast is a general guideline. The optimal rate of contrast injection and timing of scanning 
initiation after contrast injection will vary with patient size, anatomic region of interest, and intravenous 
line size and location.  
 
Selection of the CT acquisition parameters should be made to achieve the best compromise between lesion 
conspicuity, acquisition time, and patient dose, and may vary with the imaging equipment available at each 
institution. The choice of technical CT parameters should be according to standard institutional protocol, 
optimized for pediatric imaging, with adherence to ALARA principles. Exposure parameters for pediatric 
CT may be adjusted based on:  
 
1) Child size: guidelines based on individual size/weight parameters. 
2) Region scanned: the region of the body scanned should be limited to the smallest necessary area. 
3) Organ systems scanned: lower mA and/or kVp settings should be considered for skeletal and lung 
imaging. 
4) Scan resolution: the highest quality images (i.e., those that require the most radiation) may not be 
necessary to make diagnoses, particularly for routine follow up imaging. 
 
Multiphase CT examinations that use multiple scans obtained during different phases of contrast 
enhancement are rarely necessary, result in a considerable increase in dose, and in general should be 
avoided. For staging and duration of protocol therapy, MRI is allowable only in special circumstances as 
outlined above. For guidance in selecting CT parameters that are optimized for pediatric use, information 
is readily available at www.imagegently.org. 
 
CT Interpretation 
Image display considerations include field-of-view, window width and level, and availability of both thin-
section source images and multi-planar reconstructions. Follow-up studies should be performed and 
interpreted with parameters as close as possible to the baseline study to optimize validity of comparisons. 
For example, lesions should be measured with the same window settings and reconstruction intervals. 

  
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Acquisition slice thickness and collimation are modulated according to age/size. For interpretation, 
reconstructed slice thicknesses of 3-5 mm are typical for infants and small children, for older children and 
adolescents a thickness of 5-7 mm is acceptable. Thicker slices decrease spatial resolution, contribute to 
errors from partial volume effects and are of limited value in assessing small lesions, such as pulmonary 
nodules.  
 
Helical/spiral CT allows volumetric acquisition and generation of overlapping axial image reconstructions, 
as well as sagittal and coronal reconstructions, all of which improve the accuracy that lesions are measured 
and characterized. Because of the wide variability in parameters selected to produce longitudinal (coronal, 
sagittal) reconstructions which may produce some inaccuracy, as a rule the diameter of lesions should be 
measured in the axial plane only with the exception of determining whether a nodal lesion represents bulk 
when it is < 6 cm in the axial plane but > 6 cm. in the craniocaudal plane. 
 
FDG-PET IMAGING 
Please refer to the American College of Radiology (ACRIN) PET Core Laboratory Standard Operating 
Procedures, which is also adapted from the NCI consensus recommendation,46 at the following weblink for 
more detailed information, unless otherwise specified below. 
(http://www.acrin.org/CORELABS/PETCORELABORATORY/PETSOPS/tabid/484/Default.aspx) 
 
The following generally accepted FDG-PET issues and items should be adhered to as much as possible in 
this clinical trial to allow for uniformity of inter- and intra-patient FDG-PET imaging and analysis needed 
for this study: 
 
Summary of Definite Requirements 
1) PET/CT, in place of stand-alone PET imaging, should be performed if at all possible for anatomical 
correlation, especially on the follow-up PET imaging. If a stand-alone PET scan is performed, 
correlative contemporaneous CT should be provided for anatomical correlation, especially at site 
of involved disease. 
2) Patients should be fasted for at least 4 hours before [18F]FDG administration. 
3) PET imaging should begin at 60 ± 10 min after injection of [18F]FDG. 
4) For follow-up PET imaging of the same patient, all attempts should be made to image the patient 
on the same PET/CT scanner. 
5) The following PET parameters should be recorded for each imaging session: 
a. Patient’s weight and height 
b. [18F]FDG dose and time of administration 
c. Start time of PET imaging 
d. Serum glucose level (or verify that level is less than 200 mg/dL) 
e. Use of low-dose propranolol or fentanyl for pharmacologic suppression of activated brown 
adipose tissue 
6) DICOM PET/CT or PET images should be sent for central review as a full unprocessed data set 
including PET SUV for possible subsequent quantitative analysis. 
7) Institutional radiologist or nuclear medicine physician assessment and report of the PET2 scan for 
qualitative visual classification (5-point or Deauville criteria) and anatomical location of the single 
most prominently increased (“hottest”) intrapatient lymphoma site. 
a. This visual PET criteria are scored according to uptake in sites initially involved by 
lymphoma as: (1) no uptake, (2) uptake ≤ mediastinal blood pool, (3) > mediastinal blood 
pool but ≤ liver, (4) moderately increased uptake > liver, or (5) markedly increased uptake > 
liver and/or new lesions. Physiologic FDG liver uptake is used as a reference with score of 1 
to 3 regarded as PET negative and 4 or 5 as positive. 
 

  
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Summary of Other Optional Recommendations 
1) State some type of annual scanner QC/QA. 
 
 
Recommend either: 
• 
American College of Radiology (ACR) - Nuclear Medicine/PET accreditation Program 
(http://www.acr.org/accreditation/nuclear.aspx) or 
• 
Intersocietal Commission for the Accreditation of Nuclear Medicine Laboratories 
(ICANL) PET accreditation (http://www.icanl.org/icanl/index.htm) 
a) If either of these PET QC/QA are not used in your facility, please provide your 
PET scanner QC/QA accreditation. 
 
2) FDG dosing requirements 
a) Confirm dosing in recommended dosing is in the range of 0.10 – 0.14 mCi/kg 
b) If recommended dose range is not used, state institutional pediatric PET dosing formula or 
schema. 
c) Dose should not be above 0.15 mCi/kg. 
 
3) After FDG injection, the patient is kept at rest in a warm room through imaging to minimize FDG 
uptake in activated brown adipose tissue or other physiologic FDG artifacts. 
 
Pregnancy 
All female patients ≥ 10 years of age should be asked about their pregnancy potential prior to FDG 
injection. Patients who are pregnant or breast feeding will only be injected if the PET scan is deemed 
necessary for clinical management by the patients’ primary physician and the patient agrees to the study. 
Patients who are sexually active and unsure of their pregnancy status should undergo a urine or serum 
pregnancy test prior to FDG injection. Pregnant guardians should not be allowed in the FDG uptake room. 
 
Recommended Technique 
Patients should be fasted for at least 4 hours before imaging. Total parenteral nutrition and intravenous 
fluids containing glucose should also be discontinued for at least 4 hours before the study. The patient 
should be well hydrated (oral or intravenous fluid administration) before administration of FDG. Fluids 
administered for hydration should not contain glucose. 
 
It is suggested that the patient’s measured height and weight on the day of the PET scan be recorded for 
each imaging session. 
 
If intravenous access is not already in place, this should be obtained, typically in the antecubital fossa, for 
patient hydration (if needed), determination of serum glucose and FDG administration. Good hydration is 
required as the primary route of FDG excretion is renal. The patient should drink water or receive 
intravenous fluids after injection to promote urinary FDG excretion. 
 
Venous serum blood glucose will be measured and recorded just prior to injection of the FDG and must be 
≤ 200 mg/dL.  
 
Diabetic patients should be scheduled in the morning after an overnight fast before the first meal, and dose 
of insulin should be titrated appropriately in consultation with the patient’s referring physician to keep the 
serum glucose ≤ 200 mg/dL at the time of scheduled FDG injection. If the serum glucose is significantly 
elevated (> 200 mg/dL) then the test should be rescheduled if at all possible with better glucose control or, 
if necessary, insulin can be used to achieve normoglycemia. After regular insulin the patient should wait 
2-4 hours (after ultrashort acting insulin, 1-2 hours) prior to administration of FDG in order to minimize 
physiologic skeletal muscle and myocardial FDG uptake. 

  
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In patients with tumors in the pelvis, placement of a Foley catheter is recommended. Patients in whom a 
Foley catheter is not placed should be asked to void immediately prior to imaging in order to minimize 
bladder activity and to reduce their radiation exposure. 
 
FDG Dosing and Injection 
[18F]FDG is administered intravenously at a dose of 0.10 – 0.14 mCi/kg with a minimum dose of 1.0 mCi 
and maximum dose of 10 mCi.  
 
After injection, the patient is kept at rest in a warm room until imaging. After voiding the bladder, whole-
body imaging should begin at 60 ± 10 min after injection of [18F] FDG. For serial scans of the same patient 
it is important to start the PET scan with the same delay time after injection of the FDG radiotracer. 
Therefore, it is recommended that all subsequent PET scans have approximately the same delay time 
(± 10 min) as the baseline scan. The use of low-dose propranolol or fentanyl for pharmacologic suppression 
of [18F] FDG uptake in activated brown adipose tissue can be applied as per institutional protocol and 
recorded. 
 
It is suggested that the net injected FDG dose and time of injection should be recorded. The peripheral IV 
or central line injection site location should also be recorded. 
 
PET Scanning Protocol 
A whole body PET imaging protocol is utilized, covering the area from the base of skull/top of the ears to 
the proximal/mid-thigh, just below the pubis. If there is suspicion of involvement in the lower extremities, 
skull, or skull contents, the volume that is imaged may be expanded. The patient will be positioned supine, 
with arms comfortably positioned above the head if at all possible (to limit attenuation of the thorax), or at 
the side of the patient if necessary. Scans should proceed upward from the pelvis to diminish the effects of 
accumulation of FDG activity in the bladder.  
 
Transmission scanning matching the areas covered by the emission scan will need to be performed for 
attenuation correction of the emission scan. This will be done after injection of FDG. With a combined 
PET/CT scanner, attenuation correction should be done with non-IV contrast CT data per manufacturer 
recommendations. It is recommended that the COG institution adjust the CT dose used for attenuation 
correction to limit the CT radiation dose to the patient without significantly affecting PET quality or 
anatomic correlation to CT. Please refer to protocol recommendations from the Image Gently website 
(http://www.imagegently.org/Home.aspx). 
 
The 511 KeV-annihilation photons, produced by interaction of positrons with electrons, are imaged. 
Because of the short physical half-life of 1.8 hours and the high photon energy of 511 KeV, FDG imaging 
may follow bone or gallium scintigraphy, or a MUGA study on the same day (that use lower energy 
photons) or FDG imaging may be performed on the day preceding any of these other nuclear medicine 
studies. 
 
It is suggested that the following acquisition parameters should be recorded: start time of emission scan and 
type of transmission scan. 
 
It is recommended that PET images be reconstructed with and without attenuation correction. It is also 
recommended that for serial scans of the same patient, image reconstruction techniques and parameters be 
consistent across all scans, including filters and application of the attenuation map. 
 
 

  
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After Completion of the PET Scan 
The patient must empty his or her urinary bladder as soon as possible after imaging. Image reconstruction 
will depend on the scanner manufacturer. An iterative reconstruction method with parameters chosen to 
yield 6-8 mm resolution in the reconstructed images is recommended. 
 
FDG Handling and Dose Documentation 
FDG is to be synthesized by standard methods and tested for pyrogenicity and radiochemical purity on each 
production run, or purchased from nuclear pharmacies licensed to sell FDG. The radiochemical purity of 
the FDG should be > 90%.  
 
PET Imaging Quality Control Standards 
FDG-PET imaging will be performed using "state-of-the-art" equipment (either a dedicated NaI, BGO, 
LSO or GSO full-ring PET system), that will have a field of view appropriate for body imaging ( 10 cm), 
high resolution (FWHM  6.0 mm), high sensitivity, and post-injection transmission capability. 
 
Daily and monthly steps will be taken to assure quantitative accuracy of PET imaging studies and reliable 
imaging results at all performance sites, with recommended clinical standards described above under 
“Summary of Other Optional Requirements” under “State some type of annual scanner QC/QA”. 
 
The level of tumor uptake is assessed subjectively by visual inspection as described in the Evaluation 
Criteria (see Section 10). Semi-quantitative assessment of response by determination of standardized 
uptake values (SUV) is not utilized in this protocol response criteria, however SUV parameters can 
be provided as per routine clinical practice. Deauville score assessment should be performed utilizing 
coronal attenuation corrected PET images rather than MIP or fused images. 
 
 

  
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APPENDIX III: CYP3A4 SUBSTRATES, INDUCERS AND INHIBITORS 
This is NOT an all-inclusive list. Because the lists of these agents are constantly changing, it is important 
to regularly consult frequently updated medical references. 
CYP3A4 substrates 
Strong Inhibitors1 
Moderate 
Inhibitors 
Strong 
Inducers 
Moderate 
Inducers  
acalabrutinib5 
alfentanil4,5  
amiodarone4 
aprepitant/fosaprepitant 
atorvastatin 
axitinib 
bortezomib 
bosutinib5 
budesonide5 
buspirone5 
cabozantinib 
calcium channel blockers 
cisapride 
citalopram/escitalopram 
cobimetinib5 
conivaptan5 
copanlisib 
crizotinib 
cyclosporine4 
dabrafenib  
dapsone 
darifenacin5 
darunavir5 
dasatinib5 
dexamethasone2 
diazepam 
dihydroergotamine 
docetaxel 
doxorubicin 
dronedarone5 
eletriptan5 
eplerenone5 
ergotamine4 
erlotinib 
estrogens 
etoposide 
everolimus5 
fentanyl4 
gefitinib 
haloperidol 
ibrutinib5 
idelalisib 
imatinib 
indinavir5 
irinotecan  
isavuconazole5 
itraconazole 
ivacaftor 
atazanavir 
boceprevir 
clarithromycin 
cobicistat 
darunavir 
delavirdine 
grapefruit3 
grapefruit juice3 
idelalisib 
indinavir 
itraconazole 
ketoconazole 
lopinavir/ritonavir 
nefazodone 
nelfinavir 
posaconazole 
ritonavir 
saquinavir 
telaprevir 
telithromycin 
voriconazole 
aprepitant 
conivaptan 
crizotinib 
diltiazem 
dronedarone 
erythromycin 
fluconazole 
fosamprenavir 
grapefruit3 
grapefruit juice3 
imatinib 
isavuconazole 
mifepristone 
nilotinib 
verapamil 
barbiturates 
carbamazepine 
enzalutamide 
fosphenytoin 
phenobarbital 
phenytoin 
primidone 
rifampin 
St. John’s wort 
 
bosentan 
dabrafenib 
efavirenz 
etravirine 
modafinil 
nafcillin 
rifapentin 
 

  
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ketoconazole 
lansoprazole 
lapatinib 
losartan 
lovastatin5 
lurasidone5 
macrolide antibiotics 
maraviroc5 
medroxyprogesterone 
methadone 
midazolam5 
midostaurin5 
modafinil 
nefazodone 
nilotinib 
olaparib 
ondansetron 
osimertinib  
paclitaxel 
palbociclib 
pazopanib 
quetiapine5 
quinidine4  
regorafenib 
romidepsin 
saquinavir5 
sildenafil5 
simvastatin5 
sirolimus4,5 
sonidegib 
sunitinib 
tacrolimus4,5  
tamoxifen 
telaprevir 
temsirolimus 
teniposide 
tetracycline 
tipranavir5 
tolvaptan5 
triazolam5 
trimethoprim 
vardenafil5 
vemurafenib 
venetoclax5 
vinca alkaloids 
zolpidem 
1Certain fruits, fruit juices and herbal supplements (star fruit, Seville oranges, pomegranate, gingko, goldenseal) may 
inhibit CYP 3A4 isozyme, however, the degree of that inhibition is unknown.  
2Refer to Section 4.1.1 regarding use of corticosteroids.  
3The effect of grapefruit juice (strong vs moderate CYP3A4 inhibition) varies widely among brands and is 
concentration-, dose-, and preparation-dependent. 
4Narrow therapeutic range substrates 
5Sensitive substrates (drugs that demonstrate an increase in AUC of ≥5-fold with strong inhibitors) 
 

  
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APPENDIX IV: MODIFIED (“BALIS”) PEDIATRIC SCALE OF PERIPHERAL 
NEUROPATHIES 
 
Peripheral Motor Neuropathy: 
 
• Grade 1: Subjective weakness, but no deficits detected on neurological exam, other than abnormal deep 
tendon reflexes. 
 
• Grade 2: Weakness that alters fine motor skills (buttoning shirt, coloring, writing or drawing, using eating 
utensils) or gait without abrogating ability to perform these tasks. 
 
• Grade 3: Unable to perform fine motor tasks (buttoning shirt, coloring, writing or drawing, using eating 
utensils) or unable to ambulate without assistance. 
 
• Grade 4: Paralysis. 
 
Peripheral Sensory Neuropathy: 
 
• Grade 1: Paresthesias, pain, or numbness that do not require treatment or interfere with extremity function. 
 
• Grade 2: Paresthesias, pain, or numbness that are controlled by non-narcotic medications (without causing 
loss of function), or alteration of fine motor skills (buttoning shirt, writing or drawing, using eating 
utensils) or gait, without abrogating ability to perform these tasks. 
 
• Grade 3: Paresthesias or pain that are controlled by narcotics, or interfere with extremity function (gait, 
fine motor skills as outlined above), or quality of life (loss of sleep, ability to perform normal activities 
severely impaired). 
 
• Grade 4: Complete loss of sensation, or pain that is not controlled by narcotics. 
 
 

  
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APPENDIX V: CORRELATIVE IMAGING STUDIES 
Correlative study design  
Aim: To incorporate qualitative visual FDG-PET into response directed treatment algorithms and refine 
quantitative FDG-PET and CT definitions of tumor burden and response for future incorporation into next 
generation pediatric HL risk-stratification schemes. 
 
Specific Aim 1: Interim Visual PET - Incorporation of 5-point visual FDG-PET criteria for risk-adapted 
interim PET response assessment in COG initial therapeutics protocol AHOD1331 for early responders. 
 
Definition of PET response: The COG AHOD1331 high-risk HL initial therapeutics clinical protocol will 
incorporate interim FDG-PET assessment as an integral part of its risk-adapted treatment stratification 
scheme. This FDG-PET assessment will consist of central review of the baseline PET (PET0) and post-
cycle 2 PET (PET2) utilizing a 5-point visual scale or Deauville criteria that has been used effectively and 
validated in other HL studies and our own COG retrospective study. This visual PET criteria are scored 
according to uptake in sites initially involved by lymphoma as: (1) no uptake, (2) uptake ≤ mediastinal 
blood pool, (3) > mediastinal blood pool but ≤ liver, (4) moderately increased uptake > liver, or (5) markedly 
increased uptake > liver and/or new lesions. Physiologic FDG liver uptake is used as a reference with score 
of 1 to 3 regarded as PET negative and 4 or 5 as positive.  
 
Imaging Review Procedure: PET images obtained at COG institutions will be forwarded electronically to 
the Clinical Trial Quality Assurance Imaging and Radiation Oncology Core Group (IROC Rhode Island) 
Group (formerly QARC) who will administrate and manage the images. Central review will be performed 
by consensus of two experienced nuclear medicine physicians and/or radiologists with review of diagnostic 
quality digital PET and CT images (DICOM files) within 2 weeks of the scan receipt in order for timely 
risk-adaptive treatment stratification for subsequent radiation need remotely on a high-quality web-based 
PET and CT software (MIMSoftwareTM). In the event of disagreement between the two central reviewers, 
there will be a convened reassessment by the two readers for consensus within three weeks of receipt of the 
PET and CT images by IROC RI. In the event when two reviewers cannot come to an agreed consensus 
adjudication by a third nuclear medicine or radiologist central reviewer will occur within four weeks. 
Discrepancies between the reviewers and/or institutional interpretations will be resolved on regular monthly 
and/or as needed ad-hoc scheduled teleconference calls. COG HL committee and IROC RI have experience 
and demonstrated track record with central review performed through a recently completed COG HL high-
risk protocol AHOD0831. 
 
In cases where PET2 is positive with intrapatient lymphoma 5-point visual or Deauville score greater than 
reference liver (Deauville 4 or 5), PET5 central review (end of chemotherapy PET) by consensus of two 
experienced nuclear medicine physicians and/or radiologists will be performed within two weeks of scan 
receipt at IROC Rhode Island. In the event of disagreement between the two central reviewers, there will 
be a rapid convened reassessment with adjudication by a third reviewer within three weeks of receipt of the 
PET and CT images by IROC-Rhode Island to allow for timely scheduling and start of radiation therapy. 
 
Central review comparison to local institution review: Post-cycle 2 PET (PET2) positive or negative PET 
interpretation, utilizing a 5-point visual scale with a threshold physiologic FDG liver uptake (score of 1 to 
3 regarded as PET negative and 4 or 5 as positive), will be compared between local institutional radiology 
review and central review. 
 

  
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Specific Aim 2: (Note: For Central Review Research Purposes Only; Not Required By Institutional 
Review)  
Interim Quantitative PET and CT Analysis - Quantitative interim FDG-PET-based assessment will assess 
PET standardized uptake value (SUV) to evaluate (1) absolute tumor interim PET (PET2) SUV based 
parameters and (2) % change of tumor PET SUV from baseline to mid-therapy and end-of-therapy in order 
to more accurately differentiate between responders and non-responders. CT tumor volume determined 
after 2 cycles of chemotherapy (CT2) will be determined and the change in tumor burden as represented by 
CT tumor volume between the baseline and post-cycle 2 imaging will also be evaluated. 
 
PET Methods: Quantitative baseline PET0 and interim PET2 assessments will be performed on a regular 
periodic basis for prospective correlation with qualitative 5-point visual scores. Quantitative FDG-PET-
based region-of-interest (ROI) analyses will include maximal voxel-based tumor SUV (SUVmax), peak 
tumor SUV (SUVpeak) with variously defined “peak” parameters, average physiologic liver SUV (Liver 
SUVavg), and physiologic mediastinal blood pool SUV (Blood pool SUVavg).  
 
Imaging Review Procedure: Individual site qualification for adequate PET/CT imaging will be performed 
by IROC, (IROC Rhode Island in conjunction with IROC Ohio). Subsequent PET0 and PET2 scan 
credentialing along with all data management and review facilitation will be performed by IROC Rhode 
Island (QARC). PET analyses will be performed by consensus of two experienced COG HL nuclear 
medicine and/or radiology central reviewers retrospectively. 
 
Interim CT tumor burden: CT tumor volume determined after 2 cycles of chemotherapy will be determined 
and the change in tumor burden as represented by CT tumor volume between the baseline and post-cycle 2 
imaging will be determined. Dedicated multi-detector IV contrast CT of the chest, abdomen and pelvis 
(head/neck as needed) will be required at baseline and at the interim therapy PET2 time points as part of 
the parent AHOD1331 study concept. An IV contrast CT obtained as the CT portion of the PET/CT used 
for attenuation correction for PET reconstruction will be accepted. Please see specific aim 3 “baseline tumor 
burden” section for specifics of the proposed CT volume method. 
 
Specific Aim 3: (Note: For Central Review Research Purposes Only; Not Required By Institutional 
Review) 
Baseline PET and CT Tumor Burden - To determine if baseline tumor burden as determined by PET- and 
CT- derived volumetrics provides prognostic information for risk stratification in pediatric HL. 
 
Baseline PET Tumor Burden: To correlate baseline tumor burden at diagnosis as determined by FDG-PET-
derived quantitative parameters with clinical outcome (EFS). 
 
PET Methods: Baseline PET images will be analyzed by various PET SUV-based threshold methods to 
determine a PET-based metabolic volume based on absolute, tumor and physiologic normal organ based 
values (i.e. tumor SUVmax, tumor SUVpeak, liver SUVavg, and mediastinal blood pool SUVavg). Various 
tumor SUVmax and SUVpeak threshold percentage will be applied (i.e. 20%, 30%, 40%, 60%). PET 
parameters will include metabolic tumor volume (MTV), total tumor glycolytic activity (TGA), and average 
tumor SUV (SUVavg). Of note the FDG-PET metabolic tumor volume using the MIMSoftwareTM 
application does not include central tumor necrosis or non-FDG avid portions of the tumor into the volume 
contour, therefore providing a “real” metabolic tumor volume. 
 
IV contrast CT method: Dedicated multi-detector IV contrast CT of the chest, abdomen and pelvis 
(head/neck as needed) will be required at baseline and at the interim therapy PET2 time points as part of 
the parent AHOD1331 study concept. An IV contrast CT obtained as the CT portion of the PET/CT used 
for attenuation correction for PET reconstruction will be accepted. 
 

  
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Imaging Review Procedure: Individual site qualification for adequate PET/CT imaging will be performed 
by IROC (IROC Rhode Island in conjunction with IROC Ohio). Subsequent PET0 and PET2 scan 
credentialing along with all data management and review facilitation will be performed by IROC Rhode 
Island (QARC). PET analyses will be performed by consensus of two experienced COG HL nuclear 
medicine and/or radiology central reviewers retrospectively. These quantitative interim PET analyses will 
be performed remotely on high-quality web-based PET/CT software (MIMSoftwareTM).  
 
Baseline CT Tumor Burden: To correlate baseline IV contrast CT-derived bulk tumor volume to clinical 
outcome (EFS) 
 
Baseline IV CT images will be analyzed remotely using a CT volumetric segmentation algorithm developed 
in the Laboratory for Computational Image Analysis (CIA Lab) at Columbia University Medical Center 
(Pending Patent: PCT/US13/36258). An early version of this algorithm can be found in this reference.47 
The algorithm is integrated into a user friendly imaging platform also developed in-house with Interface 
Description Language (IDL). This platform has major image viewing and manipulation functions and 
allows tumor contours (i.e., segmentation results) to be superimposed on original image series for 
radiologist's review and modification if needed. An experienced radiologist in the CIA lab will be 
responsible for measuring tumor volumes with the help of the segmentation based on the reference noted 
above. In a recent work published by the CIA lab, it was found that reproducibility of computer-aided 
volumetric measurements was high. The magnitude of the variability in measuring total tumor burden was 
[-25%, 35%] at 95% limits of agreement on a radiologist’s repeat measurements of tumor volumes).48  
 
Comparability of PET and CT Baseline Tumor Burden: To assess the comparability and practical analysis 
of baseline PET MTV with CT-derived tumor volumes for incorporation into future clinical trials. 
 
Specific Aim 1: Interim Visual PET - Incorporation of 5-point visual FDG-PET criteria for risk-adapted 
interim response assessment in COG initial therapeutics protocol AHOD1331. 
 
Hypothesis: 5-point visual FDG criteria can be successfully implemented in AHOD1331. 
 
Specific Aim 2: Interim Quantitative PET and CT - Quantitative interim FDG-PET-based assessment will 
assess PET standardized uptake value (SUV) to evaluate (1) the % change of tumor PET SUV from baseline 
to mid-therapy and end-of-therapy and (2) assess the absolute tumor interim PET (PET2) SUV based 
parameters to more accurately differentiate between responders and non-responders. CT tumor volume 
determined after 2 cycles of chemotherapy (PET2) will be determined and the change in tumor burden as 
represented by CT tumor volume between the baseline and post-cycle 2 imaging will also be evaluated. 
 
Hypothesis: Quantitative interim post-cycle 2 FDG-PET (PET2) percent change from baseline (PET0) and 
absolute PET2 PET SUV threshold parameters will correlate with visual PET2 response assessment and 
EFS. 
 
Specific Aim 3: Baseline PET and CT Tumor Burden-To determine if baseline tumor burden as determined 
by PET- and CT- derived volumetrics provides prognostic information for risk stratification in pediatric 
HL. 
Hypothesis: Baseline FDG-PET (PET0) and CT based quantification of nodal tumor burden will be 
correlated with EFS. 
 
 

  
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Background and Rationale 
With the paradigm that early response is more reflective of chemosensitivity than is end of chemotherapy 
response, our last series of trials required concurrent functional imaging (either gallium or FDG-PET) along 
with CT so that we could compare the utility of each method in a pediatric population and determine which 
assessment method was the best predictor of outcome.26,49 We found that 1) the use of PET added predictive 
value to CT; 2) omission of RT is optimally based on both PET2 and CT2 response; and 3) the use of either 
PET2 or CT2 response alone did not adequately define a high-risk population using the ABVE-PC treatment 
platform. Integration of novel imaging modality questions into the study platform will allow incorporation 
of such modalities into treatment considerations in subsequent studies. Standardizing measurement of 
tumor volume by CT and PET is an ongoing challenge as criteria, imaging techniques, and calculation 
formulas differ between studies. 
 
FDG-PET imaging plays an important role in Hodgkin Lymphoma management. FDG-PET has been 
incorporated in the 2007 lymphoma international working group (IWG) guidelines to standardize end-of-
therapy response criteria for lymphoma, including Hodgkin Lymphoma, using blood pool as a reference 
visual threshold to determine residual FDG uptake.41,42 Incorporation and validation of various FDG-PET 
imaging criteria more specifically for pediatric Hodgkin lymphoma patients in our upcoming trials will 
provide improved risk stratification and treatment response criteria leading to improved clinical outcome 
in subsequent studies. We propose to accomplish this in the context of our high-risk pediatric HL study 
AHOD1331 by validating integral qualitative visual FDG-PET response adapted therapy with quantitative 
FDG-PET baseline and interim response parameters. 
 
Visual Qualitative Interim PET Incorporation of FDG-PET for lymphoma interim response assessment 
however is critically dependent on the visual threshold used to determine a positive PET scan (slow-early 
responder) versus a negative PET scan (rapid early responder). The threshold for response should be 
adapted to the clinical outcome goals of the study with a threshold for high negative-predictive value chosen 
if the goal is treatment reduction in order to reduce chemotherapy related toxicity but a threshold for high 
positive-predictive value applied if the goal is treatment intensification for high-risk disease. Therefore, a 
graded method of visual criteria that is conducive to different positivity thresholds could be used to adjust 
for the required test specificity in a given trial design. Guidelines for standardization using visual FDG-
PET for interim response assessment are still developing with improved outcome on interim PET in 
Hodgkin Lymphoma when applying a higher visual PET threshold compared to current IWG thresholds.43,44 
A recent study demonstrated that visual 5-point score or Deauville criteria can improve prediction of 
outcome and reproducible enough in advanced-stage Hodgkin Lymphoma for recommendation as a 
standard reporting criterion in clinical practice and for clinical trials.44,45  

  
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Our own COG retrospective 
PET study analyzed multi-site 
FDG-PET or PET/CT images 
from AHOD0031,50 a phase III 
COG study for newly diagnosed 
pediatric intermediate-risk HL.26 
FDG-PET 
was 
obtained 
at 
baseline (PET0), at mid-therapy 
after 2 cycles of ABVE-PC 
chemotherapy (PET2) and if the 
PET2 
was 
positive, 
after 
completion 
of 
further 
chemotherapy 
(PET3). 
We 
randomly selected 150 patients 
with 
PET2 
enrolled 
since 
1/2007, a cohort likely to have 
high-quality archived PET images, and that represented 5 specific groups (Stage I, IIA, IIB, III, and IV) in 
proportion to their representation in the AHOD0031 study. From this cohort, a subset of patients (n=94) 
with qualified PET images were selected for review. Our visual assessment applying a 5-point scale 
Deauville criteria at PET2 and PET3 demonstrated a pronounced (but not complete) response at mid-
therapy, as measured using a five-point visual FDG-PET assessment with liver (not blood pool) as a 
reference threshold (visual scale ≥ 4 as positive) is highly predictive of EFS, as seen in Figure 1. 
 
Quantitative SUV Interim PET: 
Quantitative PET SUV-based response criteria using a percent change in SUV between baseline PET and 
after two cycles of chemotherapy in non-Hodgkin lymphoma, diffuse large B-cell lymphoma, was found to 
lead to better performance and interobserver reproducibility compared to the visual criteria, including the 
Deauville criteria.51,52 However, for interim PET interpretation in Hodgkin lymphoma, visual assessment is 
recommended and currently preferred over quantitative SUV-based PET response criteria due to the 
inherently relatively abrupt and rapidity of the metabolic response seen in Hodgkin lymphoma compared 
to more gradual FDG-PET response seen in non-Hodgkin lymphoma during therapy.53 However, a 
prospective study of FDG-PET response assessment in pediatric Hodgkin lymphoma patients showed the 
median SUVmax reduction from baseline to interim PET scan was significantly higher in responders 
(median, 81.3%) compared with non-responders (median, 38.6%), P=0.006. ROC analysis estimated an 
optimal threshold cutoff value for identification of relapse patients at less than 58% SUVmax reduction at 
interim PET.54 A more comprehensive analysis of the prognostic benefit of interim therapy PET SUV 
measurements in pediatric Hodgkin lymphoma demonstrated by ROC-analysis the most accurate 
differentiation of responders and non-responders with percent change in SUVmax with an optimal threshold 
cutoff value of 75%.55 
 
 
p=0.017
0.00
0.25
0.50
0.75
1.00
0
1
2
3
4
5
Time(years)
Visual scale 1-3
Visual scale 4-5
Figure 1. Interim therapy PET (PET2) response assessment using 
5-point score visual Deauville criteria, using PET score ≥ 4 (> reference 
liver) as PET positive. 

  
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Our COG retrospective FDG-PET analysis 
of FDG-PET from AHOD0031,50 a phase 
III COG study for newly diagnosed 
pediatric 
intermediate-risk 
HL, 
also 
assessed interim PET quantitative tumor 
SUV parameters. Event free survival (EFS) 
was chosen as a clinical endpoint of interest 
and analyzed by Cox proportional hazards 
model for the SUV parameters. Mid-
therapy PET (PET2) Tumor SUVmax 
normalized to liver SUVavg (TL-SUV) was 
most highly predictive of EFS (P=0.02). An 
evaluation of the predictive value of percent 
change in SUV between PET scans showed 
that the percent reduction in SUV in the 
interval from baseline (PET0) to mid-
therapy (PET2) was most predictive of EFS 
using TL-SUV12 (P=0.03). An ROC analysis derived optimized threshold cutoff threshold was determined 
for TL-SUV (≥ 1.26) to determine PET positive at PET2. Kaplan-Meier curve using this optimized cutoff 
value for PET2 is shown in Figure 2. Our retrospective analyses and other published studies provide 
rationale for a systematic comprehensive assessment in our COG study of quantitative PET SUV response 
assessment in pediatric Hodgkin lymphoma due to the potential for improved interobserver reproducibility 
and improved accuracy of SUV analysis compared to current 5-point Deauville visual criteria. 
 
Baseline PET and CT Tumor Volumetrics 
FDG-PET and CT based tumor volume measurements has been widely applied in solid tumors and is now 
being reported to be prognostic in non-Hodgkin lymphoma.56,57 Standardization for the measurement of 
tumor volume by CT and PET is an ongoing challenge as criteria, imaging techniques, and calculation 
formulas differ between studies. Reproducible and accurate tumor volume assessment, and definition of 
bulk tumor at initial diagnosis, can potentially affect risk stratification and consolidation radiation therapy. 
 
Retrospectively COG AHOD0031 FDG-PET based volumetric measurement of our pediatric Hodgkin 
lymphoma nodal tumor volume was retrospective analyzed at Johns Hopkins University IRAT facility and 
submitted as an abstract for the 9th International Symposium on Hodgkin Lymphoma. FDG-PET and CT 
based volumetric measurement of our pediatric Hodgkin lymphoma nodal tumor volume was retrospective 
analyzed. The purpose of this study was to assess the prognostic value of baseline tumor burden as 
determined by both FDG-PET and anatomic CT parameters in pediatric HL. Our unpublished data is 
provided below that demonstrates the prognostic significance of baseline PET and CT volumetric data 
[pending publication and submitted as an abstract to the 2013 9th international symposium on Hodgkin 
Lymphoma in Cologne, Germany]. We retrospectively analyzed multi-site FDG-PET/CT images from 
COG AHOD0031, a phase III study for newly diagnosed pediatric intermediate-risk HL. We randomly 
selected 150 patients who were randomized or assigned to the same standard therapy and had post-cycle 2 
PET with 50 patients each of three response groups in the study based on post-cycle 2 and end-of-therapy 
CT. From this cohort, a subset of patients (N=90) with qualified PET/CT scans were selected for review. 
Baseline PET images were analyzed by consensus of 2 readers blinded to clinical outcome data using 
MIMSoftwareTM application. A variety of PET standardized-uptake value (SUV) threshold values based on 
absolute, liver, blood pool and tumor were assessed to derive PET parameters for total body nodal tumor 
burden including: average tumor SUV (SUVavg), metabolic tumor volume (MTV) and total tumor 
glycolytic activity (TGA). Event free survival (EFS) was chosen as a clinical endpoint of interest and 
p=0.015
0.00
0.25
0.50
0.75
1.00
0
1
2
3
4
5
Time(years)
Negative PET (TL-SUV < 1.26)
Positive PET (TL-SUV >= 1.26)
Figure 2. EFS at interim PET (PET2) using an optimized 
threshold cutoff tumor SUV criteria (tumor SUV 
normalized to liver uptake). 

  
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analyzed by log-rank and Cox proportional hazard model. Selected parameters were further assessed using 
receiver-operating-characteristic (ROC) analysis where the outcome was 2-year EFS. Baseline FDG-PET 
SUV derived MTV and TGA parameters were found to be highly predictive for EFS for a variety of 
thresholds (P<0.05). PET SUV threshold values found to be most predictive and reliable included: 1.5Lv + 
2xliver standard deviation (1.5Lv+2SD), 2x mediastinal blood pool (2BP) and 20% maximal tumor SUV 
(TSUVmax). ROC area under the curve (AUC) for MTV using 1.5Lv+2SD, 2BP and TSUVmax threshold 
was 0.77, 0.84, and 0.79, respectively. Use of an “optimal cut-off” PET MTV value based on the ROC for 
1.5Lv+2SD, 2BP and TSUVmax was able to separate EFS groups (P < 0.005). Baseline tumor SUVavg 
was not found to be predictive for EFS. In conclusion, baseline FDG-PET SUV derived total body tumor 
burden as represented by tumor volume (MTV) and total tumor glycolytic activity (TGA) was hypothesized 
to be predictive of EFS in pediatric HL. 
 
Similarly, the optimal imaging study and criteria used to assess tumor burden is not adequately defined, 
especially as measured by anatomic scans including CT. We retrospectively analyzed multi-site CT images 
from COG AHOD0031. We randomly selected patients who were randomized or assigned to the same 
standard therapy and had PET post-cycle 2, with 50 patients from each of the three response groups in the 
study defined by post-cycle 2 and end-of-therapy CT. From this cohort, a subset of patients (N=84) with 
qualified CT scans were selected for review. Using software developed by the Computational Image 
Analysis (CIA) Lab at Columbia University that incorporates an advanced segmentation algorithm for 
assessment of tumor volume, uni-dimensional, bi-dimensional and 3-dimensional measures of total tumor 
burden were assessed at baseline and after 2 cycles of chemotherapy. Event free survival (EFS) was chosen 
as a clinical endpoint of interest. Receiver-operating-characteristics (ROC) analysis was used to select an 
“optimal” cutoff of tumor burden for predicting 2-year EFS. Association between tumor burden 
(above/below median or “optimal” cutoff) and EFS was examined by log rank test. Baseline tumor burden 
as assessed by uni, bi and 3-D measures was highly predictive of EFS (p < 0.05 for analyses with median; 
< 0.003 with “optimal” cutoffs). Similarly, tumor burden following 2 cycles of chemotherapy was 
prognostic for EFS (p<=0.05 for analyses with median; < 0.02 with “optimal” cutoffs). Further analyses 
evaluating percentage change with/without threshold tumor measure were not significantly prognostic of 
EFS. Baseline and interim total tumor burden but not change in tumor burden as measured by CT is highly 
predictive of EFS in pediatric HL. Incorporation of tumor burden assessment by CT may be useful for 
baseline risk stratification and for further refinement of therapy in conjunction with PET as part of a 
response-based strategy. 
 
 

  
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Statistical Considerations: 
For aim 1, PET2 by 5-point visual scale after 2 cycles will be centrally reviewed to determine early 
response. We will monitor the rate of initial review completion within 2 weeks of scan receipt and 
hypothesize that we can have 90% or more reviews successfully completed in time. The study has 90% 
power to detect an 86% or lower rate of reviews completed in-time in a one-sample test of proportions with 
one-sided alpha level of 0.05. Descriptive statistics will be used to summarize the review between the 
2 blinded reviewers in terms of RRL (i.e., PET2 negative with Deauville score of 1-3) vs. SRL (i.e. PET2 
positive with Deauville score of 4-5) for each lesion(s) in a given patient. Inter-reviewer agreement between 
the 2 blinded reviewers in their initial review will be estimated by Cohen’s κ coefficient. Assuming the rate 
of RER by PET is 70-80% for each reviewer, with 580 eligible patients, the 95% CI for the estimate of 
Cohen’s κ will have half width of 0.08 or less if Cohen’s κ is 0.6 or higher. We are also interested in 
assessing the agreement between institution assessment of positive or negative PET interpretation, utilizing 
a 5-point visual scale with a threshold physiologic FDG liver uptake (score of 1 to 3 regarded as PET 
negative and 4 or 5 as positive), and the central review response assessment, and similar approaches will 
be used to describe and assess the agreement between central review and institution review. 
 
For aim 2, we will assess the quantitative SUV-based PET measures and the quantitative CT tumor burden 
at 2 cycles and the percent change in these measures from baseline to 2 cycles. Descriptive statistics will 
be used to summarize these measures and their percentage changes. Association between the PET 5-point 
scale and these quantitative SUV measures after 2 cycles will be assessed by rank correlation coefficient 
statistics such as Spearman’s ρ and Kendall’s τ. We will examine the association between EFS and these 
interim quantitative SUV-based PET measures/their change from baseline and the interim quantitative CT 
tumor burden/their change from baseline in log rank test and Cox proportional hazard models. Response 
(and LMA)-adapted RT introduces confounding effect in examination of the association of these 
quantitative SUV-based measures with EFS, as the association will be confounded by non-random 
administration of RT. It is possible that patients with the large values in these measures and especially those 
with smaller change in these measures from baseline to 2 cycles will be associated with being SER as 
defined by the PET 5-point visual criteria, and thus more likely to receive RT that may reduce the risk for 
failures. Such confounding effect is expected to reduce the extent of raw association observed between 
these measures and EFS, therefore makes the observed association conservative.  
 
For aim 3, we will assess the baseline tumor burden as determined by PET- and CT-derived volumetric 
measures. Correlation between tumor burden assessed by the PET volumetric measures and CT volumetric 
measures will be examined by Pearson correlation coefficient. Early response on prior studies has been 
shown to correlate with EFS, so will be used as one surrogate for examining the association between 
baseline tumor burden and EFS. We will examine the association between baseline tumor burden measures 
and early response after chemotherapy by two-sample t-tests and/or Wilcoxon rank sum test within each 
randomized arm separately. Logistic regression model on early response will also be used to explore the 
impact of baseline tumor burden combining data from the 2 arms with adjustment for randomized 
chemotherapy. Due to lack of prior data on the distribution of these tumor burden measures in the high-risk 
population, power estimation is difficult. Similar to the analyses above on interim quantitative PET- or CT-
based measures, response (and LMA)-adapted RT introduces complication in directly examining and 
interpreting the association of baseline tumor burden with EFS, as the association will be confounded by 
non-random administration of RT. It is possible that patients with higher baseline tumor burden (expect 
higher risk for failures) will be more likely to be have LMA and be SER, and thus more likely to receive 
RT that may reduce their risk for failures. Log rank test and Cox models adjusting for randomization arm 
will be used to explore the association between the baseline tumor burden acknowledging the potential 
confounding effect of RT. The expected confounding effect caused by non-random assignment of RT 
should only reduce the degree of association that makes the estimates conservative. 

  
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Power estimation: 
For aim 1, we will monitor the rate of initial review completion within 2 weeks of scan receipt and 
hypothesize that we can have 90% or more reviews successfully completed in time. The study has 90% 
power to detect an 86% or lower rate of reviews completed in-time in a one-sample test of proportions with 
one-sided alpha level of 0.05. Inter-reviewer agreement between the 2 blinded reviewers in their initial 
review will be estimated by Cohen’s κ coefficient. Assuming the rate of early response by PET is 70-80% 
for each reviewer, with 580 eligible patients, the 95% CI for the estimate of Cohen’s κ will have half width 
of 0.08 or less if Cohen’s κ is 0.6 or higher.  
For aim 2 and 3, power estimation is difficult for these analyses partly due to lack of estimates for the 
distribution of these interim quantitative SUV-based PET measures and CT measures and baseline tumor 
burden measures in this high-risk study population. The retrospective analyses on these measures were done 
in a cohort (from AHOD0031) that included few high-risk patients eligible for this study. Assuming a 
median cutoff for such interim quantitative measure or baseline tumor burden measure that create 2 groups 
of patients with equal size (n=290 per group), the individual analysis comparing EFS between the 2 groups 
defined by above/below the median of a measure will have power similar to that for the primary aim of the 
study, i.e., > 80% power for 8% EFS difference at 3 years (see Section 9.3.1.2. for details). Similarly, using 
median as cutoff, the analysis for association between a quantitative measure (defined as either above or 
below median) with early response will have power similar to that for the secondary aim on early response 
rate, i.e., > 80% power for 9% difference in early response rate between the 2 groups (see Section 9.3.2.2 
for details). Assuming some other cutoff for such quantitative measure that defines 2 groups of patients 
with the smaller group being 20% to 40% of the total sample size, the power for detecting the association 
between such measure with early response or EFS are similar to those power discussed for the aim on 
CHIPS (see Section 9.3.4.2 for details). 
 
 

  
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APPENDIX VI: CORRELATIVE BIOLOGY STUDIES 
Samples will be collected prospectively and will be available for analysis at the end of the clinical trial. 
Research proposals will be submitted in the future for retrospective studies on these samples. The immune 
function studies will be performed on prospectively collected peripheral blood, as these studies have to be 
performed in fresh tissue samples. A brief description is provided of the types of analyses to be done on 
prospectively collected samples. This section provides a rationale for tissue collection for analysis which 
can be addressed in future protocols. 
 
Please note: Patients may also be enrolled on the current COG Biology Banking study which includes pre-
therapy specimens. If patients are enrolled on both AHOD1331 and a biology banking study, the priority is 
to submit the specimens through AHOD1331 first. 
 
A. SAMPLE COLLECTION SCHEDULE 
 
1. Paraffin Embedded Material: A representative block (preferred) or unstained and stained slides 
should be processed according to Section 13.2. Send one of the following:  
a. Surgical biopsy specimen: One paraffin block with representative sample (formalin preferred). 
b. If blocks cannot be sent, submit 10 unstained and unbaked sections (4 microns thick) and 2 H&E 
stained sections from one representative block on silanized slides (i.e. Fisher Superfrost Plus). 
If the patient was diagnosed by biopsy before referral to the treating institution, a good faith effort 
should be made to obtain either a block or 10 unstained slides and 2 H&E stained slides. 
 
2. Snap frozen tumor tissue: From surgical biopsy. See Section 13.2 for detailed processing instructions. 
Snap frozen tissue will be collected for future molecular classification studies as described below. 
  
3. Peripheral blood: See Table 7.2 for detailed overview of sample collection time points, volumes and 
tube types. Shipping and handling instructions for BPC and the Bollard Lab are found on the pages 
that follow.  
 
A. Immune function studies (shipped to Bollard lab) should be collected in heparin tubes only and 
held at room temperature until shipment. It is acceptable for blood to be collected from a central line. 
1. Pre-treatment: 2 mL/kg with a maximum volume 20 mL (max 10 mL for patients 
weighing < 12 kg) 
2. Post-treatment, after completion of all therapy: 2 mL/kg with a max volume 40 mL (max 
20 mL for patients weighing < 12 kg).  
 
B. Other correlative biology studies (shipped to BPC): Planned studies include EBV viral load, 
TARC, cytokine studies and WBC and plasma banking. The specified volume should be collected 
in heparin tubes and held at 4°C until shipment (see below). Either sodium heparin or lithium 
heparin tubes are acceptable. Please do NOT use plasma separator tubes. 
 
What if a specified time point is missed? 
Every effort should be made to obtain the time points that occur before chemotherapy starts (i.e. diagnosis 
or Cycle 1 Day 1). During therapy missed time points should be omitted. Once therapy is complete, and 
the patient is in follow up, if biology specimens are not obtained at any requested time point, please send 
specimens at the next requested time point or at the next clinic visit, whichever is sooner.  
 
 

  
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INSTRUCTIONS FOR BIOLOGY SPECIMEN HANDLING AND SHIPPING  
Please be aware that biology specimen shipments must comply with IATA standards (www.iata.org). 
Specimen Labeling 
• Label all blood samples with the COG Patient ID number, specimen type (blood), and collection date. For 
Bollard Lab specimens also include: protocol number (AHOD1331), accession number, and time point.  
• Tissue samples must be labeled with the COG Patient ID number, specimen type (P for primary or M for 
metastatic) and collection date. Blocks and slides must also include the surgical Pathology ID number and block 
number from the corresponding pathology report. 
Specimen Storage 
• If not shipped on the day of collection, blood for the BPC should be stored at 4°C until shipment. 
• Blood for the Bollard Laboratory should be stored at ambient temperature until shipment. 
• Snap frozen tissue should be stored in a -70ºC freezer until shipment. 
Transmittal forms: 
• An AHOD1331 transmittal form and a pathology report (with tissue submissions) must accompany each 
shipment of specimens to the BPC.  
• For shipments to the Bollard lab, please note the patient’s WBC (from the day of or immediately prior to the 
date of collection) on the transmittal form. 
 
SHIPMENT OF SPECIMENS TO THE BPC 
Frozen Tissue, blocks or slides and ambient blood at baseline can be shipped to the BPC together in a dual-
chambered Specimen Procurement Kit (provided upon request by the BPC via the BPC Kit Management 
System accessible online at: https://ricapps.nationwidechildrens.org/KitManagement/).  
 
If frozen tissue is not submitted, then blood and block and slides must be shipped in your own container. 
The shipping container must be insulated to provide temperature stability during shipment. 
 
Specimens may be shipped to the BPC on Monday-Thursday for Tuesday-Friday delivery. Saturday 
delivery is only available for fresh blood. Do not ship specimens the day before a holiday. 
 
The BPC provides a shipping label for shipment of the dual chambered kit at baseline and shipments of 
ambient blood. Blocks and/or slides shipped separately are shipped at the institution’s expense. 
 
Arrange for FedEx pickup per your usual institutional procedure or by calling 1-800-238-5355. Ship 
specimens to: 
Biopathology Center 
Children's Hospital 
700 Children’s Drive, WA1340* 
Columbus, OH 43205 
Phone: (614) 722-2865 
Fax:  
(614) 722-2897 
Email: BPCBank@nationwidechildrens.org  
 
* Be sure to include the room number. Packages received without the room number may be returned to sender. 
 
Instructions for packaging specimens in a dual chambered kit provided by the BPC: 
1. Before specimens are placed into the Specimen Procurement Kit they first need to be placed in three 
separate layers of packaging. Package the frozen specimens and the ambient specimens separately since 
they will be placed in separate compartments of the kit. Two sets of the biohazard and Tyvek diagnostic 
envelopes are provided in the kit for this purpose. 
a. Place the specimens in zip lock bags (one bag per specimen type/time point).  

  
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b. Place the zip lock bags in the biohazard envelope with the absorbent material. Expel as much air 
as possible and seal the envelope securely. 
c. Place the biohazard envelope inside the Tyvek envelope. Expel as much air as possible and seal securely. 
2. Frozen specimens should be placed in one of the kit compartments filled with dry ice.  
a. Layer the bottom of the compartment with dry ice until it is approximately one-third full.  
b. Place the frozen specimens on top of the dry ice.  
c. Cover the specimens with the dry ice until the compartment is almost completely full.  
d. Place the cover on top of the kit chamber to insulate the specimens during shipment. 
3. Ambient temperature specimens should be shipped in the other kit compartment at room temperature.  
a. Place the transmittal form(s) and any other required paperwork in a plastic bag and place inside the kit 
chamber with the ambient specimens. 
b. Place the cover on top of the kit chamber to insulate the specimens during shipment. 
4. Close the outer lid of the Specimen Procurement Kit and tape with filament or other durable sealing tape. 
5. Print a shipping label via the BPC Kit Management application and attach to the top of the kit. 
6. Complete the dry ice label (UN 1845). Place the dry ice and Exempt Human Specimen labels on the side of 
the kit. 
 
SHIPMENT OF SPECIMENS TO THE BOLLARD LABORATORY 
 
Notify Hema Dave or Bollard lab representative prior to shipment of the sample*  
Email: cogsamples@childrensnational.org OR Phone: (202) 476 6397 or (202) 476 8005.  
* If prior notification is not possible, proceed with shipment without delay and email the FedEx 
tracking number to: cogsamples@childrensnational.org . 
 
DO NOT ship samples for delivery on a weekend or holiday without prior authorization. Contact the 
Bollard Lab for special instructions if samples are collected on Friday for Saturday delivery. Although not 
preferred, samples collected on Saturday/Sunday can be shipped Monday for Tuesday arrival. If you have 
any questions regarding shipping, please contact Dr. Hema Dave at the Bollard Lab.  
 
Blood should be shipped to the Bollard Lab using the COG FedEx account: 
See: https://www.cogmembers.org/_files/reference/FEDEXmemo.pdf  
 
Ship specimens by Federal Express Priority Overnight delivery to: 
 
Dr. Catherine Bollard c/o Hema Dave   
Children’s National Medical Center 
111 Michigan Ave NW 
5th Floor Main, Rm 5220 
Washington DC 20010 
Phone: (202) 476 8005 
 
Instructions for Packaging the Bollard Lab Specimens: 
1. If a ThermoSafe shipping container is not available, send samples in a comparably thick container such 
as a Styrofoam box (not a clini-pack).   
2. Place blood collection tubes in a primary container, wrapping each collection tube separately to protect 
from breakage during shipment. 
a. Place at least one ice pack in the secondary/outer container.  
b. If the shipment will be in transit for greater than 24 hours, and during non-winter months 
(April-October), place additional ice packs in the secondary container (Styrofoam box) to maintain 
temperature stability during shipment.  

  
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3. Reminders:  
a. Notify Hema Dave or a Bollard lab representative prior to shipment of the sample.  
Phone: (202) 476-6397 or (202) 476-8005.  
Email: hkdave@childrensnational.org and cogsamples@childrensnational.org  
b. On the AHOD1331 Specimen Transmittal Form, record the exact time and date that the sample is 
drawn and note the white blood cell count (WBC). 
 
 
B. SUMMARY OF CORRELATIVE BIOLOGY STUDIES 
 
CORRELATIVE BIOLOGY STUDY 1: To determine the incidence of tumor-specific antigens (PRAME, 
MAGE-A4, and testis-specific antigens) and the incidence of EBV antigens (EBNA1, LMP1, LMP2) in 
newly-diagnosed, high-risk cHL, and to determine the difference in immune function (CTL number and 
function, cytokine secretion) between those treated with standard chemotherapy vs. brentuximab-
containing chemotherapy. 
 
Rationale 
Many studies have demonstrated the importance of the immune system and the microenvironment in 
Hodgkin lymphoma.58,59 However, little is known about the effect of treatment on the immune cells in the 
microenvironment or the incidence of CTL target antigens in pediatric/AYA HL patients. In high-risk 
pediatric cHL, absolute numbers of CD3-positive T cells are significantly reduced (CD4 > CD8), and 
virtually all patients with HD have a degree of lymphopenia. There is an unmet need to assess immune cell 
recovery between patients treated with standard therapy and those treated with brentuximab-containing 
chemotherapy. Several previous studies have shown that brentuximab may influence the HL 
microenvironment, making it more conducive to CTL expansion and function.58 This information will 
provide a better understanding of how the recovery of tumor-specific and pathogen specific T cells affects 
the patient’s response to therapy both in terms of disease response and therapy related toxicity (infection). 
Similarly, if manipulation of tumor-specific antigens is contemplated as a method to prevent relapse, 
understanding the dynamics of tumor-specific T cells and reconciling their dynamics with clinical changes 
during therapy are requisite to rationally design a therapeutic intervention using adoptive T cell 
immunotherapy. The ultimate goal is to determine if CTL therapy can be added to the treatment of high-
risk HL patients to prevent relapse. 
 
Hypothesis and specific aims 
We hypothesize that patients with TAA (tumor associated antigens) expression will be less likely to relapse. 
We also hypothesize that patients treated with brentuximab-containing chemotherapy will have a less 
immunosuppressive environment following treatment, and that patients with a less immunosuppressive 
micro-environment following chemotherapy will be less likely to relapse. We plan to test these hypotheses 
with the following specific aims:  
 
1) To determine the incidence of EBV-associated antigens (EBNA1, LMP1 and LMP2) and incidence of 
tumor-associated antigens (PRAME, MAGE-A4 and testis-associated antigens) in cHL tumors, and to 
determine if the incidence of tumor-associated antigens correlates with EBV status or EFS; and 
 
2) To characterize pre- and post-treatment systemic immunosuppressive environment: 
a. To determine if specific pre or post-treatment effector immune functions correlate with EFS,  
b. To determine if there are differences between post-treatment or changes over time in specific immune 
functions between brentuximab-containing chemotherapy vs. standard chemotherapy, and  

  
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c. To determine if we can identify pre-treatment immune functions that control brentuximab-mediated 
treatment effects. 
 
Methods 
The incidence of tumor-specific antigens will be determined by immunohistochemistry (IHC) from pre-
treatment biopsy tissue. Immune function will be determined by CTL activation (IFN-gamma secretion), 
cytokine excretion, and gene expression as determined by a GEP array as previously described.60 
 
Contribution to current knowledge base 
Tumors frequently modulate target antigen expression to prevent T-cell recognition. Based on our 
preliminary data in the phase I setting,61 there is an apparent lack of tumor specific t-cell response in non-
responding patients. In contrast >50% of relapsed HL patients achieving durable clinical responses post-
therapy produce T-cells specific for tumor associated antigens within 2 months. If this therapy is to be 
expanded to larger patient groups, it is necessary to confirm these observations in a prospective, phase 3 
cooperative group setting. The confirmation of the potential importance of eliciting a T-cell response to 
tumor –associated antigens (TAAs), the adoptive transfer of tumor specific T-cells could be eventually 
incorporated into upfront therapy in HL. 
 
Preclinical studies 
Tumor specific CTLs have been generated in several hematologic malignancies, including ALL,62 EBV-
positive HL63,64 and EBV negative lymphomas.65 There have been CTLs generated for multiple tumor-
specific antigens, including testis-specific antigens and MAGE-A4.66 Tissue microarray studies have shown 
that MAGE-A4 is strongly expressed on most pediatric/AYA tissue biopsy samples collected on the 
AHOD0031 clinical trial (Bollard, personal communication).66 CTLs against both EBV and non-EBV 
antigens have been shown to be specific for the tumor antigen and have generated persistent CTLs 
production that has generated robust anti-TAA responses in HL mouse xenografts. These CTL are long-
lasting and induce sustained complete responses in mouse xenografts.48  
 
Clinical studies  
The Bollard lab has conducted a phase I study in which relapsed HL adult patients were treated with TAA 
non-EBV CTL post stem cell transplant.66 Following treatment they evaluated tumor-specific T-cell 
specific populations form seven responding patients and five non-responding patient with lymphoma to 
identify the breadth of the tumor specific T cell response to PRAME, MAGE-A4 and survivin.49 This study 
showed that cytotoxic T cells were generated specifically recognizing MAGE-A4 expressed by autologous 
HL targets. Decitabine, an epigenetic modifier previously shown to increase tumor antigen expression in 
HL, did not compromise MAGE-A4-specific T-cell phenotype and function. In patients treated with 
decitabine, expanded MAGE-A4-specific T cells had a broader antitumor T cell repertoire, consistent with 
increased antigen stimulation in vivo. This suggests that adoptive transfer of MAGE-A4-specific T cells, 
combined with either epigenetic modifying drugs or other therapies that alter the T-cell peptide antigen 
repertoire, such as brentuximab, could improve treatment of HL.66  
 
Study design 
The long-term goal of this study is to further delineate immune responses in the cHL microenvironment. 
This information is needed to determine if immunotherapy can be incorporated into therapy regimens for 
newly-diagnosed cHL. Although immunotherapy holds great promise for the future of cHL therapy,60,64-66 
it is necessary to determine if changes in the microenvironment following treatment will allow for the 
expansion of tumor-specific CTL in vitro. 
 

  
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1) Tissue analysis  
The incidence of tumor-specific EBV antigens, MAGE-A4, PRAME and testis-specific antigens will be 
assessed by one of two methods. If adequate diagnostic tissue blocks are available, tumor specific antigens 
will be determined using a tissue microarray as described.67,68 If blocks are not available, the tumor specific 
antigens will be assessed using pre-treatment biopsy slides obtained from all consenting patients with 
available unstained slides. Unstained slides will be examined for relevant antigens using IHC and 
commercially available antibodies as described.66 
 
2) Peripheral blood analysis  
Peripheral blood will be obtained for immune studies. Immune function assays will include assessment of 
general immunity and reconstitution (e.g. anti-infectious and anti-tumor specific T-cell immunity). Blood 
will also be used for analysis of peripheral lymphocyte cell-specific gene expression. Blood will be used to 
measure general immune reconstitution and in particular the recovery of T cells specific for tumor 
associated antigens (TAA) such as MAGE A4, PRAME, Survivin, SSX2 and EBV antigens LMP1 and 
LMP2. Response to these tumor-specific antigens will be determined pre-treatment and at the completion 
of treatment. 
 
Comparability of methods 
We will use the same methods that we have used in previous studies60-64 and we do not expect technical 
problems completing either the TAA antigen studies or the immune function assays. These methods have 
been used to evaluate responders vs. non-responders in a phase I study61 and these methods will be extended 
to a larger patient sample set in this phase 3 cooperative group trial.  
 
Reason for selection of assay methodology 
No other methodologies have been developed for use with shipped, small volume samples. Our published 
preliminary date provides evidence that this is the best methodology for evaluating tumor-specific T-cell 
responses in HL patients.66  
 
Technical performance characteristics 
ELISPOT analysis will be used to determine the frequency and function of T-cells secreting IFN- in 
response to EBV and tumor-associated antigen peptide mixtures (pepmixesTM (JPT)). Technical 
performance characteristics have been previously published.60 
 
The experience of the investigators with the assay 
Dr. Bollard is well published in the role of EBV antigens and the role of CTL immunotherapy.59-66 Drs. 
Horton and Bollard have worked together previously on the assessment of tumor-associated antigens in HL 
samples from the AHOD0031 clinical trial.  
 
Site performing the correlative studies 
The Bollard laboratory is in a GMP facility at Nationwide Children’s Hospital, a state-of-the-art facility 
that is actively involved in assessment of immune function and the development of immunotherapy. 
 
Assurance of quality control 
The Bollard Laboratory serves as the central pathology review for Phase I/II HL immunotherapy studies. The 
Bollard Laboratory will use their standard QA/QC procedures during the procedures outlined above.59-65 
 
Prevalence of tumor-associated antigens: 
Because we are assessing both EBV and non-EBV antigens, the prevalence of different markers will vary. 
Preliminary data from the Bollard lab and others suggests that EBV antigens are present in approximately 
40% of newly-diagnosed HL patients.66 Based on IHC performed on samples from the AHOD0031 clinical 

  
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trial, tumor-associated antigens varied from >80% (MAGE-A4) to approximately 20-40% (Bollard, 
personal communication).  
 
Proportion of patients on a therapeutic trial will have available sample for correlative study analysis 
and statistical analysis plan  
This study plans to accrue approximately 600 patients. In the last COG phase 3 HL clinical trial 
(AHOD0031) the BPC acquired 307 blocks from the 1712 eligible patients, or 18% of tissue blocks from 
eligible patients. However, since tissue samples will be collected prospectively on this study, we expect 
that our sample acquisition rate will be substantially higher. Assuming a success rate of 30% with 
prospective collection of tissue, this should result in approximately 180 pre-treatment tissue samples for 
evaluation (90 samples per treatment arm). In AHOD0031, at least one peripheral blood sample was 
collected for 40% of patients. Assuming 40% rate of collection of peripheral blood for pre-treatment and 
post-treatment samples, this should result in blood samples from 240 patients (120 per arm) for each 
collection. Of the patients with blood samples collected over time, we project approximately 80% will have 
both pre-treatment and post-treatment samples submitted, which results in 192 patients (96 per arm) with 
both pre- and post-treatment blood samples. 
 
For estimating the incidence of EBV antigens (EBNA1, LMP1, LMP2) and incidence of tumor-associated 
antigens (PRAME/MAGE4, testis-associated antigens) in cHL tumors, the binary incidence will be 
estimated from the tissue samples along with its 95% confidence interval (CI). With 180 samples, at a 
projected 20-40% incidence for EBV antigens, the standard error for the binary incidence rate estimate will 
be 3-3.7%; in other words, the width for the 95% CI will be 12-14%. For PRAME/MAGE4, with a projected 
incidence of 70-80%, the standard error will be 3-3.4% and the width for the 95% CI will be 12-13%. For 
testis-specific antigens, with a projected incidence of 30-40%, the standard error will be 3.4-3.7% with the 
width of 95% CI being 13-14%. To examine the correlation between tumor-associated antigen (TAA) and 
EBV status, the incidence of TAA will be compared between EBV positive and EBV negative tumors. 
Assuming a 20% EBV positive rate, the comparison has a sample size of 36 vs. 144. It is powered to detect 
a 26% (or less) difference in the incidence of TAA between the 2 groups; the detectable difference can be 
less than 26% and varies depending on the incidence rate for the 2 groups. Similarly, if the incidence of 
positive EBV is 40%, which results in a sample size of 72 vs. 108, the study is powered to detect a 22% (or 
less) difference in the incidence of TAA between the EBV positive and negative groups. To examine the 
correlation of TAA with EFS, assuming the tissue samples are obtained from random subsets of the study 
participants, we will have approximately 23 EFS events for this correlative study (30% of 77 events from 
the parent study). To detect a difference in EFS between 2 groups with a total of 23 events, it requires a 
hazard ratio of 4.3/0.23 if the group sizes are 36 vs. 144 (20% vs. 80%), or a hazard ratio of 3.6/0.28 if the 
group sizes are 54 vs. 126 (30% vs. 70%). 
 
For analyses of immune functions from blood samples (quantitative measures), we project 240 samples will 
be collected from either pre-treatment or post-treatment collection, and 192 paired samples. To investigate 
the correlation of pre-treatment immune function with EFS, assuming these samples were from random 
subset of study participants, we will have approximately 31 events (40% of 77 events from the parent study). 
For an analysis comparing EFS between 2 groups of patients defined by immune function above/below 
median (120 vs. 120), we will have power to detect a hazard ratio of 2.7/0.37. To examine the effect of 
brentuximab-containing treatment on immune functions, we will compare the post-treatment immune 
functions between the 2 arms. With 120 patients per arm, the power is 80% to detect a 3.7 SD (SD: standard 
deviation of the post-treatment measure) difference in the mean. We will also compare the change in 
immune function from pre-treatment to post-treatment between the 2 arms. With 96 patients per arm with 
paired samples, the detectable difference is 4.1 SD (SD: standard deviation of the change between pre-
treatment and post-treatment). In an attempt to identify pre-treatment immune functions that determine 
brentuximab-mediated treatment effect, we will explore the interaction term between pre-treatment immune 

  
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function (2 categories) and treatment arm (total 4 groups) using EFS as outcome. With a total of 31 events, 
this analysis has limited power due to testing an interaction term. The smallest detectable interaction term 
(ratio of the hazard ratio) is estimated to be 7.5, but the detectable interaction can be larger than that 
depending on the number of failures in the 4 groups. 
 
Table 1summarizes the effect sizes for this biology aim:  
 
Table 1: Standard error or effect size (2-sided alpha=5%, power 80%) based on sample size for each 
experiment (total patients in study: n=600) 
1. Antigens measures from pre-
treatment biopsy tissue (n=180) 
Samples size  
Standard Error or Effect-Size 
a. 
Incidence of EBV* antigens 
(est. 20-40%) 
180 
Standard error:  
3%-3.7% 
b. Incidence of TAA* 
(est. 70-80% for PRAME 
/MAGE4, 30-40% for testis-
associated antigens) 
180 
Standard error: 
3-3.4%, (PRAME/MAGE4) 
3.4-3.7% (testis associated antigens) 
c. 
Correlation of TAA with EBV  
36 vs. 144 (if 20% EBV+), 
72 vs. 108 (if 40% EBV+) 
Detectable difference for incidence of 
TAA in EBV + vs. EBV - :  
≤26% (36 vs. 144),  
≤22% (72 vs. 108). 
d. Correlation of TAA with EFS  
36 vs. 144  
(if TAA incidence 80%),  
54 vs. 126  
(if TAA incidence 30%) 
Detectable hazard ratio:  
4.3/0.23 (36 vs. 144) 
3.6/0.28 (54 vs. 126) 
 
2. Immune function measures from 
pre-/post treatment blood (n=240) 
 
 
a. 
Correlation of pretreatment 
immune function (above/below 
median) with EFS 
120 vs. 120 
Detectable hazard ratio:  
2.7/0.37 
b. Compare post-treatment and 
the change in pre- and post- 
therapy in immune function by 
treatment arm.  
120 vs. 120  
(post-treatment) 
96 vs. 96  
(change in pre-/post- therapy) 
Detectable difference in mean:  
3.7 SD (SD: standard deviation of the 
post-treatment measure) 
4.1 SD (SD: standard deviation of the 
change in pre- &post- measures) 
c. 
Interaction between pre-
treatment immune function and 
treatment arm on EFS  
4 groups total 240 
Detectable interaction term (ratio of 
hazard ratio) >7.5  
*EBV = Epstein Barr Virus, TAA = Tumor associated antigens 
 
The incidence of EBV-specific antigens, PRAME/MAGE4, and testis-specific antigens will be estimated 
from pre-treatment biopsy samples along with their 95% confidence intervals. The association between 
presence of TAA and EBV status will be examined by Chi-square tests. Kaplan-Meir curves will be used 
to estimate EFS for patients with/without TAA, and log rank test will be used to determine if there is any 
association between TAA and EFS.  
 
Descriptive statistics will be used to summarize immune function measures from pre-treatment and post-
treatment blood samples. Cox proportional hazards models will be used to examine if pre-treatment immune 
functions (may be analyzed as categorical variable or continuous variable) correlate with EFS. Post-
treatment immune functions or change in immune functions from pre-treatment to post-treatment will be 
compared between the standard arm and the experimental arm via two-sample t-test to determine if 
brentuximab-containing therapy leads to more suppressed immune function than standard therapy. Cox 

  
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proportional hazards models will be used to explore the interaction between pre-treatment immune 
functions and treatment arm on EFS to see if pre-treatment factors important for brentuximab-mediated 
treatment effect can be identified. Pre-treatment immune functions may be analyzed as categorical variable 
or continuous variable for such analysis. Although the power for this interaction analysis will be low due 
to testing of an interaction effect, we expect the impact of the immune function and treatment with 
brentuximab-containing chemotherapy will be sufficiently large to be detectable. 
 
Corrections for multiple comparisons 
Most of these comparisons are exploratory and we do not plan to correct for multiple comparisons. 
 
Discuss how the results will have an impact on future studies 
One of the long-term goals of the COG HL and non-Hodgkin lymphoma (NHL) committees is to 
incorporate cytotoxic T lymphocyte (CTL) immunotherapy into treatment regimens for HL. CTL therapy 
is well tolerated and CTLs can be “trained” in vitro to recognize tumor specific antigens (EBNA1, LMP1 
and LMP2 for EBV-positive HL and PRAME, MAGE4 and SSX in EBV-negative HL). However, one of 
the challenges in allowing for the expansion of tumor-specific T cells in newly diagnosed HL patients is 
the immunosuppressive environment surrounding the Hodgkin/Reed Sternberg (H/RS) cells. H/RS cells are 
surrounded by T-helper cells, regulatory T cells (Tregs), and tumor-activated macrophages, all of which 
secrete immunosuppressive chemokines/cytokines that suppress CTL expansion in vivo.58 There is an 
unmet need to determine how to reverse or ameliorate this immunosuppression to allow the expansion of 
anti-tumor CTLs in HL patients. The ability to comprehensively evaluate tumor-specific T-cell responses 
will enhance the development of a highly immunogenic and potent cell therapeutics that could prevent 
relapse in high-risk HL patients. 
 
The objective of this research is to delineate alterations in immune modulation following chemotherapy, 
both with and without brentuximab. Based on extensive preliminary data from the Bollard lab and our 
experience collecting patient samples in the cooperative group setting, the proposed translational research 
will greatly expand the implementation of CTL therapy into the cooperative group setting. 
 
C. ADDITIONAL PLANNED STUDIES 
Samples will be stored for these planned studies at the Biopathology Center (BPC in Columbus, OH) and 
be available for use in future HL research. In the future, specific hypotheses and statistical design will be 
submitted along with each proposal for tissue samples, and will undergo review as per COG and NCTN 
policies and procedures. 
 
Planned Biology Study #1: To determine if a molecular classifier can be developed that 1) identifies early 
response patients at increased risk of relapse, and 2) correlates with 3-year EFS in high-risk pediatric HL. 
 
While early PET response and CHIPs help to stratify patients into treatment arms and determine the need 
for radiotherapy, many of the patients that subsequently relapse initially respond well to therapy. There is 
an unmet need to determine which early response patients will require additional, more intensive therapy 
to prevent relapse occurrence. We propose to identify these patients using a molecular classifier based on 
transcript, genome and protein analysis. 
 
Prior work in adult HL has used gene, miRNA, and protein expression analyses of HL tumor tissue to 
identify putative molecular markers prognostic of clinical outcome.69-82 However, the prognostic 
significance of these markers in pediatric HL is unknown. We hypothesize that an integrated molecular 
analysis will assist in risk-stratification for pediatric HL. The goal of these experiments will be to learn 
more about the biology of HL tumors, and what factors can predict treatment success (early response or 3-
year EFS) vs. treatment failure (presence of any SRL, progressive disease or relapse). A comprehensive, 

  
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mechanism-based evaluation of cHL will allow for not only the identification of reliable predictors of 
outcome (3-year EFS), but will also inform us of the mechanisms responsible for adverse outcome, allowing 
for the identification of molecular pathways that could be targeted with future therapies. 
 
Snap frozen tissue samples will be banked for use at the end of the study. Genome, exome and protein 
analysis will be submitted at that time to CTEP/NCTN for approval. We expect the methods will include 
both whole tissue expression arrays using Nanostring (paraffin-embedded tissue) and whole exome 
sequencing of isolated H/RS cells.  
 
Advances in the field of HL biology have shown suggested that the development of a molecular classifier 
would be beneficial for several reasons. The first is that a comprehensive analysis of GEP, genetic 
rearrangements, and protein changes in HL will help us gain a better understanding the biology of AYA-
HL. This information will not only aid in finding reliable predictors of outcome, but the predictors should 
inform us of the mechanisms responsible for adverse events and could aide in determining which patients 
would potentially benefit from molecularly targeted therapies. Second, similar to adult HL,83 there is an 
unmet need to identify biomarkers that retain their prognostic significance in the AYA population. 
Successful completion of these experiments will allow for us to establish a pediatric/AYA biomarker 
signature that can be tested in future trials to determine the prognostic significance of molecular 
classification. Third, since most pediatric HL relapses come from patients that initially respond well to 
therapy, there is a need to be able to accurately identify these patients after their initial treatment in order 
to aid with risk stratification.  
 
Work from our lab and others have shown that GEP derived from whole tissue biopsy specimens can predict 
overall survival (OS),62 indicating the importance of GEP in the microenvironment. Recent studies from 
have suggested that tumor-associated macrophages predict inferior outcomes in adult cHL,77 including 
samples prospectively collected from the E2496 intergroup clinical trial.84 However, the prognostic value 
of tumor-associated macrophages could not be reproduced in two small pediatric/AYA cohorts,85,86 strongly 
suggesting that biomarkers have to be reassessed in AYA- HL. A current retrospective review of GEP and 
TMA from the AHOD0031 and AHOD0831 clinical trials is ongoing (AHOD12B2). The data from this 
retrospective study, in combination with the technology that will have advanced molecular methods, will 
be combined to propose a series of experiments for the development of a retrospective study to identify 
prognostic molecular classifiers using prospectively collected samples. 
 
There is an unmet need to determine which patients with a RRL to therapy (as determined by CT/PET) 
require additional, more intensive therapy to prevent relapse. A molecular will aid in the process of 
identifying patients with a “high-risk” molecular genetic profile. This classifier will be examined 
prospectively in the nest clinical trial. The eventual goal, if the classifier is validated, is to combine imaging 
data and the molecular score with other known risk factors to risk stratify patients following initial 
chemotherapy. The goal is to improve long-term survival by preventing the under treatment of RER patients 
and lowering the relapse rate for all patients. The details of the statistical methods will be determined with 
the submission of the biology trial at the completion of sample collection for this clinical trial. An 
assessment of clinical utility would be included in any future proposals for molecular analyses. 
 
Planned Biology Study #2: Quantitation of EBV DNA and RNA in serial specimens in cell-free blood to 
explore their utility as prognostic or tumor markers. 
 
This planned study will characterize EBV DNA and RNA in serial specimens in cell-free blood and explore 
their utility as prognostic or tumor markers. Samples will be obtained from all consenting patients on study. 
Plasma will be collected from peripheral blood samples (2 mL/time point) prior to treatment, at 8 days after 
the start of the first cycle, at the completion of cycles 1 (3 weeks), 2 (6 weeks), 5 (15 weeks), at end of 

  
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therapy evaluations 4-6 weeks from the last dose of treatment on Cycle 5 if no RT, or 6-9 weeks from last 
RT treatment for patients receiving RT, and during follow-up at 3 months, 6 months, 9 months, 12 months, 
and 24 months after the completion of therapy. Plasma will be used to characterize viral DNA and EBV-
associated miRNA. EBV copy number will be determined by Real-Time PCR.  
 
Detection of methylated DNA Enrichment: A new method has been recently developed that efficiently 
distinguishes tumor DNA from virion DNA by characterizing CpG methylation of viral DNA. This method 
will be performed as previously described.87 
 
Planned Biology Study #3: Expression of TARC as a biomarker for early response to therapy  
 
Research in adult HL has shown that TARC is expressed by H/RS cell in nodular sclerosing HL.80 Decreases 
in the chemokine TARC correlate with early response to therapy.80 In recent work, pre-treatment TARC 
levels were associated with both increased clinical risk factors and decreased response to treatment in a 
German Hodgkin Study group trial.88 Soluble TARC also associated with outcome in an Australian study 
of 47 patients, particularly when combined with sCD163, which measures tissue-associated microphages.89 
Peripheral blood will be collected from all consenting patients at three time points during therapy: pre-
treatment, Day 1 (prior to therapy) of Cycle 2 and Day 1 (prior to therapy) of Cycle 3 (Table 7.2). TARC 
will be assessed by commercially available ELISA for sCD30. MicroRNA profiling and TARC assays will 
be done in collaboration with Anke van den Berg, who is experienced in this technique. 89,4,90 
 
Planned Biology Study #4: Examination of multi-drug resistance proteins, the NF-κB pathway, and soluble 
CD30/CD168  
 
The goal of this aim is similar to the first in providing and in-depth examination of cell signaling pathways 
important in cHL resistance to chemotherapy, in particular, the mechanisms of brentuximab resistance. A 
comprehensive mechanism-based analysis should allow us to identify targeted therapies to overcome 
brentuximab resistance. Pre-treatment biopsy slides will be collected from consenting patient treated with 
brentuximab vedotin. The P-glycoprotein (MDR-1) and MRP3 will be detected by immunohistochemistry 
(IHC) or similar methods using commercially available antibodies as described.66 DNA from patients with 
increased MDR-1 or MRP3 will be tested for DNA polymorphisms that result in protein upregulation. NF-
κB pathway proteins will be examined in pre-treatment HL tissue using the previously constructed tissue 
microarray (TMA).68 Soluble CD30 will be quantitated prior to start of chemotherapy and (if feasible) in 
post-treatment samples. This is currently not feasible as brentuximab vedotin interferes with CD30 binding 
of current commercially available antibodies (Seattle Genetics, personal communication).  
 
Planned Biology Study #5: Future research in Host DNA for Hodgkin lymphoma predisposition, treatment, 
toxicities and long-term complications.  
 
The banking of biologic specimens is a requirement for innovative and potentially therapeutic biologic 
studies. Thus, this trial will strongly encourage banking of specimens at diagnosis (blood, unstained biopsy 
slides, and tissue blocks), at the end of each cycle of therapy (peripheral blood), at end of therapy (peripheral 
blood), and at relapse (biopsy tissue and blood). These samples will be stored at the Biopathology Center 
for use in future research. Specific hypotheses and statistical design will be submitted along with each 
proposal for tissue samples, and will undergo review as per COG policies and procedures. Banking of 
specimens is further outlined in the COG Biospecimen Manual of Procedures.  
 
 

  
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APPENDIX VII: CORRELATIVE PERIPHERAL NEUROPATHY (CIPN) STUDY 
Background: Several widely used chemotherapy agents including the vinca alkaloids, platinum 
compounds, taxanes, thalidomide, and bortezomib cause peripheral neuropathy (PN),91-93 although this side 
effect is often both under-recognized and under-diagnosed.94 With early recognition and clinical 
management, often involving dose modification, chemotherapy induced-PN (CIPN) can be effectively 
managed in the majority of patients. Up to 40% of adult cancer patients, however, experience permanent 
symptoms and disability.95  
CIPN typically involves three principal manifestations: sensory; motor; and autonomic. These 
manifestations vary by drug class and by cumulative exposure. For example, the vinca alkaloids generally 
cause a sensory neuropathy (e.g., loss of deep tendon reflexes or paresthesias/dysesthesias), but can also 
produce motor neuropathy and autonomic neuropathy (e.g., constipation/ileus). 
Assessment Methods: CIPN is clinically assessed with grading scales, such as the Common Terminology 
Criteria for Adverse Events (Neuropathy subscales)96 and in children, the Balis Pediatric Scale of Peripheral 
Neuropathy. These scales, although widely used, have been found to have variable degrees of inter-rater 
reliability, a narrow response scale (0-5), and limited responsiveness to change. Substantial floor effects 
have also been reported.97  
Hybrid measures, such as the Total Neuropathy Score (TNS), originally developed to assess peripheral 
neuropathy among adults with diabetes, include subjective symptoms scores and formal neurologic 
assessment to characterize the deficits. TNS has much better inter-rater reliability and has a much broader 
response range than the grading scales.91 The TNS has undergone two modifications, the first for its use 
with adult patients with breast cancer,98 and subsequently, for use with children ages 5-18 years.99 Although 
the item content was preserved in the modification from adult to pediatric ages, the language was revised 
to improve understanding, particularly for younger children. After an initial pilot study of 20 children, the 
ped-m-TNS was tested in 41 children with cancer and 41 controls, demonstrating significant differences 
between patients and controls across both the subjective symptoms and components of the neurological 
assessment.100 The ped-m-TNS identified 40% of subjects with sensory neuropathy and 15% of patients 
with motor neuropathy who were not identified on clinical grading scales.101 Separately, Smith et al. further 
modified the TNS as the TNS-Pediatric Vincristine (TNS-PV) and evaluated it in longitudinal assessment 
over 15 weeks in 65 children with acute lymphoblastic leukemia; neuropathic pain was assessed with the 
FACES Pain Scale. Assessments were attainable in nearly all children 6 years and over, but not in younger 
children. Responsiveness to change was detected, with vibration and reflex items being the most responsive. 
While this measure has promising application in clinical management, the requisite inclusion of a trained 
examiner to assess neurologic function in key domains, including vibration, reflex, and strength, precludes 
its ready inclusion into group-wide clinical trials. 
Self-report measures of CIPN have been used successfully in several adult cooperative group studies across 
a wide range of agents and disease groups. The 11-item Functional Assessment of Cancer 
Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT-GOG-Ntx),102,103 the first and most widely 
used self-report measure in the US, has been found to have strong psychometric properties, including 
responsiveness to change over time.104 Similar patterns were also reported by the National Surgical 
Adjuvant Breast and Bowel Project.105 Scale scores were related to clinical grading scores non-linearly (i.e., 
2.4 for clinical Grade 0 to 24.5 for clinical Grade 3). The scale allowed for discrimination among patients 
with similar clinical grade and highlighted different symptoms as being bothersome at different points 
during therapy. As a measure of criterion validity, Huang et al. demonstrated that scale scores were able to 
discriminate the presence or absence of CIPN, based on clinical grading, with an area under the receiver 
operating characteristics curve (AUC of ROC) of 81%.106 Of note, there are no validated self-report 
measures of CIPN for children. 
 

  
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CIPN has been shown to have a negative effect on health-related quality of life (HRQL) in several diverse 
populations. Large effect sizes, equivalent to two standard deviations, were detected in HRQL comparisons 
between chemotherapy naïve patients and those with CIPN in a study of women with ovarian cancer.104 
Mols et al. demonstrated in a sample of over 1600 patients that those in the top decile of neuropathy 
symptoms had statistically significant worse HRQL across all measured domains,107 a finding echoed in the 
qualitative research of Textor et al.108 To date, there have been no reports of the association of CIPN with 
HRQL in children undergoing cancer treatment. The proposed study will address this important gap.  
Objectives: Within the randomized comparison of the role of Brentuximab vedotin in the treatment of 
children with newly diagnosed classical Hodgkin Lymphoma (cHL), we propose the following specific 
aims:  
 
I. Primary aim: 
1. To characterize the extent of chemotherapy-induced peripheral neuropathy (CIPN), as reported by 
the patients (ages ≥ 11) and parent proxies of patients 5-17.9, using the serial administration of 
the FACT-GOG-NTX, from initial HL diagnosis to three years after completion of initial therapy. 
a. In this objective, the extent of CIPN due to vincristine in the standard arm will be 
compared to CIPN due to the combination of vincristine plus Brentuximab vedotin (Bv) 
in the experimental arm at the completion of planned chemotherapy. 
 
Hypothesis: We hypothesize that patients randomly assigned to the experimental arm will have 
more self-reported or proxy-reported CIPN, at the end of planned chemotherapy. (See Table, 
Time 4 Assessment).  
 
II. Secondary aims: 
1. To describe the trajectory of CIPN over time by study arm and by rater from baseline to 36 months 
off planned chemotherapy.  
2. To compare the FACT-GOG-Ntx scores, as reported by the patients and parent proxies, to clinical 
grading scale (Balis Pediatric Scale of Peripheral Neuropathy in Appendix IV) at each scheduled 
assessment points.  
3. To describe the HRQL consequences of CIPN by severity and over time by correlating the 
summary neuropathy scores (as measured by FACT-GOG-Ntx) with summary scores from the 
CHRIs-Global scale These measures will be collected serially in six planned assessments from 
initial cHL diagnosis to 36 months after the completion of initial therapy for patients randomly 
assigned to either study arm. 
 
Rationale for Study Hypothesis: Brentuximab vedotin contains an anti-microtubule agent, monomethyl 
auristatin E (MMAE), which binds to tubulin and prevents microtubule assembly, leading to cell cycle 
arrest and cell death (See Figure). In the 2013 report of a Phase 1 dose escalation study of adult patients 
with newly diagnosed HL, 75% of patients developed peripheral neuropathy (sensory and motor), although 
most of these events were Grade 1 or 2 and manageable by dose modification.109 This compares to rates of 
Vincristine-induced neuropathy of 35-45% across all grades.91 In the recent AHOD0831 and AHOD0031 
protocols, 3% of pediatric/adolescent patients developed Grade 3 or higher Vincristine-induced neuropathy, 
based on clinical grading scales. Rates of mild to moderate neuropathy were not routinely collected. 
Approach: In the absence of validated self-report or proxy-report measures of CIPN in children, we have 
elected to rely on the well-validated FACT-GOG-Ntx, which has been used in several cooperative group 
trials across myriad diseases and CIPN-causing agents. In collaboration with the instrument’s author, Dr. 
David Cella, a world-renowned psychometrics expert and leading architect of both the PROMIS and 
NeuroQOL initiatives, we will modify the FACT-GOG-Ntx in two principal ways. Prior to initiation of the 
trial, the item content of the FACT-GOG-Ntx will be modified for parent raters (voice change from “I” to 

  
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“my child”). Additionally, for youth self-report, item wording will be reviewed, following procedures 
outlined by Gilchrist et al.99 and Smith97 to ensure comprehension by youth 11 years of age and older. 
Parenthetic descriptors may be added. For example, Gilchrist added a parenthetic tag to the word “numb” 
as “can hardly feel.” The youth report measure will undergo gatekeeper review prior to administration. No 
planned modifications will be made in the FACT-GOG-Ntx for patients 18 and over, as this measure has 
been extensively validated for self-report 
Patient self-and proxy-rated measures will be collected from all youth 11 years of age and older at time of 
enrollment and from parents of all child participants ages 5 – 17.99 years at the time of enrollment. Proxy 
reports will not be collected for participants who are age 18 or older. For each measure for which dual rating 
is planned, there will be a ‘youth’ version and a parent proxy version. While the FACT-GOG-Ntx is 
available in English, Spanish and French in both the parent proxy- and youth self-report versions, the 
demographics and the CHRIs-Global are available only in English and Spanish. Therefore, French-
speaking participants will complete only the FACT-GOG-Ntx. The planned demographics assessment, 
which is a one-time (baseline) assessment, will be collected from the parent of enrolled children 
5-17.9 years or directly from the patient, if the patient is 18 years of age or older at the time of enrollment. 
Study measures will be collected by CRAs from each designated rater at each participating institution at 
six scheduled time points, beginning with the initiation of chemotherapy at ‘baseline’ through 36 months 
following the completion of therapy (see Table 1 below). Both Times 2 and 3 will be collected Day 8 of 
the Cycles 2 and 5, respectively, when the Day 8 Vincristine is scheduled. CRAs at each site should 
endeavor to collect the measures after the administration of the Vincristine, so as to not ‘script’ the clinical 
encounter. The rationale of the two on-treatment time points is to capture early onset CIPN and the pattern 
of change or worsening over time. The Time 4 assessment, corresponding to the end of therapy, is designed 
to capture the anticipated peak of CIPN temporally associated with the dose density peak exposure of both 
Bv and Vincristine. The Time 5 time point at 12-month follow up will evaluate persistence of CIPN off 
planned therapy. Beginning with Amendment #6, the assessment window for the Time 6 time point has 
been expanded from +/- 3 months to +/- 6 months to ensure optimal response rate (see Tables 1a and 1b). 
Notably, Time 6 at 36-month follow up will allow us to estimate the persistence or reversal of neuropathy 
at both 1 and 3 years following a period from completion of therapy in children. Similar data on time to 
resolution of neuropathy in adults, following treatment with brentuximab vedotin, have demonstrated 
resolution beyond one year. The restricted number of assessments is designed to limit burden to the sites. 
All measures have a recall period of the past week.  
 
 

  
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Assessments required for patients enrolled before the CIPN sub-study reached accrual on 9/8/2017: 
Table 1a. Assessment Schema by Measure, Rater, and Timepoint for Patients 5-17.9 years 
Measure/ 
Timepoint  
Time 1 
(baseline, prior 
to therapy) 
Time 2 
(Day 8 of 
Cycle 2) 
Time 3 
(Day 8 of 
Cycle 5) 
Time 4 
(End of 
Therapy)  
Time 5 
(12 months  
± 3  months) 
Time 6 
(36 months   
± 6 months) 
Demographics 
XParent 
-- 
-- 
-- 
-- 
 
FACT-GOG-Ntx 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent,  
XYouth>11 
XParent,  
XYouth>11 
XParent,  
XYouth>11 
CHRIs-Global 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent,  
XYouth > 11 
XParent refers to parent proxy ratings of CIPNs for all minors 5-17.9 years; 
XYouth≥11 refers to youth ages 11-17.9 self-report of CIPNs. 
 
Table 1b. Assessment Schema by Measure and Timepoint for Patients ≥ 18 years 
Measure/ 
Timepoint  
Time 1 
(baseline, prior 
to therapy) 
Time 2 
(Day 8 of 
Cycle 2) 
Time 3 
(Day 8 of 
Cycle 5) 
Time 4 
(End of 
Therapy)  
Time 5 
(12 months ± 
3 months) 
Time 6 
(36 months   
± 6 months) 
Demographics  
X 
-- 
-- 
-- 
-- 
 
FACT-GOG-Ntx  X 
X 
X 
X 
X 
X 
CHRIs Global  
X 
X 
X 
X 
X 
X 
X refers to self-report measures required at each time point for patients ≥ 18 years of age. 
 
Collection Timing Specifics:  Time 1: baseline, prior to therapy. 
Times 2 and 3: Day 8 of Cycle 2 and Cycle 5, respectively.  
Time 4: End of Therapy is 4-6 weeks from last dose of Cycle 5 if no RT, or 
6-9 weeks from last RT treatment for patients receiving RT. 
Time 5: 12 ± 3 months post completion of therapy.  
Time 6: 36 ± 6 months post completion of therapy.  
 
Measures: FACT-GOG-Ntx: Functional Assessment of Cancer Therapy/Gynecologic Oncology Group--
Neurotoxicity 
CHRIs-Global: Child Health Ratings Inventories-Global Quality of Life scale  
 
Analysis Plan:  
Preparation for the planned analyses: Mean scale scores and standard deviation will be calculated for 
each measure by time point and rater, using established scoring algorithms. In the planned CIPN analysis, 
we will calculate the mean summary scores calculated from the FACT-GOG-Ntx for each rater (youth and 
parent). In the planned HRQL analysis, mean summary scores will be calculated for the CHRIs-Global 
scale (for physical and mental health, respectively).  
 
Primary analysis 
Non-inferiority assumptions: For the primary analysis, the null hypothesis is that the experimental arm is 
inferior to the standard arm. H0: µe -µs > d. The alternative hypothesis is that the experimental arm is non-
inferior to the standard arm with regard to patient and parent report of CIPN. To compare the mean scores 
at Time 4 between study arms, we will perform a two-sample t-test, assuming equal variance. This analysis 
will be performed separately for youth- and parent-reported CIPN scores. A Bonferroni correction has been 
made to account for multiple comparisons (α=0.05/2=0.025). 
 

  
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Secondary analyses:  
1. CIPN:  
a. Longitudinal analysis: Since differences in CIPN are hypothesized between study arms and over time, we 
propose a longitudinal analysis, a mixed model will be constructed to account for within subject 
correlations. We expect observations to be correlated within subjects for each of the proposed assessments 
and between raters (parent and child). Initially, we will model CIPN as a function of rater, time point, and 
randomization assignment. Where appropriate, both raters will be analyzed in the same model the effect 
of rater can be measured and the correlation between raters can be modeled. We will test different forms 
of the time variable (linear and nonlinear) to determine which form provides the best fit. This model will 
also allow the evaluation of persistence of CIPN over time, especially between Times 4-6.  
b. Distribution of neuropathy by type (sensory vs. motor) to be examined over time by study arm, based 
on FACT-GOG-Ntx subscores. These will be described as frequencies by time point. 
c. Functional consequences of CIPN will be estimated in two ways: based on specific responses to 
functional items within the CIPN scale (e.g., I have trouble walking), as well as through correlations 
between CIPN items and the measures of HRQL. Specifically, motor neuropathy sub scores could 
be compared to the physical health subscales and pain items of the CHRIs-Global.  
d. Relationship between FACT-GOG-Ntx scores and clinical grading: At each planned assessment 
CIPN scores will be compared using the Spearman’s correlation to clinical grading, based on the 
Balis Pediatric Scale of Peripheral Neuropathy (see Appendix IV).  
e. To formally assess persistence of CIPN off planned chemotherapy from Time 4 to Time 6, we will 
calculated the difference in FACT-GOG-Ntx summary scores for those time points and compare 
that difference between study arms using the two-sample t-test.  
 
2. HRQL: Differences in HRQL, as measured by the CHRIs-Global, are also expected to differ between 
study arms and over time. To evaluate this we will utilize a mixed model, accounting for within subject 
correlations. Specifically, we expect observations to be correlated within subjects for each of the proposed 
assessments and between raters (parent and child). Initially, we will model HRQL as a function of rater, 
time point, and randomization assignment. Both raters will be analyzed in the same model so the effect 
of rater can be measured and the correlation between raters can be modeled. We will test different forms 
of the time variable (linear and nonlinear) to determine which form provides the best fit.  
 
3. Validation: The psychometric performance of the FACT-GOG-Ntx scale will be evaluated among 
pediatric patients and proxy raters using baseline data from both study arms. Principal components 
analysis will be performed to confirm the unidimensional scale structure and item-total scale 
correlations will be calculated using Pearson correlations. Internal consistency reliability will be 
described for each rater, using Cronbach’s α. To establish criterion validity, comparisons with clinical 
toxicity scales will also be performed using data at Time 2 and Time 3. As a measure of construct 
validity, we will compare Time 4 assessments by total delivered dose of brentuximab vedotin 
(experimental arm) and vincristine (experimental and standard arm).  
 
Power Calculation: 
Power has been calculated for the primary aim, which is a non-inferiority design with a continuous outcome 
(CIPN scores). The following assumptions have been made: the significance level is set at 0.05; the power has 
been set at 80%; and the inferiority limit (d) has been set at 0.35 standard deviation units (2.45 points with a scale 
standard deviation of 7 on the FACT-GOG-Ntx). Based on the experience of recent COG studies with patient-
reported outcomes (e.g., AAML1031), we anticipated follow-up rates at our primary endpoint (Time 4) to be no 
better than 67% (L. Sung, personal communication 4/8/14). Accounting for this attrition over time, we estimated 
that we would need 101 evaluable subjects per study arm at time point 4 (total sample size of 202). A total of 
320 patients were enrolled as of 9/8/17. Accrual is closed to patient entry on this embedded study.  
 
 

  
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APPENDIX VIII: COST EFFECTIVENESS OF BRENTUXIMAB VEDOTIN FOR US 
INSTITUTIONS ONLY 
Cost Effectiveness Analysis (CEA) of Brentuximab Vedotin in Newly Diagnosed High-Risk Classical 
Hodgkin lymphoma (cHL) in Children and Young Adults  
 
The study will prospectively compare the cost effectiveness of Bv versus standard chemotherapy among 
newly diagnosed high-risk cHL patients from diagnosis to 3 years after treatment completion. Addition of 
Bv is being evaluated in a randomized fashion in the upfront Phase III therapeutic trial (see Study Schema). 
This ancillary study will be focused on COG institutions in the US and include all enrolled patients between 
the ages of 5 – 21.9 years. We anticipate enrolling eligible participants over the first two years of the study 
with two and a half years of planned follow up after the completion of initial therapy. Given the increased 
incidence of mixed cell histology among Latinos and the higher than anticipated number of Latinos enrolled 
at the AHOD0831 study, we will offer participation to English- and Spanish-speaking parents. We 
anticipate approximately 50 within this subgroup. 
 
A.  Proposed outcomes with associated measures: 
1. Health care cost (direct and indirect) (for Bv arm and standard chemotherapy arm): 
a. Units of health care utilization will be collected prospectively from patients 18 – 21.9 years of 
age (at the time of enrollment) and from parents of enrolled patients ages 5-17.9 (at the time of 
enrollment) using the well-validated Stanford Health Care Utilization110,111 instrument. This 4-
item instrument quantifies patient visits to a physician’s office, emergency department, 
hospitalizations, and lengths of hospitalizations. The reference period for data collection has 
been adjusted to fit the intervals between scheduled assessments. Therefore, study personnel 
will take note of the different versions of the measure for specific assessment time points. 
b. Utilization units will be monetized using administrative data based on cost component of 
interest. These include hospitalizations, emergency room visits, major procedures/surgeries, 
radiation therapy, clinic visits, day-hospitalization/chemotherapy infusions, hematopoietic stem 
cell transplantation (HSCT) (in those that relapse within the 2.5 years of follow up). To augment 
planned cost analyses, we will link ICD-9/10 codes to collected adverse events (as routinely 
collected as part of the upfront trial) and estimate the average costs using administrative data. 
This information will generate the direct cost components.  
c. Indirect costs will be estimated based on parent (caregiver) productivity loss, measured as parent 
reported absenteeism and presenteeism. This will be measured by the Caregiver Work 
Limitations Questionnaire, a 23-item validated questionnaire.112 For patients 18 years or older 
at the time of enrollment, the Caregiver WLQ will not be collected. 
 
2. Quality-adjusted life-years (QALYs) determination (for Bv and standard chemotherapy arms):  
a. Serial utility weights will be calculated utilizing the Health Utilities Index (HUI) 2/3,113-115 a 
validated preference-based instrument, collected for both the Bv and standard chemotherapy 
arms. These utility weights will then be multiplied by the duration of observed survival to yield 
quality-adjusted life years (QALYs).  
b. Respondent Type: Parents of enrolled patients within the 5-17.9 age range at time of enrollment 
for all study measures; youth 11-17.9 years at time of enrollment will complete the HUI 2/3 
only; young adults aged ≥ 18 years at time of enrollment will complete the HUI 2/3 and Stanford 
Healthcare Utilization only 
c. Language Availability: The Stanford Healthcare Utilization measure and the HUI 2/3 are 
available in English and in Spanish. The Caregiver Work Limitations Questionnaire is available 
in English only. 
d. Recall: Past week. 
 

  
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B. Assessment time points:  
Required for US patients who enrolled before the CEA sub-study reached accrual on 9/8/2017. 
A total of six time points have been selected (see Tables below): 
1. Baseline assessment prior to first cycle of chemotherapy. This assessment time point will allow us 
to compare any differences between study arms prior to the initiation of active treatment. 
Conventionally, the baseline assessment is the time point against which all change scores are 
calculated.  
2. Day 8 of Cycles 2 and 5 (time points 2 and 3). These will allow us to assess both utilities and 
healthcare utilization during chemotherapy administration.  
3. At the end of planned therapy (time point 4). This will allow us to examine healthcare through the 
end of therapy.  
4. 12 and 36 months off planned therapy. This will allow us to examine healthcare utilization incurred 
one and three years off planned therapy, inclusive of salvage therapy. 
 
Table 1a. Assessment Schema by Measure, Rater, and Time point for Patients 5-17.9 years 
Measure/Timepoint  
Time 1 
Time 2 
Time 3 
Time 4 
Time 5 
Time 6 
Baseline 
Cycle 2, 
Day 8 
Cycle 5, 
Day 8 
At the end of 
therapy 
12 months (± 3) 
off therapy 
36 months ( ± 6) 
off therapy 
Health Utility Index 2/3  
XParent 
XYouth 
XParent 
XYouth 
XParent 
XYouth 
XParent  
XYouth 
XParent, 
XYouth 
XParent,  
XYouth 
Stanford Healthcare 
Utilization 
XParent 
XParent 
XParent 
XParent 
XParent 
XParent 
Caregiver Work 
Limitation Questionnaire 
XParent 
---- 
---- 
XParent 
XParent 
--- 
XParent refers to parent proxy ratings for all minors 5-17.9 years of age; 
XYouth refers to youth ages 11-17.9 self-report of CEAs 
 
Table 1b. Assessment Schema by Measure, Rater, and Time point for Patients ≥ 18 years  
Measure/Timepoint  
Time 1 
Time 2 
Time 3 
Time 4 
Time 5 
Time 6 
Baseline 
Cycle 2, 
Day 8 
Cycle 5, 
Day 8 
At the end of 
therapy^ 
12 months (± 3) 
off therapy 
36 months (± 6) 
off therapy 
Health Utility Index 2/3  
X 
X 
X 
X 
X 
X 
Stanford Healthcare 
Utilization 
X 
X 
X 
X 
X 
X 
X refers to self-report measures required at each time point for patients ≥ 18 years of age.  
 
Collection Timing Specifics: 
Time 1: baseline, prior to therapy. 
Times 2 and 3: Day 8 of Cycle 2 and Cycle 5, respectively.  
Time 4: End of Therapy is 4-6 weeks from last dose of Cycle 5 if no RT, 
or 6-9 weeks from last RT treatment for patients receiving RT.  
Time 5: 12 ± 3 months post completion of therapy.  
Time 6: 36 ± 6 months post completion of therapy.  
 
Measures: 
Health Utilities Index 2/3 (HUI 2/3): 15-Item Questionnaire, Self-administered Versions for 
Self-report or for Parent/Proxy  
Stanford Healthcare Utilization: for parent proxy report (for patients 5-17.9 years of age) 
or for patient self-report (≥ 18 years of age)  
Caregiver WLQ: Caregiver Work Limitation Questionnaire (parent only) 
 

  
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Specific hypotheses: 
Hypothesis 1: While drug cost will be higher in the Bv arm, overall healthcare utilization will be lower in 
the Bv arm, based on less radiation and lower relapse rate (resulting in less need for salvage therapy, 
including hematopoietic cell transplant).  
 
Hypothesis 2: Health-related quality of life (HRQL), as measured by QALYs, will be better for patients 
treated on the Bv arm as compared to the conventional treatment arm as measured from diagnosis until 
3 years after completion of therapy. 
 
Hypothesis 3: Productivity costs will be lower for parent caregivers in the experimental arm compared 
with the standard arm, as a function of less radiation-associated work loss (absenteeism) and less workplace 
presentee-ism (poor functioning while at the workplace). 
 
Background: 
While 5-year overall survival approaches 98% and event-free survival (EFS) approaches 80% in children 
and adolescents with low-risk HL,116 EFS for youth presenting with high-risk HL remains closer to 70%. 
Despite these high rates of treatment success, these survivors have substantially elevated mortality rates in 
the decades following treatment.3,117 The relative risk of all-cause mortality among HL survivors treated in 
the 1970’s and 1980’s remains 7-8 fold higher than the general population with an 11.4-year loss of life 
expectancy.118-120 Thus, the major challenge in the development of modern therapies is to optimize the 
balance between maintaining excellent disease control and minimizing treatment-related burden. Improved 
risk stratification methods, addition of a biologically targeted agent, Bv, and a novel targeted approach to 
radiation therapy (RT) delivery such that the RT is minimized when necessary, is the approach proposed to 
attain this balance on the phase III trial for newly diagnosed high-risk cHL in the COG.  
 
We propose to evaluate whether the addition of Bv in high-risk cHL patients alters quality-adjusted health 
care costs through measurement of health care utilization over the acute treatment phase, and subsequent 
three-year follow-up period (translating to 3 ½ since diagnosis). We believe this is an important question 
given the well-documented burden of morbidity and premature mortality in cHL survivors.3 Understanding 
acute and subsequent three-year implications of adding Bv to standard of care are important because these 
periods are when patients are at the highest risk for relapse, and consequently, would require salvage therapy 
and HSCT. For example, the addition of Bv is hypothesized to increase direct medication costs by $50,000 
per patient (5 cycles * $10,000 per cycle) but reduce relapse rates in the first year by 8% over standard 
therapy. The reduction in the latter costs will in turn reduce the very high costs associated with salvage 
therapy and HSCT in the second or third year post drug treatment. According to a 2011 Milliman report, 
the costs of autologous HSCT amounted to $300,000 per patient, including 30-day pre-transplant and 
medical costs up to 180 days post HSCT alone.121 As it is estimated 50% of those who undergo autologous 
HSCT will relapse (within 7 months to 2 years),122 for the purposes of illustration, we assume that those 
50% will also require an allogeneic HSCT. Again according to Milliman, the 30-day pre-transplant and 
direct medical costs up to 180-days post transplantation for allogeneic transplantation amounted to 
$800,000 per patient.121 Our initial estimated calculations suggest accounting for these costs alone will 
make the inclusion of Bv into standard therapy reduce direct costs to care of the study population by 
approximately $800,000-1,200,000. We also believe there will also be cost reduction in the care of the 
treatment arm related to reductions in the use of radiation therapy. Reduction of radiation therapy will 
reduce the health care costs associated with RT itself, but also reduce the late effects of RT, including 
second malignant neoplasms (SMN), cardiac and pulmonary disease.3 The benefits of Bv’s inclusion in 
standard of care include improvements in mortality, morbidity and HRQL for study participants. 
 
By understanding the balance of costs and benefits of this new intervention, stakeholders (e.g., patients, 
parents, providers, payers, purchasers of health care), and policy makers) can decide whether the 

  
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intervention provides “good” value. Bv is patent protected and an extremely expensive new oncologic; cHL 
is a disease with one of the highest cure rates of any cancer. There is limited (no) information regarding the 
resource use and/or HRQL implications of incorporating Bv into the treatment of cHL among children, 
adolescents and young adults. If cost increases are observed alongside improvements in mortality/morbidity 
or HRQL, the additional immediate burden on the health care system may still be justified. The results of 
this study will be of high impact to physicians and payers. 
 
In addition, the proposed study will serve as a paradigm proof of principle to the COG and other cooperative 
groups regarding the feasibility and value of incorporating health utilization outcomes as a component of 
cancer care delivery research into phase III clinical trials. There have been no resource use or direct medical 
costs studies incorporated into COG phase III clinical trials to date. We have assembled a team including 
experts in cHL, survivorship, health economics, cancer control, epidemiology and pediatric HRQL, to help 
answer this question. This study will build capacity and expertise for future COG studies of the economic 
burden of innovative treatment on patients, families and the health care system. Lastly, this study answers 
the call for examination of cancer care delivery research in the Children’s Oncology Group cooperative 
trial setting. 
 
Statistical design: 
 
Endpoints: Endpoints for this study include: estimated cost (for the period from diagnosis until 3 years after 
therapy completion) and QALYs from the HUI 2/3. These data inputs together will yield an incremental 
cost effectiveness ratio (ICER), defined as the difference in cost for the two treatment groups divided by 
the change in QALYs. In healthcare interventions, a “favorable” ICER is estimated to be $50,000, although 
for cancer treatments this figure is sometimes higher.123  
 
Estimated cost: 
• 
The “unit cost” or price associated with each direct cost component (eg, type of clinic visits, 
radiation therapy, imaging studies, surgeries and other procedures) will be obtained using 
information from published sources. The unit cost information obtained from published sources 
will provide information on the ranges of unit cost for a specific item of resource. For example, 
inpatient costs for a specific admission diagnosis or ICD-9/10 procedure will be retrieved from the 
HCUPnet (https://hcupnet.ahrq.gov), an on-line query system based on data from the AHRQ’s 
Healthcare Cost and Utilization Project. Outpatient costs will be based on Medicare’s resource-
based relative value scales (RBRVS) fee schedule. Using DRG codes from the HCUPnet, we can 
obtain the ranges of hospital costs for interventions across various regions of the country. Similar 
range 
for 
a 
CPT 
code 
can 
be 
found 
in 
Medicare 
fee 
schedule 
(https://www.cms.gov/Medicare/Medicare.html?redirect=/home/medicare.asp) from adjustments 
across geographic regions. These form the range of unit cost values for each item of resource. For 
each patient, we will match patients’ geographic region with unit costs reported for that region from 
the published sources to obtain unit costs most relevant to the patient. 
 
• 
Costs will be estimated by combining the information of resource use with unit costs. Clinical 
events gathered from the trial provide information on resource utilization over time. Denote Qi is 
the count of resource i (e.g., MRI, office visits) and Pi is the unit cost for the health care resource, 
costs will be calculated as: P1 x Q1 + P2 x Q2 + … + PN x QN. Each item of resource utilization will 
be identified from DRG, ICD-9/10 diagnosis/procedure code or CPT codes provided by the CRA. 
Once we obtain information on the “counts” of each resource item from the trial, we will combine 
the unit cost value with counts to calculate the cost associated with a specific resource item. We 
then aggregate all resource items to obtain the cost for that patient. That is, all costs of add specifics 
of cancer care will be tallied for each participant.  

  
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• 
Workplace participation and productivity: Caregiver WLQ scale scores will be computed using 
established scoring algorithms. Four at-work performance scale scores reflect the percentage of 
time in the previous 2 weeks emotional and/or physical health problems limited ability to perform 
specific job tasks. The WLQ scales measure the following 4 dimensions of performance: (1) time 
management, and performance of (2) physical tasks, (3) mental–interpersonal tasks, and (4) output 
tasks (e.g., handling the workload and finishing work on time). Scores range from 0% (limited none 
of the time) to 100% (limited all of the time). A fifth outcome is the WLQ at-work productivity 
loss score, which may be stated in terms of productivity loss or cost. The productivity loss score, 
the weighted sum of the 4 scale scores, indicates the percentage reduction in at-work productivity 
relative to a healthy benchmark group. This is converted to a dollar figure typically by assigning 
an average annual wage of $50,000 to generate productivity cost. The WLQ Work Absence Module 
measures self-reported time missed from work in the past 2 weeks because of health or medical 
care. Absence-related productivity loss is the ratio of time missed in the past 2 weeks to time usually 
spent working. Using WLQ scale scores, a validated productivity loss score can be computed, 
which may be stated in terms of productivity loss or costs.  
 
Sample size and monthly accrual rate: The sample size estimates for this aim are designed to detect a 
clinically meaningful difference (CID) in QALY between the experimental and standard arm of 0.03, based 
on a standard deviation of 0.13. (Feeny, personal communication, 4/7/14). This CID is empirically derived 
from several clinical trials, based on differences in the area under the curve (AUC) for QALY for each arm. 
The calculation assumes six planned assessments and accounts for an estimated 80% participation rate. 
Further, the calculation accounts for within-person correlation of 0.5, assumes an alpha of 0.05, and 80% 
power. Two years of recruitment at the targeted enrollment rate of 11-12 patients per month will be 
sufficient to detect a CID of 0.036. Twenty-seven months of recruitment would be needed to detect a CID 
of 0.03 (with 130 participants/study arm). 
 
Power calculations were performed separately for the Caregiver WLQ. Assuming a standard deviation of 
18 for the WLQ scales, we sought to detect a difference of 6 points between arms, which translates to 1/3 a 
standard deviation. In this type of measure, differences of 1/3 to 1/2 a standard deviation have been found 
to be clinically meaningful. Assuming a within-person correlation of 0.5, completed of three assessments 
(restricted to baseline, Time 4 and 12 months off treatment to minimize burden) and an alpha of 0.05, we 
would have 80% power to detect this clinically meaningful difference with 127 subjects per arm.  
 
CEA accrual was reached on 9/8/2017 and this embedded study was closed to further patient entry. 
 
Analysis Plan: Differential mean costs will be compared between the two groups (standard arm of ABVE-
PC vs. experimental arm Bv-AVEPC). We will assume 1-3% discount rates apply to costs incurred in the 
second and third years of the study.124 To examine whether patients randomized to the Bv arm have reduced 
cost than patients randomized to the standard arm after controlling for confounding factors, we will rely on 
multivariate statistical models. In addition to the main impact variable — the binary indicators for the 
“treatment group” — all analyses will control for patient and hospital characteristics that might differ by 
chance among patients in the two randomization groups. Because cost estimations are generally highly 
skewed, we will model all of our cost equations using the method of extended estimation equation (EEE).125 
Contrary to the traditional approach of applying least squares to log-transformed data, the EEE method is 
a recently developed econometric method that specifies a highly flexible mean model to accommodate data 
of various functional forms, including highly skewed cost data. Total costs will be aggregated for the 
2.5 year period by study arm. Similarly, QALYs will be calculated, using global utility scores from the HUI 
2/3 for each time period. The AUC of QALYs will then be compared by study arm. The difference in cost 
will be divided by the difference in QALYs to generate the ICERs. 
 

  
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APPENDIX IX: CTEP AND CTSU REGISTRATION PROCEDURES 
CTEP INVESTIGATOR REGISTRATION PROCEDURES 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy require all 
individuals contributing to NCI-sponsored clinical trial to register and to renew their registration annually. 
To register, all individuals must obtain a Cancer Therapy Evaluation Program (CTEP) Identity and Access 
Management (IAM) account (https://ctepcore.nci.nih.gov/iam). In addition, persons with a registration type 
of Investigator (IVR), Non-Physician Investigator (NPIVR), or Associate Plus (AP) (i.e., clinical site staff 
requiring write access to OPEN, RAVE, or TRIAD or acting as a primary site contact) must complete their 
annual registration using CTEP’s web-based Registration and Credential Repository (RCR) 
(https://ctepcore.nci.nih.gov/rcr). Documentation requirements per registration type are outlined in the table 
below. 
 
Documentation Required 
IVR 
NPIVR 
AP 
A 
FDA Form 1572 
 
 
Financial Disclosure Form 
 
 
 
NCI Biosketch (education, training, 
employment, license, and certification) 
 
 
 
HSP/GCP training 
 
 
 
Agent Shipment Form (if applicable) 
 
CV (optional) 
 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access all CTEP and 
CTSU (Cancer Trials Support Unit) websites and applications.  In addition, IVRs and NPIVRs must list all 
clinical practice sites and IRBs covering their practice sites on the FDA Form 1572 in RCR to allow the 
following: 
• 
Added to a site roster 
• 
Assigned the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
• 
Act as the site-protocol PI on the IRB approval 
• 
Assigned the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL). 
 
Additional information can be found on the CTEP website at 
https://ctep.cancer.gov/investigatorResources/default.htm. For questions, please contact the RCR Help 
Desk by email at RCRHelpDesk@nih.gov. 
 
 

  
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CTSU REGISTRATION PROCEDURES 
This study is supported by the NCI Cancer Trials Support Unit (CTSU).  
 
Requirements for AHOD1331 Site Registration: 
• 
IRB approval (For sites not participating via the NCI CIRB; local IRB documentation, an IRB-
signed CTSU IRB Certification Form, Protocol of Human Subjects Assurance Identification/IRB 
Certification/Declaration of Exemption Form, or combination is accepted ) 
• 
IROC Credentialing Status Inquiry (CSI) Form  
NOTE: For studies with a radiation and/or imaging (RTI) component, the enrolling site must be 
aligned to a RTI provider. To manage provider associations access the Provider Association tab on 
the CTSU website at https://www.ctsu.org/RSS/RTFProviderAssociation, to add or remove 
associated providers. Sites must be linked to at least one IROC credentialed provider to participate 
on trials with an RT component. 
 
Submitting Regulatory Documents: 
 
Submit required forms and documents to the CTSU Regulatory Office, where they will be entered and 
tracked in the CTSU RSS.  
 
Regulatory Submission Portal: www.ctsu.org  (members’ area) → Regulatory Tab  
→Regulatory Submission  
 
When applicable, original documents should be mailed to: 
CTSU Regulatory Office 
1818 Market Street, Suite 3000 
Philadelphia, PA 19103 
 
Institutions with patients waiting that are unable to use the Portal should alert the CTSU Regulatory Office 
immediately at 1-866-651-2878 in order to receive further instruction and support. 
 
Checking Your Site’s Registration Status: 
 
You can verify your site registration status on the members’ section of the CTSU website. (Note: Sites will 
not receive formal notification of regulatory approval from the CTSU Regulatory Office.) 
▪ 
Go to https://www.ctsu.org and log in to the members’ area using your CTEP-IAM username 
and password 
▪ 
Click on the Regulatory tab at the top of your screen 
▪ 
Click on the Site Registration tab 
▪ 
Enter your 5-character CTEP Institution Code and click on Go 
 
Note: The status given only reflects compliance with IRB documentation and institutional compliance with 
protocol-specific requirements as outlined by the Lead Network. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling investigator’s status with 
the NCI or their affiliated networks. 
 
Data Submission / Data Reporting 
 
Data collection for this study will be done exclusively through the Medidata Rave clinical data management 
system. Access to the trial in Rave is granted through the iMedidata application to all persons with the 

  
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appropriate roles assigned in Regulatory Support System (RSS). To access Rave via iMedidata, the site 
user must have an active CTEP-IAM account (check at https://ctepcore.nci.nih.gov/iam) and the appropriate 
Rave role (Rave CRA, Read-Only, CRA (Lab Admin, SLA or Site Investigator) on either the LPO or 
participating organization roster at the enrolling site. To the hold Rave CRA role or CRA Lab Admin role, 
the user must hold a minimum of an AP registration type. To hold the Rave Site Investigator role, the 
individual must be registered as an NPIVR or IVR. Associates can hold read-only roles in Rave. If the study 
has a DTL, individuals requiring write access to Rave must also be assigned the appropriate Rave tasks on 
the DTL. 
 
Upon initial site registration approval for the study in RSS, all persons with Rave roles assigned on the 
appropriate roster will be sent a study invitation e-mail from iMedidata. To accept the invitation, site users 
must log into the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-IAM user name 
and password, and click on the “accept” link in the upper right-corner of the iMedidata page. Please note, 
site users will not be able to access the study in Rave until all required Medidata and study specific trainings 
are completed. Trainings will be in the form of electronic learnings (eLearnings), and can be accessed by 
clicking on the link in the upper right pane of the iMedidata screen. 
 
Users that have not previously activated their iMedidata/Rave account at the time of initial site registration 
approval for the study in RSS will also receive a separate invitation from iMedidata to activate their account. 
Account activation instructions are located on the CTSU website, Rave tab under the Rave resource 
materials (Medidata Account Activation and Study Invitation Acceptance). Additional information on 
iMedidata/Rave is available on the CTSU members’ website under the Rave tab at www.ctsu.org/RAVE/ 
or by contacting the CTSU Help Desk at 1-888-823-5923 or by e-mail at ctsucontact@westat.com. 
 
 
 

  
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APPENDIX X: POSSIBLE DRUG INTERACTIONS 
The lists below do not include everything that may interact with chemotherapy. Study Subjects and/or 
their Parents should be encouraged to talk to their doctors before starting any new medications, using 
over-the-counter medicines, or herbal supplements and before making a significant change in diet. 
 
Brentuximab vedotin 
 
Drugs that may interact with brentuximab vedotin 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antifungals  
o Itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, sirolimus, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Nicardipine, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o 
Aprepitant, bosentan, deferasirox, dexamethasone, lomitapide, natalizumab, nefazodone 
 
Food and supplements that may interact with brentuximab vedotin* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. 
All forms should be avoided. 
 
 

  
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Bleomycin 
 
Drugs that may interact with bleomycin* 
• Arthritis medications like leflunomide or tofacitinib 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Other medications like digoxin or natalizumab 
 
Food and supplements that may interact with bleomycin* 
• Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. 
All forms should be avoided. 
 
Cyclophosphamide 
 
Drugs that may interact with cyclophosphamide 
• 
Allopurinol 
• 
Chloramphenicol 
• 
Cyclosporine 
• 
Digoxin  
• 
Etanercept  
• 
Hydrochlorothiazide 
• 
Indomethacin 
• 
Nevirapine 
• 
Pentostatin  
• 
Warfarin  
 
Food and supplements that may interact with cyclophosphamide* 
• 
St. John’s Wort 
• 
Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
 
 

  
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Doxorubicin 
 
Drugs that may interact with doxorubicin 
• Some antiepileptics (carbamazepine, oxcarbazepine, phenobarbital, phenytoin, fosphenytoin) 
• Some antiretrovirals (stavudine, zidovudine) 
• Other agents, such as clozapine, cyclosporine, verapamil, and warfarin 
 
Food and supplements that may interact with doxorubicin* 
• Echinacea 
• Glucosamine  
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
• Drinks, food, supplements, or vitamins containing “flavonoids” or other “antioxidants” 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided. 
 
Etoposide 
 
Drugs that may interact with etoposide 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Aripiprazole, clozapine, nefazodone 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, dronedenarone, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, atovaquone, bosentan, deferasirox, dexamethasone, ivacaftor, lomitapide, 
mifepristone, natalizumab, pimozide, sitaxentan 
 
Food and supplements that may interact with etoposide* 
• Echinacea 
• Glucosamine 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried 
herbs. All forms should be avoided.  
 
 

  
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Prednisone 
Vincristine 
Drugs that may interact with vincristine 
• Antibiotics  
o Clarithromycin, erythromycin, nafcillin, rifabutin, rifampin, telithromycin 
• Antidepressants and antipsychotics  
o Aripiprazole, nefazodone, trazodone 
• Antifungals  
o Fluconazole, itraconazole, ketoconazole, posaconazole, voriconazole 
• Arthritis medications  
o Leflunomide, tocilizumab, tofacitinib 
• Anti-rejection medications 
o Cyclosporine, tacrolimus 
• Antiretrovirals and antivirals  
o Atazanavir, boceprevir, darunavir, delaviridine, efavirenz, etravirine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, nevirapine, ritonavir, saquinavir, Stribild, telaprevir, tenofovir, tipranavir 
• Anti-seizure medications  
o Carbamazepine, oxcarbazepine, phenobarbital, phenytoin, primidone 
• Heart medications  
o Amiodarone, digoxin, dronedenarone, propranolol, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Many other drugs, including the following: 
o Aprepitant, deferasirox, ivacaftor, lomitapide, mifepristone, natalizumab, pimozide, warfarin  
 
Food and supplements that may interact with vincristine* 
• Echinacea 
• St. John’s Wort 
• Grapefruit, grapefruit juice, Seville oranges, star fruit 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms 
should be avoided.  
Drugs that may interact with prednisone 
• Arthritis medications  
o Leflunomide, tofacitinib 
• Antiretrovirals and antivirals  
o Boceprevir, ritonavir, telaprevir 
• Anti-seizure medications  
o Phenobarbital, phenytoin, primidone 
• Growth hormones 
• Heart medications  
o Diltiazem, verapamil 
• Some chemotherapy (be sure to talk to your doctor about this) 
• Some oral contraceptives or birth control medications 
• Many other drugs, including the following: 
o Aprepitant, aripiprazole, aspirin, cyclosporine, deferasirox, ibuprofen, itraconazole, mifepristone, 
natalizumab, rifampin, warfarin 
 
Food and supplements that may interact with prednisone* 
• Echinacea 
*Supplements may come in many forms, such as teas, drinks, juices, liquids, drops, capsules, pills, or dried herbs. All forms 
should be avoided. 

  
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APPENDIX XI: YOUTH INFORMATION SHEETS 
INFORMATION SHEET REGARDING RESEARCH STUDY AHOD1331 
(for children from 7 through 12 years of age) 
 
A Study of Brentuximab Vedotin for Children with High-risk Hodgkin Disease 
 
1. We have been talking with you about Hodgkin disease. Hodgkin disease is a type of cancer that 
grows in the tissues in your body that make and store white blood cells. White blood cells help 
protect your body against infections. Sometimes Hodgkin disease is called “high risk” because it is 
more likely to come back after treatment. High-risk cancer is treated with stronger medicine to 
make it less likely to come back. After doing tests, we have found that you have this type of cancer. 
 
2. We are asking you to take part in a research study because you have high-risk Hodgkin disease. A 
research study is when doctors work together to try out new ways to help people who are sick. 
Children with Hodgkin disease are usually treated with chemotherapy and radiation therapy. 
Chemotherapy is medicine that destroys cancer cells. Radiation therapy is the use of high energy 
x-rays to kill cancer cells.  
 
Radiation therapy used to treat Hodgkin disease can cause unwanted side effects. If patients can be 
treated with less radiation or without radiation completely, then we hope there will be less bad 
effects later in life. We will use your tumor’s response after the first two cycles of chemotherapy 
to decide if you need radiation therapy. Children whose tumor responds quickly to treatment will 
not receive radiation. Children whose tumor responds slowly to treatment will receive radiation. 
Only the areas at high risk for the cancer coming back will receive radiation.  
 
Chemotherapy used to treat Hodgkin disease can cause unwanted side effects too. We will ask you 
(only for children 11 or older) and your parent to answer some questions about how you are feeling 
and doing to better understand how treatment changes your daily life. These questions will be asked 
at five or six different time points throughout the study. 
 
3. Children who are part of this study will be treated with chemotherapy and some will be treated with 
radiation therapy. All children will receive 5 cycles of chemotherapy. Some of the children who 
are part of this study will get the usual treatment doctors use for Hodgkin disease. Some of the 
children will get the experimental drug brentuximab vedotin in addition to usual chemotherapy. 
The chemotherapy you get will be decided by chance, like flipping a coin for “heads” or “tails.” 
You will have regular tests during your treatment. These tests help doctors in deciding the best 
treatment for your Hodgkin disease and to see how you are doing with treatment. Some of the tests 
may hurt some, but medicines will be given to keep it from hurting too much. 
 
• 
If the cancer responds to treatment quickly in all areas, you will not have radiation therapy 
(except patients with a large tumor in the chest at diagnosis). 
• 
If the cancer responds to treatment slowly in some areas, you will have radiation therapy. 
 
It is common for radiation therapy to target all areas of the body that were affected by the cancer. 
But in this study, we will only target those parts of the body at highest risk of the cancer returning. 
We hope to lower the risk of side effects.  
 
4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is that your cancer 

  
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will go away and that you will have less bad effects later in life. But we don’t know for sure if there 
is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may not get rid of 
your cancer as well as a non-study treatment.  
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have. 
 
7. We are asking your permission to collect additional tissue and blood. These studies will help us 
better understand Hodgkin lymphoma and why some people respond to treatment better than other 
people. The tissue sample would be taken during the standard biopsy. The blood draws would be 
taken when other standard blood tests are being performed. We would also like to save any leftover 
samples for other research tests in the future. You can still take part in this study even if you do not 
allow us to collect the extra tissue and/or blood samples or save the leftover samples for research.  
 
 

  
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INFORMATION SHEET REGARDING RESEARCH STUDY AHOD1331 
(for teens from 13 through 17 years of age) 
 
A Study of Brentuximab vedotin for Children with High-risk Hodgkin Disease 
 
1. We have been talking with you about Hodgkin disease. (Hodgkin disease is also known as Hodgkin 
lymphoma.) Hodgkin disease is a type of cancer that grows in the tissues in your body that make 
and store white blood cells. White blood cells help protect your body against infections. Sometimes 
Hodgkin disease is called “high risk” because it is more likely to come back after treatment. High-
risk cancer is treated with stronger medicine to make it less likely to come back. After doing tests, 
we have found that you have this type of cancer.  
 
2. We are asking you to take part in a research study because you have high-risk Hodgkin disease. A 
research study is when doctors work together to try out new ways to help people who are sick. 
Children with Hodgkin disease are usually treated with chemotherapy and radiation therapy. 
Chemotherapy is medicine that destroys cancer cells. Radiation therapy is the use of high energy 
x-rays to kill cancer cells. 
 
Radiation therapy used to treat Hodgkin disease can cause unwanted side effects. If patients can be 
treated with less radiation or without radiation completely, then we hope there will be less bad 
effects later in life. We will use your tumor’s response after the first two cycles of therapy to decide 
if you need radiation therapy. Children and teens whose tumor responds quickly to treatment will 
not receive radiation. Children and teens whose tumor responds slowly to treatment will receive 
radiation. Only areas at high risk for the cancer to come back will receive radiation.  
 
Chemotherapy used to treat Hodgkin disease can also cause unwanted side effects. We will ask you 
and your parent to answer some questions about how you’re feeling and doing to better understand 
the side effects of chemotherapy. These questions will be asked at five or six different time points 
throughout the study. 
 
3. Children and teens that are part of this study will be treated with chemotherapy and some will be 
treated with radiation therapy. All patients will receive a total of 5 cycles of chemotherapy. Some 
of the patients in this study will be treated with some of the common chemotherapy drugs used to 
treat Hodgkin disease. These drugs are: doxorubicin, bleomycin, vincristine, etoposide, 
cyclophosphamide and prednisone. Some of the children and teens who are part of this study will 
receive an experimental drug called brentuximab vedotin in addition to the usual chemotherapy. 
The chemotherapy you get will be decided by chance, like flipping a coin for “heads” or “tails.” 
After 2 cycles of chemotherapy, we will look at changes on special scans (called CT and PET scans) 
to measure how the cancer is responding to therapy. We will use the response after 2 cycles to help 
decide if you need radiation therapy. 
 
• 
If the cancer responds to treatment quickly in all areas, you will not have radiation therapy 
(except patients with a large tumor in the chest at diagnosis). 
• 
If the cancer responds to treatment slowly in some areas, you will have radiation therapy. 
 
It is common for radiation therapy to target all areas of the body that were affected by the cancer. 
But in this study, we will only target those parts of the body at highest risk of the cancer returning. 
By targeting the radiation therapy we hope to lower the risk of side effects while keeping up the 
effectiveness. 
 

  
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4. Sometimes good things can happen to people when they are in a research study. These good things 
are called “benefits.” We hope that a benefit to you of being part of this study is to get rid of the 
cancer for as long as possible. We also hope that you will have less bad effects later in life. But we 
don’t know for sure if there is any benefit of being part of this study. 
 
5. Sometimes bad things can happen to people when they are in a research study. These bad things 
are called “risks.” The risks to you from this study are that the study treatment may not get rid of 
your cancer as well as a non-study treatment. This could increase the chance of the cancer returning. 
Other things may happen to you that we don’t yet know about.  
 
6. Your family can choose to be part of this study or not. Your family can also decide to stop being 
in this study at any time once you start. There may be other treatments for your illness that your 
doctor can tell you about. Make sure to ask your doctors any questions that you have.  
 
7. We are asking your permission to collect additional tissue and blood. These studies will help us 
better understand Hodgkin lymphoma and why some people respond to treatment better than other 
people. The tissue sample would be taken during the standard biopsy. The blood draws would be 
taken when other standard blood tests are being performed. But, due to the amount of blood draws, 
it will likely require some extra needles sticks. We would also like to save any leftover samples for 
other research tests in the future. You can still take part in this study even if you do not allow us to 
collect the extra tissue and/or blood samples or save the leftover samples for research.  
 
 

  
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