A Phase III, Randomized Study of Nivolumab (Opdivo) Plus AVD or Brentuximab Vedotin (Adcetris) Plus AVD in Patients (Age &gt;/= 12 Years) With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma
Phase: PHASE3
Conditions: Ann Arbor Stage III Hodgkin Lymphoma, Ann Arbor Stage III Lymphocyte-Depleted Classic Hodgkin Lymphoma, Ann Arbor Stage III Mixed Cellularity Classic Hodgkin Lymphoma, Ann Arbor Stage III Nodular Sclerosis Classic Hodgkin Lymphoma, Ann Arbor Stage IV Hodgkin Lymphoma, Ann Arbor Stage IV Lymphocyte-Depleted Classic Hodgkin Lymphoma, Ann Arbor Stage IV Mixed Cellularity Classic Hodgkin Lymphoma, Ann Arbor Stage IV Nodular Sclerosis Classic Hodgkin Lymphoma, Classic Hodgkin Lymphoma, Lymphocyte-Rich Classic Hodgkin Lymphoma
Sponsor: National Cancer Institute (NCI)

 
Version Date:  September 2, 2023 
 
 
TO:  
ALL NATIONAL CLINICAL TRIALS NETWORK (NCTN) MEMBERS AND NCI 
COMMUNITY ONCOLOGY RESEARCH PROGRAM (NCORP) AFFILIATES AND 
SUBAFFILIATES; CTSU  
 
FROM: 
SWOG Operations Office (protocols@swog.org) 
 
RE: 
S1826 “A Phase III, Randomized Study of Nivolumab (Opdivo) Plus AVD or 
Brentuximab Vedotin (Adcetris) Plus AVD in Patients (Age >/= 12 Years) with Newly 
Diagnosed Advanced Stage Classical Hodgkin Lymphoma” Study Chairs: Drs. A. F. 
Herrera, J. Friedberg, S. M. Castellino, S. Parsons, S. C. Rutherford, A. M. Evens, A. 
Punnett, K. Davison, D. Hodgson, L. S. Constine, L. Kostakoglu Shields, J. Y. Song. 
 
  
REVISION #6 
 
Study Chair:  Alex F. Herrera, M.D. 
Phone number: 626/256-4673 
E-mail: aherrera@coh.org 
 
Action Codes 
(√) 
Expedited review allowed 
 
Key Updates   
(√)  
Eligibility changes* 
 
*Patient notification not required 
(√)  
Data Submission changes  
(√)  
Editorial / Administrative changes 
 
Sites using the CIRB as their IRB of record:  The protocol and/or informed consent form 
changes have been approved by the CIRB and must be activated within 30 days of 
distribution of this notice through the CTSU Bi-Monthly Broadcast email.  
 
Sites not using the NCI CIRB:  Per CTMB Guidelines, the protocol updates and/or 
informed consent changes must be approved by local IRBs within 90 days of distribution 
of this notice through the CTSU Bi-Monthly Broadcast email. The changes are effective 
upon approval by the local IRB; however, any changes to eligibility are effective 30 days 
after distribution of this notice. If local IRB approval is not granted within 30 days, new 
registrations must meet any revised eligibility criteria included in the revision or accrual 
must be suspended until approval is obtained. 
 
 
REVISION #6 
The above referenced study has been revised to: (1) primarily ask sites to submit two additional, previously 
collected, scans based on protocol specifications; (2) Expand eligibility. The changes are as follows: 

1SPUPDPM$IBOHFT

1. 
The version date has been updated. 
 
2. 
Throughout the protocol, formatting, typographical errors, pagination, and cross-references have 
been corrected as needed. 
 

S1826 
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Version Date 09/02/2023 
3. 
Section 5.6a: This section has been expanded upon to include, “Patients who do not complete 
PRO instruments prior to registration but are otherwise eligible will remain eligible for the primary 
analysis and other secondary analyses” to maintain eligibility for patients.  
 
4. 
Section 9.2: Footnote “e” was edited to emphasize CT scan requirements.  
 
5. 
Section 13.5g: The request for Patient SSN information was removed.  
 
6. 
Section 14.4a: The location of the Imaging Adjunctive Data Sheet link was updated.     
 
7. 
Section14.4f: This section has been inserted to include, “All contrast-enhanced CT images 
involved at baseline or contraindicated from scans performed to assess disease as specified in 
Section 15.4.  Submit to IROC Ohio (via TRIAD strongly preferred) for retrospective central 
imaging review.” 
 
x 
The location of the Imaging Adjunctive Data Sheet links were updated.     
x 
For patients who have had 1-year and 2-year after registration contrast-enhanced CT (or if 
contra-indicated, PET-CT, CT, MRI, or MR-PET) scan performed prior to activation of S1826 
Protocol Revision 6, submit images to IROC Ohio within 60 days after participating site 
activation of S1826 Protocol Revision 6 (Version Date 9/2/2023). 
 
x 
If CT scan is contraindicated and PET-CT scan is submitted, S1826 Imaging Adjunctive Data 
Sheet for PET scans is required. This form is submitted electronically via the IROC website. 
 
8. 
Section 15.4a: Under Image Collection and Submission Time Points: 
 
x 
“If performed” was removed from criterion 4. 
 
x 
Criteria 5 and 6 were inserted to indicate the required scan submissions as 1 and 2 years 
after registration, respectively. 
 
$POTFOU$IBOHFT

1. 
The version date has been updated. 
 
2. 
Throughout the consent, formatting, typographical errors, pagination, and cross-references have 
been corrected as needed. 
 
3. 
The reading scores were updated.  
 
4. 
“What exams, tests, and procedures are…”: Under the subheader, “For both Groups 1 and 
2,”: 
o 
In the seventh bullet regarding Patient Reported Outcomes, language requiring patient 
reported outcomes for participation in the overall study was removed.  
 
o 
In the eighth bullet regarding patient scans, patients are informed that scans from 
their 1st and 2nd years after registration will be submitted to the study for review.  
 
Patient Notification and use of Consent Addendum: 
 
Please note that the information provided below regarding patient notification and amendments to local 
consent forms reflects SWOG’s minimum requirements.  Sites should refer to the policies/procedures of 
the IRB of record to determine whether they have any more stringent requirements. 
 

S1826 
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Version Date 09/02/2023 
SWOG has determined that the changes above that are bolded may affect a patient’s willingness to 
participate in the study; therefore, SWOG requires that patients be notified of these changes.  
 
Who must be informed?   
x 
All patients who have been consented to the study and received treatment. 
 
How must patients be notified? 
x 
Notification must take place either via the attached Consent Addendum or via amended consent 
form by next study visit.  After the change has been discussed with the patient, the patient must 
sign and date either the Consent Addendum or the [Publish Date] version of the consent form. 
 
What is the notification deadline and process? 
x 
Patients must be notified by their next scheduled visit or within 90 days after CTSU distribution 
of this revision, whichever is sooner. 
 
x 
Sites using the NCI CIRB as their IRB of record:  CIRB has approved the attached Consent 
Addendum; therefore, the Consent Addendum may be utilized immediately to notify patients of 
these changes.  
x 
Sites not using the NCI CIRB as their IRB of record:  If local IRB approval of the Consent 
Addendum is required before sites may utilize it, the site must still notify patients verbally prior to 
the notification deadline and notification must be documented in the patient chart.  The site must 
then obtain patient signature on the Consent Addendum or updated consent form once the 
addendum and/or revised consent is locally approved. Important: Any changes to eligibility 
criterion are effective 30 days after distribution of this notice. If local IRB approval is not granted 
within 30 days, new registrations must meet any revised eligibility criteria included in the revision 
or accrual must be suspended until approval is obtained. 
 
Regulatory Considerations: 
 
Do local consent forms need to be updated? 
x 
Yes, local consent forms must be updated to include all the changes in this revision. 
 
The updated protocol and model informed consent form can be accessed from the CTSU website 
(www.ctsu.org).  Please discard any previous versions of the documents and replace with the updated 
versions. Please contact lymphomaquestion@crab.org  or 206/652-2267 with any questions. 
 
This memorandum serves to notify the NCI, and SWOG Statistics and Data Management Center. 
 
cc: 
PROTOCOL & INFORMATION OFFICE  
Hildy Dillon, MPH - Patient Advocate 
Sharon M. Castellino, MD, MSc - COG 
Susan K. Parsons, MD, MRP - COG 
Angela Punnett, MD, FRCPC - COG 
Catherine Shannon – COG 
Tiffany Liu, MS, MA - COG 
Sarah C. Rutherford, MD - Alliance 
Andrew M. Evens, MD - ECOG-ACRIN 
Kelly Davison, MD - CCTG 
Michael Crump, MD - CCTG 
Joo Y. Song, MD - Pathology 
Louis S. Constine, MD, FASTRO, FACR - Radiation Oncology 
David Hodgson, MD - Radiation Oncology 
Lale Kostakoglu Shields, MD, MPH - Radiology 

S1826 
 
Consent Addendum (Revision #6) 
 
Page 1 
 
Version Date 9/2/2023 
Informed Consent Addendum Model for S1826 
 
S1826, “A Phase III, Randomized Study of Nivolumab (Opdivo) 
Plus AVD or Brentuximab Vedotin (Adcetris) Plus AVD in Patients 
(Age >/= 12 Years) with Newly Diagnosed Advanced Stage Classical 
Hodgkin Lymphoma” 
 
The following information should be read as an update to the original Consent form that you read 
and signed at the beginning of the study. Unless specifically stated below, all information 
contained in that original Consent Form is still true and remains in effect. Your participation 
continues to be voluntary. You may refuse to participate, or may withdraw your consent to 
participate at any time, and for any reason, without jeopardizing your future care at this 
institution or your relationship with your study doctor. 
 
New or additional information 
 
The consent form has been updated to include two additional scan reports you've already 
had as part of your care. We are requesting the two new reports from one and two years 
after you joined the study. There will be no extra appointments as these scans are already 
done.  
 
Patient Signature and Date  
 
By signing this form, I acknowledge that I have read the information above or had it read to me. 
I have discussed it with a member of the study team and my questions have been answered. I 
understand that I will be given a copy of this form.  
 
Participant’s signature 
 
 
Date of signature_____________________________________ 
 
 
Signature of person(s) conducting the informed consent discussion________________________ 
 
Date of signature_____________________________________ 
 

S1826 
Page 1 
 
Version Date 09/2/2023 
 
PRIVILEGED COMMUNICATION 
FOR INVESTIGATIONAL USE ONLY 
 
SWOG CANCER RESEARCH NETWORK 
TITLE 
A PHASE III, RANDOMIZED STUDY OF NIVOLUMAB (OPDIVO) PLUS AVD OR BRENTUXIMAB 
VEDOTIN (ADCETRIS) PLUS AVD IN PATIENTS (AGE >/=  12 YEARS) WITH NEWLY DIAGNOSED 
ADVANCED STAGE CLASSICAL HODGKIN LYMPHOMA  
NCT# 03907488 
 
This study is being conducted under DCTD, NCI IND  
 
This trial is part of the National Clinical Trials Network (NCTN) program, which is sponsored by 
the National Cancer Institute (NCI). The trial will be led by SWOG with the participation of the 
network of NCTN organizations: Alliance for Clinical Trials in Oncology; Children’s Oncology 
Group; ECOG-ACRIN Medical Group; NRG Oncology; and Canadian Cancer Trials Group. 
 
 
STUDY CHAIRS:
 
 
Alex F. Herrera, M.D. 
(Hematology, Medical Oncology, U.S. Adult) 
City of Hope, Department of Hematology 
1500 E. Duarte Road 
  
Duarte, CA 91010 
Phone: 626/256-4673 
Fax: 626/301-8256  
Email: aherrera@coh.org  
 
 
Jonathan Friedberg, M.D. (Medical Oncology) 
 
University of Rochester 
 
604 Elmwood Ave., Box 704 
  
Rochester, NY 14642 
 
Phone: 585/275-4911                                             
Fax: 585/276-2743 
 
E-mail: jonathan_friedberg@urmc.rochester.edu  
 
COG CHAIR: 
 
Sharon M. Castellino, M.D. MSc  
Emory University,  
Children’sHealthcare of Atlanta 
2015 Uppergate Drive, 4th Floor ECC 
Atlanta, GA 30322  
Phone: 404/785-3616  
Fax: 404/785-3600 
Email: Sharon.Castellino@choa.org  
 
  
AGENTS: 
 
NCI Supplied Investigational Agents: 
BMS-936558 (Nivolumab, MDX-1106) 
(NSC-748726) (IND #)
 
 
Commercially Available Agents: 
SGN-35 (Brentuximab Vedotin)  
(NSC- 749710) 
Doxorubicin hydrochloride  
(NSC-123127) 
Dacarbazine (NSC-45388) 
Vinblastine sulfate (NSC-49842) 
Filgrastim (r-metHuG-CSF) (Neupogen®) 
(NSC 614629) 
Pegfilgrastim (Neulasta™) (NSC 725961) 
 
BIOSTATISTICIANS: 
 
Michael LeBlanc, Ph.D. 
Hongli Li, M.S. 
Joseph Unger, Ph.D. (QOL Correlatives) 
Riha Vaidya, Ph.D.  
SWOG Statistical Center 
Fred Hutchinson Cancer Research Center 
1100 Fairview Avenue North, M3-C102 
P.O. Box 19024 
Seattle, WA 98109-1024 
Phone: 206/667-4623 
FAX: 206/667-4408 
E-mail: mleblanc@fredhutch.org  
E-mail: hongli@fredhutch.org  
E-mail: junger@fredhutch.org  
E-mail: rrvaidya@fredhutch.org  
 
 
 

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Version Date 09/2/2023 
 
ALLIANCE CHAMPION: 
 
Sarah C. Rutherford, M.D.  
Weill Cornell Medicine 
Department of Medicine  
Division of Hematology/Oncology 
1305 York Ave., 7th Floor 
New York, NY 10021 
Phone: 646/962-2064 
Fax: 646/962-1617 
Email: sar2014@med.cornell.edu  
 
CCTG CHAMPION: 
 
Kelly Davison, PhD, MDCM, FRCPC 
Royal Victoria Hospital  
McGill University Health Centre 
1001 Decarie Blvd 
Montreal, Quebec 
H4A 3J1 
Phone: 514/934-1934, ext 31558 
Fax: 514/934-8221 
E-mail: kelly.davison@mcgill.ca  
 
COG CHAMPION: 
 
Angela Punnett, M.D., FRCPC 
SickKids Hospital 
555 University Ave, Rm 1448 Black Wing 
Toronto ON M6G 1V9 Canada 
Phone: 416/813-5394 
Fax: 416/813-5230 
E-mail: angela.punnett@sickkids.ca  
 
ECOG-ACRIN CHAMPION: 
 
Andrew M. Evens, D.O., M.Sc., F.A.C.P.  
Rutgers Robert Wood Johnson Medical School  
Rutgers Cancer Institute of New Jersey  
195 Little Albany Street 
New Brunswick, New Jersey 08903-2681 
Phone: 732/235-9289 
Fax: 732/448-7894 
Email: ae378@cinj.rutgers.edu  
 
QOL CHAIR: 
 
Susan K. Parsons, M.D., M.R.P. 
Reid R. Sacco AYA Cancer Program 
Tufts Medical Center 
800 Washington St., #345 
Boston, MA 02111 
Phone: 617/636-5168 
Fax: 617/636-6280 
Email: sparsons@tuftsmedicalcenter.org   
PATHOLOGY CHAIR: 
 
Joo Y. Song, M.D.  
City of Hope Medical Center 
1500 E Duarte Rd, # 2202A 
Duarte, CA 91010 
Phone: 626/256-4673 ext:62037 
Fax: 626/218-8463 
Email: josong@coh.org 
 
RADIATION ONCOLOGY CHAIRS: 
 
David Hodgson, M.D. 
Princess Margaret Cancer Centre 
Department of Radiation Oncology, Princess 
Margaret Cancer Centre 
OPG- Radiation Oncology 
700 University Ave, Room 7-322 
Toronto, ON M5G 1Z5 
Phone: 416/946-2121 
Fax: 416/946-2111 
Email: David.Hodgson@rmp.uhn.ca  
 
Louis S. Constine, MD, FASTRO, FACR 
Department of Radiation Oncology 
James P. Wilmot Cancer Center,  
P.O. Box 647 
University of Rochester Medical Center 
Rochester, N.Y. 14642 
Phone: 585/275-5622 
Fax:  585/275-1531 
E-mail: Louis_Constine@urmc.rochester.edu  
 
RADIOLOGY CHAIR: 
 
Lale Kostakoglu Shields M.D., MPH  
Nuclear Medicine and Molecular Imaging  
University of Virginia Health System 
1215 Lee Street, Box 800170 
Charlottesville, VA 22908 
Phone: 434/924-9382 
Fax: 434/982-6687  
E-mail: lk3qf@virginia.edu    
 
 
 
 
 
 
*** Please see the S1826 Protocol Contact 
Information page for additional contacts.*** 
 
 
 
 

S1826 
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Version Date 09/2/2023 
 
 
PARTICIPANTS 
 
U.S.-Only Participants: 
 
ALLIANCE/Alliance for Clinical Trials in Oncology 
COG / Children’s Oncology Group  
ECOG-ACRIN/ECOG-ACRIN Cancer Research Group 
NRG/NRG Oncology 
SWOG/SWOG Cancer Research Network 
 
International Participants:  
 
CCTG/Canadian Cancer Trials Group 
 
 
 
 
 

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TABLE OF CONTENTS 
 
TITLE  ......................................................................................................................................................... 1 
PARTICIPANTS ............................................................................................................................................ 3 
TABLE OF CONTENTS ............................................................................................................................... 4 
S1826 PROTOCOL CONTACT INFORMATION ......................................................................................... 7 
CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION ....................... 9 
SCHEMA ..................................................................................................................................................... 10 
1.0 
OBJECTIVES ................................................................................................................................ 11 
1.1 
Primary Objective: .......................................................................................................................... 11 
1.2 
Secondary Objectives: ................................................................................................................... 11 
1.3 
Quality of Life Objectives ............................................................................................................... 11 
1.4 
Banking Objectives ........................................................................................................................ 11 
2.0 
BACKGROUND ............................................................................................................................. 11 
2.1 
Overview of Study Components .................................................................................................... 11 
2.2 
Introduction:  Hodgkin Lymphoma ................................................................................................. 12 
2.3 
Brentuximab Vedotin for the Treatment of Advanced Stage Hodgkin Lymphoma ........................ 15 
2.4 
The rationale for PD-1 blockade in HL ........................................................................................... 18 
2.5 
Rationale for Current Study ........................................................................................................... 20 
2.6 
Rationale for Consolidative Targeted  Radiation Therapy ............................................................. 21 
2.7 
Rationale for RT Dose for PET-positive (Deauville 4-5) lesions at EOT ....................................... 22 
2.8 
Rationale for Correlative Studies ................................................................................................... 23 
2.9 
Inclusion of Women and Minorities and Planned Enrollment Report ............................................ 26 
3.0 
DRUG INFORMATION .................................................................................................................. 28 
3.1 
Nivolumab (BMS-936558, MDX1106, Opdivo®) (NSC # 748726) (IND-) ...................................... 28 
3.2 
Brentuximab vedotin (SGN-35, ADCETRIS®) – COMMERCIALLY AVAILABLE FOR U.S. SITES – 
SUPPLIED BY SEATTLE GENETICS FOR SITES IN CANADA .................................................. 38 
3.3 
Doxorubicin (Adriamycin ®) (NSC-123127) ................................................................................... 43 
3.4 
Dacarbazine (NSC- 45388) ............................................................................................................ 45 
3.5 
Vinblastine sulfate (NSC- 49842) ................................................................................................... 47 
3.6 
Filgrastim (r-metHuG-CSF) (Neupogen®) (NSC 614629) ............................................................. 48 
3.7 
Pegfilgrastim (Neulasta™) (NSC 725961) ..................................................................................... 49 
4.0 
STAGING CRITERIA ..................................................................................................................... 51 
4.1 
Diagnostic Criteria .......................................................................................................................... 51 
4.2 
Staging Criteria .............................................................................................................................. 51 
5.0 
ELIGIBILITY CRITERIA ................................................................................................................ 52 
5.1 
Disease Related Criteria ................................................................................................................ 52 
5.2 
Age criteria: Patients must be ≥ 12 years of age. .......................................................................... 52 
5.3 
Prior/Concurrent Therapy Criteria .................................................................................................. 52 
5.4 
Clinical/Laboratory Criteria ............................................................................................................. 53 
5.5 
Specimen Submission Criteria ....................................................................................................... 55 
5.6 
Patient-reported outcomes and PRO-CTCAE criteria ................................................................... 55 
5.7 
Regulatory Criteria ......................................................................................................................... 56 
6.0 
STRATIFICATION FACTORS ....................................................................................................... 56 
7.0 
TREATMENT PLAN ...................................................................................................................... 56 
7.1 
General Treatment Information ...................................................................................................... 57 
7.2 
Pre-medication, Concomitant Therapy, and Supportive Care Guidelines ..................................... 59 
7.3 
Protocol Treatment ......................................................................................................................... 62 
7.4 
PET-CT response assessment ...................................................................................................... 64 
7.5 
Radiotherapy Indications, Dosage, Timing and Credentialing ....................................................... 66 
7.6 
Follow-up and Disease Evaluation Off-Protocol Treatment ........................................................... 68 
7.7 
Patient-Reported Outcomes .......................................................................................................... 69 
7.8 
Criteria for Removal from Protocol Treatment ............................................................................... 69 
7.9 
Discontinuation of Treatment ......................................................................................................... 70 
7.10 
Follow-Up Period ............................................................................................................................ 70 
8.0 
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS .............................................. 70 
8.1 
NCI Common Terminology Criteria for Adverse Events ................................................................ 70 
8.2 
Dose Modifications ......................................................................................................................... 70 

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8.3 
Dose Modification Contacts ........................................................................................................... 85 
8.4 
Adverse Event Reporting /Serious Adverse Event Reporting Guidance ....................................... 85 
8.5 
COVID-19 Adverse Event Reporting Requirements: ..................................................................... 86 
8.6 
Serious Adverse Event Reporting Requirements .......................................................................... 86 
9.0 
STUDY CALENDAR ...................................................................................................................... 93 
9.1 
Treatment Calendar ....................................................................................................................... 93 
9.2 
Follow-up After Off-Protocol Treatment ......................................................................................... 95 
10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS ..................................................... 96 
10.1 
Measurement of Treatment/Intervention Effect ............................................................................. 96 
10.2 
Best Response: ............................................................................................................................ 97 
10.3 
Performance Status ..................................................................................................................... 98 
10.4 
Progression Free Survival (PFS) ................................................................................................ 99 
10.5 
Event Free Survival (EFS) ........................................................................................................... 99 
10.6 
Time to Death ............................................................................................................................... 99 
11.0 
STATISTICAL CONSIDERATIONS .............................................................................................. 99 
11.1 
Primary Analysis and Power Justification ...................................................................................... 99 
11.2 
Interim Analysis ............................................................................................................................ 100 
11.3 
Analysis of Secondary Endpoints ................................................................................................ 101 
11.4 
Interim Safety Analysis ................................................................................................................. 102 
11.5 
Data and Safety Monitoring Committee ....................................................................................... 102 
12.0 
DISCIPLINE REVIEW .................................................................................................................. 102 
12.1 
Pathology Review ........................................................................................................................ 102 
12.2 
Radiology Review ........................................................................................................................ 103 
12.3 
Radiation Therapy Review ........................................................................................................... 103 
13.0 
REGISTRATION GUIDELINES ................................................................................................... 104 
13.1 
Registration Timing ...................................................................................................................... 104 
13.2 
Investigator/Site Registration ....................................................................................................... 104 
13.3 
CTEP Registration Procedures .................................................................................................... 104 
13.4 
CTSU Registration Procedures .................................................................................................... 105 
13.5 
OPEN Registration Requirements ............................................................................................... 107 
13.6 
Registration Procedures............................................................................................................... 108 
13.7 
Exceptions to SWOG registration policies will not be permitted. ................................................. 109 
14.0 
DATA SUBMISSION SCHEDULE .............................................................................................. 109 
14.1 
Data Submission Requirement .................................................................................................... 109 
14.2 
Master Forms ............................................................................................................................... 110 
14.3 
Data Submission Procedures ...................................................................................................... 110 
14.4 
Data Submission Overview and Timepoints ................................................................................ 111 
15.0 
SPECIAL INSTRUCTIONS.......................................................................................................... 117 
15.1 
Specimens for Pathology Review (REQUIRED): ......................................................................... 118 
15.2 
Banking for Planned future Translational Medicine  (REQUIRED with Patient Consent) ......... 119 
15.3 
SPECIMEN LABELING AND SHIPPING ..................................................................................... 121 
15.4 
Imaging Submission Requirements (REQUIRED*) ..................................................................... 122 
15.5 
Patient-Reported Outcomes: Instructions for Administration (REQUIRED*) ............................... 124 
15.6 
Patient-Reported Outcome Common Toxicity Criteria for Adverse Events (PRO-CTCAE) 
(REQUIRED for English- and Spanish- and French-speaking adult patients and English-speaking 
pediatric patients) ......................................................................................................................... 127 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS ................................................................. 129 
17.0 
BIBLIOGRAPHY .......................................................................................................................... 132 
18.0 
APPENDIX ................................................................................................................................... 140 
18.1 
LYRIC Criteria .............................................................................................................................. 141 
18.2 
Quality of Life ............................................................................................................................... 144 
18.3 
Management Algorithms for Immuno-Oncology (I-O) Therapy for Endocrinopathy, Gastrointestinal, 
Hepatic, Neurological, Pulmonary, Renal and Skin Adverse Events for Nivolumab (Arm 1) Adverse 
Event Management ...................................................................................................................... 152 
18.4 
Performance Status Scales ......................................................................................................... 159 
18.5 
FDG PET-CT Imaging Procedures and Image Acquisition .......................................................... 160 
18.6 
Radiation Therapy Guidelines ...................................................................................................... 162 
18.7 
Measurement-Based Response Assessment According to the Lugano Classification ............... 179 

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18.8 
Instructions for the SWOG Biospecimen Bank – Lab #201, Solid Tissue, Myeloma and Lymphoma 
Division ......................................................................................................................................... 181 
18.9 
CYP1A2 and CYP3A Inhibitors and Inducers .............................................................................. 183 
18.10 
PRO-CTCAE Common Terminology Criteria for Adverse Events (PRO-CTCAE) Instrument .... 185 
18.11 
Patient Clinical Trial Wallet Card ................................................................................................. 196 
18.12 
AYA Educational Resource Information, COG Participating Site Frequently Asked Questions, 
NCTN Adult Group Participating Site Frequently Asked Questions ............................................ 197 
 
 
 

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S1826 PROTOCOL CONTACT INFORMATION 
 
Patient Advocate  
Hildy Dillion, M.P.H. 
Email: hildy.dillon@gmail.com  
Eligibility, RAVE, Data Submission 
questions: 
SWOG Statistics and Data Management Center  
Email: lymphomaquestion@crab.org or Phone: 206/652-2267 
Regulatory, Protocol, Informed Consent 
questions: 
SWOG Operations Office: 
Email: protocols@swog.org  or Phone: 210/614-8808 
Medical Queries (treatment or toxicity 
related questions): 
Pediatric Patients:  
E-mail: S1826pediatrics@swog.org or call:  
Dr. Sharon Castellino at Phone: 404/785-3616 or 
Dr. Angela Punnett at: Phone: 416/813-5394. 
US Adult Patients:  
E-mail: S1826USAdults@swog.org or call: SWOG: Dr. Alex 
Herrera at Phone: 626/256-4673 ext. 62405 or  
Alliance: Dr. Sarah Rutherford at Phone: 646/962-2064 or  
ECOG-ACRIN: Dr. Andrew Evens at Phone: 732-235-9289. 
CCTG Adult Patients:  
Dr. Kelly Davison at: E-mail: kelly.davison@mcgill.ca or 
Phone: 514/934-1934, ext 31558 or 
Dr. Michael Crump at: Michael.Crump@uhn.ca or Phone: 
416/946-4567.   
TRIAD installations: 
https://triadinstall.acr.org/triadclient/  
Questions: TRIAD-Support@acr.org  
TRIAD image submission questions: 
IROC OH: SWOG1826@irocohio.org  
Radiology questions: 
Dr. Lale Kostakoglu Shields at E-mail: lk3qf@virginia.edu 
Phone: 434-924-9382 
Requests for Radiology courtesy review 
for pediatric patients:  
IROC RI: Sandy Kessel at: skessel@qarc.org  
 
Radiation Therapy  questions: 
Pediatric Patients: David Hodgson, M.D. at: E-mail: 
David.Hodgson@rmp.uhn.ca or call Phone: 416/946-2121 
Adult 
Patients: 
Dr. 
Louis 
S. 
Constine 
at 
Email: 
Louis_Constine@urmc.rochester.edu or call Phone: 585/275-
5622 
Proton Beam Therapy questions: 
Bradford Hoppe, MD at: Email: hoppe.bradford@mayo.edu or 
Stella Flampouri, PhD at: Email: stella.flampouri@emory.edu 
QOL/PRO questions: 
Email: sparsons@tuftsmedicalcenter.org or call: 
Dr. Susan Parsons at: Phone: 617/636-5168 
 
 
 
 

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S1826 PROTOCOL CONTACT INFORMATION CONTINUED 
 
Investigational Drug questions: 
Requests for Investigator’s Brochures: 
 
Access issues for the PMB Online 
Agent Ordering Processing (OAOP) 
application: 
See Protocol Section 3.1 or PMBAfterHours@mail.nih.gov 
See Protocol Section 3.0 or 
http://ctep.cancer.gov/branches/pmb/agent_order_processing
.htm 
IBCoordinator@mail.nih.gov 
Other Pharmaceutical questions:  
Pediatric: 
Email: 
Olga 
Militano 
at: 
omilitano@childrensoncologygroup.org 
Adult: Email: protocols@swog.org 
Specimen Tracking System (STS) 
errors or connectivity issues and 
Technical issues with the SWOG CRA 
Workbench:  
technicalquestion@crab.org 
Protocol and Consent Documents at: 
www.ctsu.org  
Investigator / Site Registration: 
See Protocol Section 13.2 or  
https://ctep.cancer.gov/investigatorResources/default.htm   
Email: RCRHelpDesk@nih.gov  
Cancer 
Therapy 
and 
Evaluation 
Program 
- 
Identity 
and 
Access 
Management (CTEP-IAM): 
To check CTEP-IAM account:  
 
To reset password or request new accounts:  
https://ctepcore.nci.nih.gov/iam/ApplicationLoginPage.do  
Access to iMedidata Rave 
See Protocol Section 14.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: ctsucontact@westat.com 
Questions related to: 
Oncology Patient Enrollment Network 
(OPEN) 
See Protocol Section 13.3 or contact  
CTSU Help Desk:  
Phone: 1-888-823-5923 or Email: ctsucontact@westat.com 
Streck Tube Kit Orders: 
https://ricapps.nationwidechildrens.org/KitManagement 
Patient Transfers: 
patienttransfer@crab.org   
Serious 
Adverse 
Event 
Reporting 
questions:  
See Protocol Section 8.6  
Email: adr@swog.org  
 
 
 

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CANCER TRIALS SUPPORT UNIT (CTSU) ADDRESS AND CONTACT INFORMATION 
CONTACT INFORMATION 
For regulatory requirements: 
For patient enrollments: 
For study data submission: 
Regulatory documentation must 
be submitted to the CTSU via 
the 
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 
866-651-2878 to receive further 
information and support.   
 
Contact the CTSU Regulatory 
Help Desk at 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_SYS
TEM/ 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 section of the 
protocol for further instructions.  
Do not submit study data or forms 
to CTSU Data Operations. Do not 
copy 
the 
CTSU 
on 
data 
submissions. 
 
Other 
Tools 
and 
Reports: 
Institutions participating through 
the CTSU continue to have 
access to other tools and reports 
available 
on 
the 
SWOG 
Workbench 
via 
the 
SWOG 
website (www.swog.org). 
  
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.  
For patient eligibility or data submission questions contact the SWOG Statistics and Data 
Management Center by phone or email: 
206/652-2267 
lymphomaquestion@crab.org   
 
For treatment or toxicity related questions contact the Study Chair by phone or email:  
US Adults: E-mail: S1826USAdults@swog.org or call: Dr. Alex Herrera (SWOG) at Phone: 626/256-4673 
ext. 62405 or Dr. Sarah Rutherford (Alliance) at Phone: 646/962-2064 or Dr. Andrew Evens (ECOG-
ACRIN) at Phone: 732-235-9289. 
Pediatrics: E-mail: S1826pediatrics@swog.org or call: Dr. Sharon Castellino at Phone: 404/785-3616 or 
Dr. Angela Punnett at: Phone: 416/813-5394. 
 
CCTG Adults: Dr. Kelly Davison at: E-mail: kelly.davison@mcgill.ca  or Phone: 514/934-1934, ext 31558. 
or Dr. Michael Crump at: Michael.Crump@uhn.ca or Phone: 416/946-4567.   
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. 

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SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CORRELATIVE: 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
a  Residual PET Radiation Therapy (Residual PET RT), at time of completion of 6 cycles of protocol 
therapy, is allowable as indicated in Section 7.5 provided that: 1) Investigator declared (at time of patient 
registration) patient as intent-to-treat with Residual PET RT, 2) Patient received Cycle 2 PET, and 3) 
Patient meets criteria indicated in Section 7.5 at time of completion of 6 cycles of protocol therapy.  
b  See Section 12.0 for Central Pathology Review, Central Radiology, and Central Radiation Therapy 
Review Requirements. See Sections 15.1 and 15.4 for specimen and image submission instructions. 
c  Doxorubicin, vinblastine, and dacarbazine. 
d  See Sections 15.5 and 15.6 for QOL and PRO-CTCAE Questionnaire administration and submission 
timepoints. 
e  See Section 15.4. 
 
 
ARM 1 
Nivolumab 
+ 
AVD c 
(Cycles 1-6) 
ARM 2 
Brentuximab Vedotin 
+ 
AVD c 
(Cycles 1-6) 
REGISTRATION/RANDOMIZATION (1:1) a 
Follow-Up 
RESIDUAL PET RT e 
QOL and  
PRO-CTCAE d 
d
Specimen 
submission b 
EOT Assessment 
(4-8 wks after  
C6, D15) e 
PET image 
submission b 
Newly Diagnosed Stage III-IV Hodgkin Lymphoma 

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1.0 
OBJECTIVES 
 
1.1 
Primary Objective: 
 
To compare the progression-free survival (PFS) in patients with newly diagnosed advanced 
stage classical Hodgkin lymphoma randomized to N-AVD (nivolumab, doxorubicin, 
vinblastine, dacarbazine) versus that obtained with BV-AVD (brentuximab vedotin, 
doxorubicin, vinblastine, dacarbazine). 
 
1.2 
Secondary Objectives: 
 
a. 
To compare overall survival (OS) in patients randomized to N-AVD versus BV-
AVD. 
 
b. 
To compare event-free survival (EFS) in patients randomized to N-AVD versus BV-
AVD. 
 
c. 
To compare the metabolic complete response (CR) rate at the end of treatment in 
patients randomized to N-AVD versus BV-AVD. 
 
d. 
To compare the physician-reported treatment-related adverse event rates between 
arms stratified by age groups. 
 
e. 
To compare patient-reported symptoms using selected PRO-CTCAE items 
between arms stratified by age groups.  
 
f. 
To compare the safety and tolerability of N-AVD versus that of BV-AVD. 
 
1.3 
Quality of Life Objectives 
 
To compare between arms patient-reported fatigue, neuropathy and health-related quality 
of life over time (baseline, beginning of Cycle 3, 4-8 weeks after the last dose of protocol 
therapy (following last dose of study drug or radiation therapy, whichever is later), and 1 
and 3 years after randomization) using the PROMIS-Fatigue, the FACT/GOG-Ntx , and the 
PROMIS Global, respectively. 
 
1.4 
Banking Objectives 
 
a. 
To bank specimens for future correlative studies. 
 
b. 
To bank PET-CT images for future correlative studies. 
 
 
2.0 
BACKGROUND 
 
2.1 
Overview of Study Components 
 
This is a randomized Phase III study comparing the addition of nivolumab or brentuximab 
vedotin to a backbone of AVD chemotherapy for the initial treatment of advanced stage 
Hodgkin lymphoma (HL). In addition to the primary therapeutic objective, we will conduct 
a series of quality of life analyses to assess the impact of each treatment regimen on patient 
well-being. We will also study the prognostic impact of imaging-based biomarkers like pre-
treatment metabolic tumor volume and we will study outcomes based on novel response 
assessment criteria (i.e. LYRIC and RECIL) that specifically address atypical responses 
observed with immunotherapy. Finally, we will bank tumor tissue and blood for future 
translational medicine studies. 
 
 

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2.2 
Introduction:  Hodgkin Lymphoma 
 
Hodgkin Lymphoma (HL) is a lymphoid neoplasm that is diagnosed in approximately 8190 
Americans annually and results in approximately 1070 deaths each year in the USA.  (1) 
HL typically affects young adults and presents with painless lymphadenopathy with or 
without splenomegaly, fevers, drenching night sweats, weight loss and pruritus.  The 
diagnosis is best established by an excisional lymph node biopsy demonstrating large, 
atypical lymphoblasts surrounded by a heterogeneous infiltrate of non-neoplastic 
inflammatory and accessory cells.  The World Health Organization's classification of 
lymphomas distinguishes two major subtypes of HL, namely, "classical HL" and "nodular 
lymphocyte predominant HL".  
  
Classical HL is characterized pathologically by the presence of bizarre monoclonal 
lymphoid cells that may be either mononuclear (Hodgkin cells) or multinucleate (Reed-
Sternberg cells).  The malignant Hodgkin and Reed Sternberg cells (HRS) cells of classical 
HL express CD15 and CD30 surface antigens, but usually not typical B cell markers such 
as surface immunoglobulin, CD20, CD79a, or the common leukocyte antigen, CD45.  (2) 
The B-cell origin of HRS cells is nevertheless demonstrable by the expression of the B-cell 
specific activator protein (BSAP) derived from the PAX 5 gene in 90% of cases.  (3) 
Immunoglobulin genes are rearranged in 98% of HRS cells but are not transcribed due to 
the absence of the transcription factor Oct-2 and its co-activator BOB-1.  The malignant 
(HRS) cells are typically surrounded by a heterogeneous infiltrate of reactive T- and B- 
lymphocytes, eosinophils, macrophages, fibroblasts, and variable amounts of collagen 
deposition (sclerosis).  (4)  Four discrete histologic subtypes of classical HL are currently 
recognized by the WHO classification including lymphocyte rich classical HL (LRCHL), 
nodular sclerosing HL, mixed cellularity HL, and lymphocyte depleted HL.  After completion 
of the diagnostic workup, the extent of involvement with HL is designated using the Ann 
Arbor staging criteria (see Section 4.0).  Patients with Stage I-II disease are considered to 
have "early stage" HL and are generally treated with short courses (2-4 cycles) of 
combination chemotherapy followed by involved field radiotherapy for some which affords 
a cure rate of 90-95%.  Historically, classification and treatment of patients with Stages IB, 
IIB, and bulky Stage II is variable in pediatric and adult HL trials and will not be addressed 
in the current protocol. (5) Patients with Stages III-IV disease are considered to have 
advanced stage HL and are generally treated with 6-8 cycles of combination chemotherapy 
(with or without radiation therapy, particularly in pediatric patients) as outlined below.  
 
a. 
History of Therapy for Advanced Stage Hodgkin Lymphoma 
 
Although HL is one of the most curable of all human neoplasms, approximately 15-
30% of patients in the United States with Stage III-IV HL still fail treatment of the 
disease with current management. (6)  Since HL typically afflicts patients between 
the ages of 15-40, many years of productive life are tragically lost to this lymphoma 
each year.  The development of the MOPP (mechlorethamine, Oncovin, 
procarbazine, 
prednisone) 
regimen 
in 
the 
1960s 
permitted 
hematologists/oncologists to cure a significant proportion of patients with 
advanced stage Hodgkin disease for the first time and represented a major 
milestone in medical oncology.  (7) After the introduction of MOPP, a number of 
MOPP-like chemotherapy regimens based on alkylating agents were developed to 
reduce acute toxicity.  These "MOPP-variant" regimens were equivalent to MOPP 
in efficacy and were associated with less early treatment-related toxicity; however, 
the major late morbidities of MOPP, sterility and an increased incidence of acute 
myeloid leukemia, persisted with the derivative regimens. (8) The ABVD regimen 
(doxorubicin, bleomycin, vinblastine, and dacarbazine) was developed by 
Bonadonna and colleagues in Milan in the 1970s containing drugs considered to 
be non-cross resistant with those in the MOPP regimen. (9) Early studies by this 
group demonstrated the ability of ABVD to successfully treat patients with 
recurrence after MOPP and the efficacy of ABVD as primary therapy.  Randomized 

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trials subsequently proved that ABVD was more effective and less toxic than 
MOPP. (10)  Alternating (MOPP-ABVD) and hybrid (MOPP-ABV) regimens were 
developed but proved to be no more effective than ABVD alone and were more 
toxic. (11,12,13,14)  Based on these studies, ABVD became the standard of care 
for adult patients in the United States and most other countries in the world.  
Administration of full doses of ABVD without treatment delays, dose reductions, or 
growth factors appears to optimize cure rates with this regimen.  (15,16)  
 
Over the years, alternative, brief duration regimens were developed for the 
treatment of advanced HL, including Stanford V and BEACOPP. Despite promising 
preliminary efficacy results with this regimen, a randomized US cooperative group 
Phase III trial of ABVD versus Stanford V with or without radiation therapy in 
patients with locally extensive or advanced stage HL (ECOG E2496) showed no 
difference in remission rates, or failure-free survival or overall survival at 5 years. 
Similarly, in a randomized trial conducted by the EORTC that randomized 
advanced stage HL patients to either ABVD or 4 cycles of BEACOPPescalated 
followed by 4 cycles of BEACOPPstandard, there was no statistically significant 
difference in disease-free or overall survival between the study arms (DFS with 
ABVD 86% vs 91%, OS 87 vs 90%). Based on these data, and due to concerns 
about the acute and late toxicities associated with BEACOPP, ABVD has remained 
the standard of care treatment for adults with advanced stage HL in the US.  
 
More recently, based on the consistent finding that interim PET positivity after 2-3 
cycles of ABVD is associated with disease recurrence and is a stronger predictor 
of patient outcome than traditional clinical prognostic factors like the IPS,  PET-
adapted therapy of advanced stage HL has been studied. (17,18,19,20,21)  A 
Phase II US Intergroup study (S0816) evaluated PET-adapted escalation of 
therapy in 336 patients with a positive interim PET (PET2) scan, with PET2- 
patients completing a full 6 cycles of ABVD while patients who were PET2+ after 
2 cycles of ABVD underwent escalation of therapy to BEACOPPescalated. The 
overall 2-year PFS in the entire study population was 79%. In the 271 patients who 
were PET2-negative and received ABVDx6,  the 2-year PFS was 82% as 
compared to a 2-year PFS of 64% in the 60 patients who were PET2+ after 
ABVDx2 and  were subsequently escalated to BEACOPPescalated. Notably, the 
majority of the treatment failures in the study were in paitents with a negative 
interim PET scan, with 58 of 271 PET2-negative patients having progression 
events.  The RATHL study was a study in 1214 patients with advanced stage HL 
(also included Stage IIA unfavorable and Stage IIB patients) evaluating PET-
adapted therapy escalation to BEACOPP in PET2+ patients with a randomized 
evaluation of therapy de-escalation with omission of bleomycin (AVD) in PET2-
negative patients. Similar to the S0816 study, the 3-year PFS was 67.5% among 
PET2+ patients escalated to BEACOPP.  The omission of bleomycin after 2 cycles 
of ABVD was demonstrated to be non-inferior to continuation of a full 6 cycles of 
ABVD with 3-year PFS in the AVD group of 84.4% versus 85.7% in the ABVD 
group. The 3-year PFS and OS in the overall study cohort were 82.6% and 95.8%. 
 
b. 
Treatment of Pediatric Patients with Advanced Stage Hodgkin Lymphoma 
 
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. Among these high-risk patients, intensification of 
treatment with current conventional agents is inadequate. While the peak age for 
Hodgkin Lymphoma is 20-34 years of age, younger adolescents (12-18 years) may 
also benefit from the study of novel agents and approaches used in young adult 
and adult Hodgkin’s populations. (22) 
 

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Risk and response-adapted combined modality therapy has been the cornerstone 
of the pediatric treatment paradigm with the goal of improving treatment outcomes 
while minimizing late effects of therapy. (23) Differences in treatment between 
adult and pediatric protocols have largely related to age-specific concerns 
regarding the late effects of alkylating agents (infertility, second malignancy), 
anthracycline (cardiac toxicity), and radiation (bone and soft tissue growth, second 
malignancy, cardiopulmonary sequealae) with an early evolution to protocols 
limiting the cumulative doses of the above chemotherapies and limiting radiation 
doses to 15 to 25Gy of involved lymph node regions only.  
 
In North America, the Children’s Oncology Group (COG) moved from ABVD with 
extended field radiation therapy to the risk adapted dose-dense ABVE-PC regimen 
(doxorubicin, 
bleomycin, 
vincristine, 
etoposide, 
prednisone 
and 
cyclophosphamide) in 1997. (24) ABVE-PC modified ABVD by (a) substituting 
vincristine for the more myelosuppressive vinblastine, (b) replacing dacarbazine 
with etoposide, (c) adding cyclophosphamide and prednisone to enhance efficacy, 
and (d) increasing dose density by giving chemotherapy every 3 weeks with use 
of filgrastim to prevent prolonged marrow nadir. (25) The P9425 study for patients 
with intermediate and high risk HL demonstrated an 84% 5 year EFS and 95% OS 
for high-risk patients using ABVE-PC and involved field radiotherapy. (26) 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 more recent AHOD0031 trial for intermediate risk (Stage IIB 
bulk, IIIA, IVA) pediatric HL used the ABVE-PC backbone and established early 
response assessment using CT and PET response as a means to tailor therapy 
and reduce radiation therapy for select groups. (27) AHOD0031 included 1712 
children, and the  4 year EFS was 85% and OS 97.8%. The cyclophosphamide 
dose was 800  mg/m2/cycle and the cumulative anthracycline dose was 200 
mg/m2. Notably, there was no benefit to the addition of IF-RT (21Gy)  for those 
patients deemed rapid early responders after 2 cycles who were in complete 
response at the end of 4 cycles of chemotherapy. Patients with bulky Stage IIB 
and Stage IVA disease were noted to have inferior outcomes (EFS 80.8%). (28)  
AHOD0831 addressed patients with Stage IIIB and IVB disease with 4 cycles of 
ABVE-PC augmenting therapy with non-cross reacting chemotherapy for slow 
early responders and response-adapted RT. The initial results estimate 4y EFS 
80.2% (29) and the approach is not recommended as standard of care. On all 
these studies interim response was assessed after 2 cycles of chemotherapy and 
used a combination of anatomic and FDG-PET criteria.  The currently enrolling 
AHOD1331 in children and adolescents up to age 21 includes patients with IIB 
bulk, IIIB, IVA and IVB.  The study gives 5 cycles of ABVE-PC with a higher 
alkylator dose (cyclophosphamide 1200 mg/m2/cycle) than delivered in 
AHOD0031, and is studying the substitution of brentuximab vedotin (Adcetris) for 
bleomycin with the goal of enhancing rapid response rates (evaluated by FDG-
PET after 2 cycles) and thereby limiting RT exposure.  Residual PET RT (21 Gy) 
is given to individual lesions with slow early response (Deauville 4,5)  and to all 
large mediastianl adenopathy (LMA) regardless of response. This was based on 
the concern of high failures in patients with mediastinal bulk /LMA on AHOD0031. 
To date the toxicity of the combination of brentuximab vedotin in combination with 
AVEPC (BV-AVEPC) has not differed from that of the standard experience of 
ABVE-PC. The overall anticipated RT use on AHOD1331 will be 60% of this high 
risk population, due to the inclusion of Stage IIB with bulk.  Accrual is anticipated 
to be complete in the fall of 2019 and results will not be available until late 2022.  
 
 

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There are limited data using ABVD in pediatric patients. In a small legacy CCG 
trial where Fryer et. al. (30) 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, suboptimal by today’s standards. In a contemporary report 
from the British Columbia Cancer Agency, ABVD in children and adolescents was 
associated with very limited pulmonary toxicity, which is more likely associated to 
bleomycin and not to dacarbazine. (31) Patients were assigned to risk groups 
based on adult criteria, and advanced stage patients received  6 cycles of ABVD 
chemotherapy with a recommendation for IFRT for CT or PET residual disease at 
the end of therapy.  RT was limited to 18% of patients. For those advanced stage 
patients <18 years of age, 5 year PFS for was 77% and OS 90%, again 
underscoring the need for more intensive and novel therapies and/or judicious 
application of consolidative RT for this group. (32) 
 
While the recent decade of COG AHOD trials has utilized an ABVE-PC 
chemotherapy backbone and a risk adapted, response based (per the initial 2 
cycles of therapy) radiation approach for advanced stage HL with valuable lessons 
learned, outcomes for children and adolescents with advanced stage disease 
remain suboptimal with 25-35% needing salvage therapy which often includes 
HSCT.  Additionaly, the current approach in children/adolescents has contrasted 
to that in adults and contiuned to utilize radiotherapy to maintain EFS: in patients 
with Stage IIIA and IVA patients on AHOD0031, an estimated 73.5% of patients 
received RT, while among statge IIIB and IVB patients on  AHOD0831, 76.4% 
received RT.  
 
A pooled analysis of COG legacy HL trials (AHOD0431, AHOD0031 and 
AHOD0831) indicates that compared to patients < 12 years fo age, adolescents > 
12 years of age have inferior outcomes. The 5-year cumulative incidence of 
relapse is higher in older children using either age 12 years or 15 years as the 
threshold for evaluation. (33) Five-year cumulative incidence of relapse in patients 
< 12 years compared to ≥ 12 years: 12% vs. 17% (p=0.03); in patients < 15 years 
compared to ≥ 15 years: 13% vs. 19% (p=0.003). When this analysis is limited to 
advanced stage patients from AHOD0031 and AHOD0831 (Stage IIB with bulk; 
IIIA; IIIB; IV A; IVB and MC/NS histology), 5-year event-free survival (EFS) was 
inferior for those ≥ 15 years of age (< 15 yrs. 85% vs. ≥ 15 yrs. 78%; p=0.0255). 
Multivariable modeling in the pooled analysis of all 3 legacy studies indicates that 
adolescent age is an independent risk for EFS (≥ 12 years HR 1.52 [95% CI 1.06, 
2.19; ref < 12 years]; ≥ 15 years HR 1.43 [95% CI 1.12, 1.83; ref < 15 years]). Age 
≥ 15 years is an independent risk for overall survival (≥ 15 years HR 2.58 [95% CI 
1.24, 5.38]). (34) 
 
2.3 
Brentuximab Vedotin for the Treatment of Advanced Stage Hodgkin Lymphoma 
 
Brentuximab vedotin (BV) is a chimeric CD30-specific IgG1 antibody conjugated to the 
microtubule-disrupting agent, monomethyl auristatin E (MMAE), by an enzyme-cleavable 
linker. Upon the binding of BV to CD30 on the Hodgkin Reed-Sternberg cell, the ADC is 
internalized and lysosomal enzymes cleave the linker allowing for the release of MMAE 
inside the cell. MMAE then binds to tubulin, resulting in cell cycle arrest and subsequent 
apoptosis of CD30-expressing cells (35, 36). In an initial Phase I, dose escalation study of 
45 patients with relapsed/refractory CD30 positive lymphoma, 93% with HL and 7% with 
anaplastic large-cell lymphoma (ALCL), 50% of patients showed an objective response 
(OR). Eighty-eight percent of responses occurred within the first 2.8 months (or 4 cycles) 
and responses lasted a median of 9.6 months. The maximum tolerated dose of BV was 
1.8 mg/kg given intravenously every 3 weeks. The most common adverse events (mostly 
Grade 1 or 2) were fatigue, pyrexia, gastrointestinal symptoms, neutropenia, and peripheral 
neuropathy. The reported dose-limiting toxicities were grade 4 thrombocytopenia, grade 3 

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hyperglycemia and febrile neutropenia. (37) In another Phase I trial, BV was given weekly 
for 3 weeks, followed by a week break to 38 patients with HL and 5 patients with ALCL. 
Fifty-four percent of the patients with HL had an objective response and dose-limiting 
toxicities in this study included grade 3 gastrointestinal symptoms and grade 4 
hyperglycemia. (38)  
 
These promising results prompted a multicenter, open label, pivotal Phase II study of BV 
for the treatment of rel/ref HL. In this study, 102 patients with were treated with BV at 
1.8mg/kg every 3 weeks for a maximum of 16 cycles. Patients had received a median of 
3.5 prior regimens, and all patients had received prior autologous hematopoietic stem cell 
transplant (autoHSCT). Seventy-five percent of patients responded, including 35% who 
had a complete response (CR). (39) Based on these results, in 2011 the FDA granted BV 
accelerated approval for the treatment of rel/ref HL after failure of at least two prior lines of 
multi-agent chemotherapy in patients who are not transplant candidates or patients with 
HL who progressed after autoHSCT. Long term follow-up showed durable remissions, with 
41% of patients still alive at 5 years. Additionally, of the patients who achieved a CR, the 
5-year overall survival (OS) and progression free survival (PFS) were 64% and 52% 
respectively. (40,41)   
 
BV was also studied as consolidation therapy after autologous HSCT. Although most HL 
patients are cured with multi-agent chemotherapy, up to 20-25% will relapse after or be 
refractory to initial therapy. The standard of care for these patients is high-dose 
chemotherapy followed by autoHSCT. (42, 43)  Despite a 50% durable remission rate, 
about 50% will still relapse after autologous HSCT. (44, 45, 46) The AETHERA trial 
examined the use of BV as consolidation therapy to improve PFS post autoHSCT. In this 
trial, patients with high risk features, including primary refractory disease, relapse within 12 
months of initial therapy, or extranodal involvement, were given BV 1.8mg/kg for 16 cycles 
following autologous HSCT. For those who received BV maintenance, median PFS was 
42.9 months compared to 24.1 months for those who received placebo. The estimated 2-
year PFS in patients who received BV consolidation was 65% compared to 45% in patients 
who received placebo. (47) As a result, the FDA granted BV additional approval as 
consolidation therapy after autologous HSCT in patients who are at high risk for relapse.  
 
Based on the promising efficacy and tolerability of BV in patients with rel/ref HL, BV was 
evaluated in the frontline setting in patients with previously untreated HL. A Phase I trial 
that included 51 patients with newly diagnosed Stage IIA bulky or Stage IIB-IV HL 
compared BV added to standard ABVD (A-ABVD) and BV added to AVD without bleomycin 
(BV-AVD). The CR rate was 95% in patients who received A-ABVD compared to 96% of 
patients who received BV-AVD. However, in the A-ABVD cohort there was an unacceptably 
high rate of adverse pulmonary events (44%); Therefore, it is recommended that BV not 
be given in combination with bleomycin. (48)  A 5-year follow-up of this study showed a 
failure-free survival of 92% and OS of 100% (49). Based on these findings, the ECHELON-
1 trial, a randomized Phase III trial of frontline BV-AVD compared to non-PET-adapted 
ABVD was conducted in patients with previously untreated advanced stage HL. The study 
met its primary endpoint, the 2-year modified PFS (with events defined as death, disease 
progression, or lack of complete response at the end of therapy followed by administration 
of a subsequent anti-lymphoma therapy) was 82.1% in the BV-AVD group versus 77.2% 
in the ABVD group. In the intent-to-treat population, 73% of patients in the BV-AVD arm 
were in CR at the end of the randomized regimen compared to 70% in the ABVD arm. 
Using the Deauville score (DS), 86% of patients in the BV-AVD arm had a DS of 1-3 at the 
end of frontline therapy compared to 82% in the ABVD arm. Notable adverse events 
included neutropenia in 58% of the patients receiving BV-AVD and in 45% of those 
receiving ABVD. Febrile neutropenia occurred in 21% of those treated with BV-AVD, 
prompting the common use of prophylactic granulocyte colony-stimulating factor (GCSF). 
In those who were then given prophylactic GCSF, the rate of febrile neutropenia decreased 
to 11%. Peripheral neuropathy occurred in 67% of patients in the BV-AVD group and in 
43% of patients in the ABVD group. Grade 2 and 3 peripheral neuropathy occurred in 20% 
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who developed peripheral neuropathy in the BV-AVD group, 67% had resolution of 
symptoms and 24% had improvement by at least one grade at the time of last follow-up. 
At the time of last follow-up, 92% of ongoing peripheral neuropathy was grade 1 or 2. (50) 
 
Of note, updated data regarding outcomes based on interim PET (PET2) response to BV-
AVD on the ECHELON-1 trial were presented at the 2018 ASCO Annual Meeting by Chen 
and colleagues. Among 664 patients treated with BV-AVD in the intent to treat population, 
588 patients had a negative interim PET scan and 47 were interim PET positive (DS 4-5). 
The 2-year mPFS in PET2+ patients was 57.5% as compared to 85.2% in patients who 
were PET2-. These data highlight both the fact that the majority of PET2+ patients 
continued to have disease control at 2 years as well as the relatively high proportion of 
treatment failures even in patients who have a negative interim PET scan. 
 
a. 
BV in pediatrics 
 
Brentuximab vedotin is generally well tolerated in pediatric patients at a dose of up 
to 1.8 mg/kg every 3 weeks. The pivotal Phase II trial that led to FDA approval of 
the drug included 5 patients with relapsed cHL aged 12-17 with cHL and there 
were no common severe toxicities or premature discontinuation of therapy related 
to an AE. (51) The combination of brentuximab vedotin with gemcitabine was 
investigated in a COG Phase I/II trial for relapsed/refractory cHL up to age 30 years 
(NCT01780662) with preliminary results confirming that the combination is 
generally well tolerated, and highly effective. (52,53) In addition, brentuximabn 
vedotin combined with chemotherapy in de novol high risk pediatric is currently 
being investigated in COG AHOD1331 as described above and as a substitute for 
vincristine in the St. Jude Children’s Research hospital trial using  OEPA/COPDac 
regimen (NCT01920932) which recently met accrual. 
 
In pediatrics, brentuximab vedotin has proven to be well-tolerated to date.  
AHOD1221, a retrieval trial using brentuximab vedotin with gemcitabine [n=42], 
(54) established 1.8 mg/kg every 3 weeks as the treatment dose in children.   
Overall complete response rate (CR) was 67% [95% CI 51–80]). The most 
common Grade 3–4 adverse events were neutropenia [36%]), rash [36%], 
transaminitis [21%], and pruritus [10%]. There were no treatment-related deaths, 
no ≥ Grade 3 neuropathy, and 1 case of pulmonary toxicity. In the ongoing 
AHOD1331 using  brentuximab vedotin in combination with the AVEPC in the COG 
(NCT02166463) targeted toxicities being monitored include neuropathy and 
myelosuppression, with protocol mandated GCSF use. BV-AVD is also being 
studied in a Phase I/II study of pediatric patients (ages 5-18) with Stage II-IV 
Hodgkin lymphoma (NCT02979522), wherein patients are receiving up to 6 cycles 
of 48mg/m2 of BV combined with standard doses of AVD. As of the time of 
reporting, (in NCT02979522) 8 patients were enrolled onto the study and 6 patients 
were evaluable for dose limiting toxicities (DLT). No patient experienced a DLT, 
and the recommended Phase II dose of BV-AVD was determined to be 48mg/m2. 
Toxicities were as expected with BV-AVD, including neutropenia, vomiting, and 
mucositis. (55) In addition, AHOD1331 (NCT02166463) recently completed 
accrual (April 30,2019) of 600 pediatric patients < 21 years of age, with n=300 
randomized to the brentuximab (+ AVEPC) arm. The AHOD1331 study has met 
no stopping rules. Myelosuppression was as expected with the dose dense 
chemotherapy regimen, and has not differed between the BV and non-BV 
containing arms to date where granulocyte stimulating factor has been applied in 
both arms a priori.  
 
 

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2.4 
The rationale for PD-1 blockade in HL 
 
HL is histologically defined by a small proportion of neoplastic Hodgkin Reed Sternberg 
(HRS) cells in a polymorphous inflammatory infiltrate. However, this inflammation does not 
appear to represent an effective host anti-tumor immune response. (56) Nearly universal 
genetic alterations of chromosome 9p24.1, which includes the PD-L1/PD-L2 loci, have 
been identified in HL, supporting the concept that the PD-1 pathway plays a key role in the 
host immune evasion that is central to HL pathogenesis. (57) The genetic alterations in 
9p24.1 are directly linked with increased expression of the PD-1 ligands, PD-L1 and PD-
L2, on HRS cells. (58,59) In addition, the JAK2 locus is also contained within the 9p24.1 
region, and JAK2 activation upregulates PD-L1 transcription and expression.4 
Furthermore, Epstein-Barr virus infection, which is frequently observed in HL, has also 
been identified as a mechanism of PD-L1 upregulation and expression in HL. (60) In 
addition to the PD-1 ligand expression observed on HRS cells, tumor-associated 
macrophages (TAMs) in the HL tumor microenvironment (TME) frequently express PD-L1. 
In fact, as might be expected due to the rarity of HRS in the HL TME, TAMs express the 
majority of PD-L1 in the TME. The topology of PD-L1 expression in the HL TME suggests 
that TAMs may play an important role in the ineffective immune response observed in HL, 
since PD-L1+ TAMs are geographically located in close proximity to PD-L1+ HRS cells as 
well as PD-1+ T-cells (especially CD4+ cells) in the HL TME. (61) Based on the multiple 
ways in which the PD-1 pathway appears to serve an important role in the pathogenesis of 
HL, there is a strong biologic rationale for PD-1 blockade in the treatment of HL. 
 
In fact, not only is the PD-1 pathway alteration a key facet of the pathogenesis of HL, more 
significant PD-1 pathway derangement in an HL tumor confers a negative prognosis in 
patients treated with standard therapies. In a cohort of 108 newly diagnosed patients with 
HL treated according to the Stanford V regimen, an increasing degree of PD-L1/PD-L2 
genetic alteration assessed by FISH (9p24.1 amplification > copy gain > polysomy vs 
disomy) was associated with inferior PFS. (62) Taken together with the near universal PD-
1 pathway alterations observed in HL these data suggest two enticing hypotheses for the 
potential role of PD-1 blockade in HL – the high levels of PD-1 pathway derangement in 
HL may predict increased susceptibility to PD-1 blockade and perhaps the use of anti-PD-
1 therapy could abrogate the negative prognostic impact of PD-1 pathway derangement 
seen in patients treated with standard therapies. 
 
a. 
Anti-PD-1 monotherapy in relapsed or refractory HL 
 
Anti-PD-1 antibody monotherapy has been evaluated in patients with relapsed or 
refractory HL and produced a high rate of objective responses in early phase 
studies. A Phase I study of nivolumab in patients with rel/ref hematologic 
malignancies demonstrated an 87% overall response rate (ORR), 17% complete 
response (CR) rate, and 100% clinical benefit rate in 23 patients with rel/ref HL. 
(63) The majority of patients enrolled on the study (78%) had failed prior 
autologous stem cell transplantation (autoSCT) and prior brentuximab vedotin 
(BV). A subsequent Phase II study (CheckMate 205) of nivolumab for rel/ref HL 
treated 243 patients who had failed prior autoSCT into 3 cohorts of patients, 
patients in Cohort A were BV naïve (n = 63), patients in Cohort B had failed BV 
that was administered after autoSCT (n = 80), and patients in Cohort C had 
received prior BV before and/or after autoSCT failure (n = 100). The ORR with 
nivolumab therapy among all treated patients was 69% with a CR rate of 16% as 
assessed by an independent review committee. The median time to response was 
2.1 months, and the median duration of response (DOR) across cohorts was 16.6 
months. The median progression-free survival (PFS) according to best response 
was 22.2 months in patients who achieved CR, 15.1 months in patients with a 
partial response, and 11.2 months in patients with a best response of stable 
disease, suggesting that even patients without an objective response benefitted 
from therapy.(64,65)  

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Pembrolizumab was evaluated in a Phase Ib study (KEYNOTE-013) of patients 
with rel/ref HL who failed prior BV (71% with prior autoSCT). More than half of 
patients (55%) had received 5 or more lines of prior therapy. Among 31 patients 
enrolled, the ORR was 65% and CR rate was 16%. The response duration was at 
least 24 weeks in 70% of responding patients, and, in the overall cohort, the PFS 
at 52 weeks after initiation of pembrolizumab was 46%. (66)  A Phase II study 
(KEYNOTE-087) of pembrolizumab in patients with rel/ref HL enrolled 210 patients 
into 3 cohorts: Cohort 1 included patients who failed autoSCT and post-autoSCT 
BV, Cohort 2 included patients who received prior salvage chemotherapy and BV 
but were refractory and ineligible for autoSCT, and Cohort 3 included patients who 
failed autoSCT but did not receive BV after ASCT. The ORR and CR rate across 
all cohorts by independent review were 69% and 22%, respectively. Similar to the 
Phase II nivolumab study, the response rates across the cohorts were similar and 
were similar regardless of number of prior therapy lines or whether or not the 
patient had received prior BV. The majority of patients (76%) had a duration of 
response of 6 months or greater, and the 9-month PFS was 63%. 
 
Checkpoint blockade, including anti-PD-1 antibody therapy, is associated with 
characteristic immune-related adverse events (AE) triggered by reversing the 
immunosuppressive effects of inhibitory checkpoints. Immune-related AEs (irAE) 
significant enough to require high-dose corticosteroids and preclude prevent 
further administration of anti-PD-1 antibodies are uncommon, but treating 
physicians should be aware of these potentially dangerous toxicities and how they 
should be managed. (67, 68) In the Phase I and II studies of pembrolizumab and 
nivolumab in patients with rel/ref HL, treatment has been well-tolerated, with very 
few grade 3 or 4 AEs reported and only 5-7% of patients discontinuing treatment 
due to treatment-related AEs. The most common irAE were hypo/hyperthyroidism 
(12-16%), rash (9%), hepatitis (5%), pneumonitis (3-4%), but most were grade 1 
or 2 and Grade 3 or higher irAEs were rare. (69, 70) 
 
b. 
Incorporation of PD-1 blockade into frontline therapy for HL 
 
Higher degrees of PD-1 pathway derangement (i.e. 9p24.1 amplification or copy 
gain) are associated with a higher likelihood of treatment failure with standard initial 
therapy for HL.5 Therefore, the incorporation of PD-1 blockade into initial therapy 
of HL is a logical strategy to attempt to overcome the negative prognostic impact 
of PD-1 pathway alteration. The preliminary findings of a study evaluating the 
addition of nivolumab to doxorubicin, vinblastine, dacarbazine (AVD) as initial 
therapy in patients with newly diagnosed advanced stage (stage IIB, III, IV) HL 
(CheckMate 205, cohort D) were reported at the ASH annual meeting in 2017. 
Fifty-one patients were enrolled and treated with nivolumab monotherapy for 4 
doses every 2 weeks followed by combination nivolumab plus AVD (N-AVD) for 12 
doses every 2 weeks. Forty-nine patients completed nivolumab monotherapy and 
ultimately 44 patients completed the full course of N-AVD. Aside from neutropenia 
(49%) and febrile neutropenia (10%), grade 3 or higher AEs were uncommon. 
There were few patients who discontinued treatment due to toxicity (4 patients, 
8%) and the profile of IrAEs was similar to what has been observed with single 
agent PD-1 blockade, with endocrinopathy (all thyroid-related) being common 
(26%, all grade 1-2) and only 1 patient requiring high-dose corticosteroids (for 
hepatitis). At the end of nivolumab monotherapy, the ORR and CR rates were 
similar to what has been observed in patients with advanced rel/ref HL (ORR 69%, 
CR 18% by independent review). In the intent to treat population, at the end of 
combination therapy, the ORR was 84% and the CR rate was 67% (ORR 93%, CR 
74% in evaluable patients). Of note, there were moderate discrepancies between 
investigator and independently-assessed responses – the end of treatment CR 
rate per investigators was 80%. Only 2 patients not in CR at the end of treatment 
received subsequent therapy. These data may speak to the difficulty of assessing 

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responses to PD-1 blockade using standard criteria and the potential utility of 
newer response criteria that account for indeterminate findings in patients 
receiving immunotherapy. (71, 72) The modified PFS in the overall cohort at 9 
months was 94%, but follow-up is too short to draw any definitive conclusions 
about the durability of responses as of yet. (73) 
 
c. 
Nivolumab in pediatrics 
 
To date the only published studies on Nivolumab in children include case reports 
in refractory  settings.  However PD-1 blockade has been shown to be safe and 
efficacious in early phase trials.  The FDA recently granted accelerated approval 
for pembrolizumab for the treatment of adult and pediatric patients who have 
refractory classical Hodgkin lymphoma, or those whose disease relapsed after ≥3 
prior lines of therapy. This approval was based on the non-randomized, open-label, 
multicenter phase 1/2 KEYNOTE-051 study which demonstrates an overall 
response rate of 50% in refractory/relapsed pediatric HL by RECIST criteria; the 
median age among 144 patients enrolled was 13 years (range 1-17), with 67% of 
patients being 10 to < 18 years of age.  (74) Nivolumab and pembrolizumab both 
target epitopes on the PD-1 molecule with high affinity and specificity.   
 
Given the excellent response rates to PD1 blockade described in relapsed and 
refractory HL in adults, nivolumab is currently under study through COG in 
combination with ipilumumab for refractory lymphoma (ADVL1412; median age 14 
years (range 1-25 years) and in combination with BV for relapsed cHL (Checkmate 
744 : AHOD1721; NCT02927769) in patients > 5 years age. Dosing is set at 
3mg/kg every 2 weeks.  Both studies continue to accrue patients. 
 
While 3 mg/kg is the initial labeling dose of nivolumab for hodgkin lymphoma, flat 
dosing (240 mg q 2 weeks) is now FDA approved for adults. With the recent 
emphasis on the earlier inclusion of adolescent patients into clinical trials, the PK 
of nivolumab in this population based on body weight > 40kgs (the average weight 
of a 12 year old male) has been investigated. These PK data have also been 
compared to PK in patients with weights < 40kg. Patients with weight > 40kg 
demonstrated an expected increased exposure (~33%) when receiving 240mg 
compared to 3mg/kg iv every 2 weeks The geometric means of Cmin, Cmax and 
Cavg at steady state are predicted to be 95.7, 185 and 122 ug/mL, respectively, 
with nivolumab i.v. 240 mg Q2W treatment, compared to the geometric means of 
Cmin, Cmax and Cavg at steady state 71.7, 139 and 91.3, respectively, with 
nivolumab i.v. 3 mg/kg Q2W treatment.  
 
Ongoing early phase  pediatric studies (ADVL1412; NCT02304458) using 
nivolumab at 3 mg/kg ( with no dose cap)  indicate the safety profile in subjects 12 
to 18 years of age is similar to that seen with adult subjects. The half life of 
nivolumab with this schedule is 10.2 ( + 1.7) days. (75)  Based on these data the 
pediatric dosing of nivolumab proposed in this trial is 3 mg/kg q 2 weeks upto age 
18 years of age. A max dose of 240 mg q 2 weeks will be used for consistency 
with adult dosing and based on the steady state data above. 
 
2.5 
Rationale for Current Study 
 
With the advances made in the treatment of advanced stage HL, from the introduction of 
ABVD, to PET-adapted treatment, and now the introduction of BV into initial treatment, a 
majority of patients with advanced stage HL will be cured with initial therapy. However, 
despite these advances, about 20-25% of patients treated for advanced stage HL will have 
relapsed or refractory disease. (76) Even though the recent RATHL study demonstrated 
that in patients with a negative interim PET scan, the omission of bleomycin after 2 cycles 
is non-inferior with regards to survival as compared to a full course of ABVD, a significant 
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BEACOPP, is a highly effective but toxic regimen associated with secondary malignancies 
and infertility – a large burden to bear in a disease that disproportionately impacts young 
patients. (77) The addition of BV to initial chemotherapy (AVD) demonstrated improved 2-
year modified progression-free survival (mPFS, with events defined as death, disease 
progression, or incomplete response with administration of subsequent anti-lymphoma 
therapy) compared to ABVD. However, the BV-AVD regimen was associated with higher 
rates of neutropenia, sepsis, and peripheral neuropathy compared to ABVD, and there still 
was an unacceptable ~20% failure rate. (78) Clearly, there remains room to improve 
outcomes in patients with newly diagnosed advanced stage cHL. 
 
In adolescents and older children in North America the Children’s Oncology Group (COG) 
has continued to use radiation therapy (RT) in 60-70% of patients in combination with 
ABVE-PC (regimen comprised of: doxorubicin, bleomycin, vincristine, etoposide, 
prenisone, and cyclophosphamide) as the chemotherapy backbone.  The 5-year event-
free survival (EFS) on AHOD0831, the landmark COG trial in advanced stage HL is 79% 
overall with Stage IV disease having EFS 77%. (79)  Hence, pediatric and adolescent 
patients with advanced stage disease could benefit from novel therapies and efforts to 
decrease radiation use while maintaining or potentially improving efficacy. 
 
The PD-1 pathway plays a critical role in the pathogenesis of cHL, as demonstrated by 
nearly universal chromosomal alterations in 9p24.1 and PD-L1 expression in Hodgkin 
Reed-Sternberg cells. (80) cHL is exquisitely sensitive to PD-1 blockade, as demonstrated 
in Phase I and II studies of nivolumab and pembrolizumab in patients with heavily treated 
relapsed/refractory cHL. (81;82) Interim results of a Phase II trial evaluating the addition of 
nivolumab to initial chemotherapy (N-AVD) demonstrated promising safety and efficacy. 
(83) The incorporation of PD-1 blockade into front-line therapy represents a clear 
opportunity to attempt to improve the outcomes and tolerability of initial therapy for patients 
with newly diagnosed advanced stage cHL. 
 
The primary endpoint of this trial is to evaluate the PFS in patients with advanced stage HL 
who receive nivolumab added to AVD (N-AVD) as compared to BV-AVD. If the primary 
endpoint of this trial is met, it would establish N-AVD as a new standard of care for the 
initial treatment of advanced stage HL in North America, improving outcomes and 
establishing a new treatment paradigm for a disease where progress has been more or 
less stagnant with only marginal improvement (i.e. BV-AVD) since ABVD was developed 
over 40 years ago. In addition, the study could have a considerable potential impact on the 
treatment of newly diagnosed cHL through the correlative studies that will be performed. 
We will perform correlative studies that could greatly inform treatment selection for this 
population by defining and prospectively validating the genetic and cellular predictors of 
response to initial therapy of cHL, thereby identifying subgroups of patients who are most 
likely to benefit from treatment with either the experimental (N-AVD) or control arm (BV-
AVD). Lastly, the integrated QoL studies will provide the opportunity to assess whether N-
AVD is associated with more favorable long term tolerability and QoL than BV-AVD, which, 
especially if PFS outcomes are similar, may inform practice and suggest a role for 
considering N-AVD as a new standard of care or the preferred approach in certain 
subgroups based on QoL outcomes.  
 
2.6 
Rationale for Consolidative Targeted  Radiation Therapy 
 
As it is an accepted standard of care, particulary in the pediatric population, a  modification 
of Residual PET Radiation Therapy (Residual PET RT) will be used to consolidate systemic 
treatment for eligible patients in either arm who do not achieve a metabolic complete 
response. In adults with cHL, RT does not significantly improve outcome among patients 
with advanced stage HL who achieve a complete response to adequate systemic therapy. 
For example, an EORTC randomized trial found that adjuvant RT did not improve outcome 
among patients with advanced stage HL who had achieved a complete anatomic response 
to 6-8 cycles of MOPP-ABV (84), Approximately 35% of the patients in that trial were 
assigned RT, however, primarily due to failure to achieve a CR. In the PET-era, the 

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GITIL/FIL HD 0607 trial found that consolidative RT to sites of initial bulk ≥ 5cm  did not 
significantly improve outcome for patients who had a negative PET scan after 2 cycles and 
were in metabolic CR after six cycles of ABVD (3-year PFS rate of 97% for RT vs 93% for 
no further therapy, P = .29). (85) 
 
However, among patients not achieving a CR, RT can effectively consolidate primary 
treatment and significantly reduce the risk of relapse, potentially avoiding the need for 
salvage chemotherapy and autologous stem cell transplant. The GHSG HD12 found that 
following 8 cycles of BEACOPP-based chemotherapy, patients with advanced stage HL 
and a residual mass > 1.5 cm who were randomized to consolidative RT had significantly 
better freedom from treatment failure compared to those treated with chemotherapy alone 
(86). This finding is consistent with results from the UKLG LY09 study demonstrating a 
significant improvement in both progression-free and overall survival associated with 
consolidative RT (not randomly assigned) in advanced stage HL patients. (87)  
 
The optimal time to assess PET response in order to guide RT use is uncertain. 
Although interim PET has been used  to guide consolidative RT use in some  trials, 
the anticipated  difference in early PET response between BV-AVD  and  N-AVD could 
cause a substantial imbalance in RT exposure between treatment arms. Hence, 
interim PET will not be used to determine RT use in this trial.  
 
Consequently, response at the end of six cycles of systemic therapy will be used to 
guide the use of RT in this trial. Specifically, localized Residual PET Radiation 
Therapy  (Residual PET RT) will be used for patients with limited residual PET-avid 
sites who have achieved a partial response (as per the 2014 Lugano Classification) 
at the completion of 6 cycles of systemic therapy on either arm. This indication for RT 
to reduce the rate of relapse in this high-risk population is consistent with available 
evidence and with recent German Hodgkin Study Group trials. (88)  This approach is 
anticipated to reduce the rate of RT in childhood HL patients from 60% to 15% in advanced 
stage HL. 
 
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 who have a complete response to 
systemic therapy (defined as Deavuville 1-3 after six cycles of systemic therapy), 
and  
 
2)  
limiting the volume of RT among patients who receive this treatment by employing 
Residual PET Radiation Therapy (Residual PET RT). 
 
2.7 
Rationale for RT Dose for PET-positive (Deauville 4-5) lesions at EOT 
 
The optimal dose of radiation in this context of course has not been determined in 
randomized trials. There is variation in practice among expert oncologists with respect to 
prescribed RT dose for patients with a positive PET scan following chemotherapy.  
 
In the United States and Canada, the common practice is to prescribe >30Gy in this 
scenario. For example, median dose prescribed to patients with post-chemotherapy 
Deauville score 4-5 was 37.8Gy in the MD Anderson series, (89) and 34.8Gy in the Dana 
Farber series. (90)  Local control and progression-free survival is not consistently reported 

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but is in the range of 65%-85% (i.e. acceptable, but not sufficient to support a lower 
radiation dose). 
 
The European practice for post-chemotherapy RT in advanced stage HL is based on 
GHSG protocols, in which 30Gy is the prescribed dose (91). Importantly, in these protocols, 
Deauville score = 3 is considered a “positive” scan, (and likely accounts for a substantial 
fraction if not the majority of positive scans on these trials). In S1826, however, RT will only 
be provided to patients with DS4-5 scans, who are at higher risk of relapse than those with 
DS3 scans.  
 
Finally, given the substantial competing risk of HL relapse in patients who have not 
achieved a metabolic CR to six cycles of systemic therapy, and the small volume of 
malignant nodal tissue that will be boosted, it seems improbable that the additional 6Gy 
will produce any meaningful increase in the lifetime risk of late toxicity among patients 
treated on this trial. 
 
So, in summary, the use of a 6Gy boost to the PET-avid abnormality 
 
a. 
consistent with current North American practice 
 
b. 
appropriate for the DS4-5 patients on the trial who are at higher risk of relapse than 
DS3-5 patients who get RT on GHSG trials, and 
 
c. 
unlikely to produce additional long-term toxicity in the in the context of high-risk HL 
with poor response to systemic therapy, where control of HL is likely the issue that 
will determine outcome. 
 
2.8 
Rationale for Correlative Studies 
 
The planned future translational objectives of this clinical trial are to identify biomarkers 
that allow for accurate risk stratification and personalized treatment selection in patients 
with advanced stage cHL. Specifically, the goal of planned future translational medicine 
objectives would be to identify tumor-derived molecular markers at baseline and 
dynamically during treatment that are prognostic of treatment outcome after BV-AVD or N-
AVD, predictive of response to nivolumab-based initial therapy (N-AVD), and have greater 
sensitivity and specificity than PET-CT scans, which are difficult to interpret in the setting 
of immunotherapy-based treatment. Sections 2.8a and 2.8b (below) describe planned 
future translational medicine objectives. 
 
Traditional clinical factors like age and stage, among others, have been used for many 
years as part of the International Prognostic Score (IPS) to risk stratify patients with newly 
diagnosed advanced stage HL. More recently, three of the IPS factors were used to 
develop a simpler, IPS-3 score for newly diagnosed advanced stage cHL which was still 
able to identify high, intermediate, and low risk groups. (92) However, the applicability of 
these traditional clinical prognostic scores across treatment regimens and data cohorts is 
variable. For example, in the SWOG S0816 study (PET-adapted ABVD with escalation to 
BEACOPP in interim PET+ patients), patients with a high-risk score (4-7) according to the 
IPS did not have a statistically significant higher risk of disease progression. Similarly, 
although gene expression profiles (GEP) have been shown in retrospective cohorts of adult 
patients with newly diagnosed advanced stage cHL to be associated with treatment 
outcomes, the applicability of these GEP-based predictor tools to prospectively treated 
patients has been limited. (93) Therefore, better biomarkers in patients with newly 
diagnosed advanced stage cHL are urgently needed. 
 
a. 
Tissue-Derived Prognostic and Predictive Biomarkers in cHL – Planned future 
integrated translational medicine objective 
 

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More specifically, in the setting of this clinical trial, in which we will be comparing 
the addition of novel, targeted agents to standard chemotherapy, there may be a 
forthcoming unique and important opportunity to define the molecular determinants 
of response and outcome to these individual regimens. Nivolumab counteracts the 
PD-1 pathway derangements that are essentially pathognomonic in cHL. In 
relapsed/refractory cHL, the degree of PD-1 pathway derangement present in a 
cHL tumor (based on immunohistochemistry and/or FISH) is associated with 
response to single-agent nivolumab. (94) A higher degree of 9p24.1 molecular 
alteration was associated with improved response and PFS to nivolumab. Notably, 
as compared to patients with 9p24.1 polysomy and copy gain, no patients with 
9p24.1 amplification had primary PD after nivolumab.  Similar to 9p24.1 alterations, 
a higher degree of PD-L1 expression by immunohistochemistry was associated 
with improved response and PFS in rel/ref HL patients treated with nivolumab. 
Patients who experienced primary PD with nivolumab treatment all had the lowest 
degree of PD-L1 expression while nearly all patients who achieved CR had higher 
degrees of PD-L1 expression (Figure 3).  These data suggest that a higher degree 
of PD-1 pathway derangement in a particular HL patient’s tumor may be predictive 
of response and DOR with anti-PD-1 antibody therapy. 
 
In addition to PD-L1/PD-L2 genetic alteration and PD-L1 expression on HRS and 
in the TME, another unique biologic feature of HL is altered antigen presentation 
machinery on HRS cells associated with molecular alterations in B2M and CIITA. 
There is no expression of MHC-I on HRS cells in about half of HL tumors and 
MHC-II expression on HRS cells is absent in a sizable minority (30%), while the 
majority of HL tumors have either absence or significant decrease of MHC-I and 
MHC-II expression. While no association between clinical features such as bulky 
disease, stage, or age has been found with expression of the antigen presentation 
proteins at diagnosis, important prognostic implications associated with lack of 
expression have emerged.  The absence of or decrease of MHC-I (and beta-2 
microglobulin) expression on HRS cells is a negative prognostic factor in HL 
patients treated with standard initial therapy, while MHC-Class II expression was 
not associated with outcome with chemotherapy.  Importantly, the negative 
prognostic impact of B2M/MHC-I expression with standard chemotherapy was 
independent of PD-L1 derangement (i.e. 9p24.1 alterations) and derangement of 
9p24.1 was not associated with expression of either Class I or Class II MHC. In 
fact, there was additive prognostic value in the evaluation of B2M/MHC-I/MHC-II 
expression, since patients with decreased/absent B2M/MHC-I expression AND 
9p24.1 amplification had markedly inferior outcomes compared to patients with 
decreased/absent B2M/MHC-I expression without 9p24.1 amplification – though 
these patients still had inferior PFS compared to patients with intact B2M/MHC-I.  
With MHC-I and B2M absent or decreased on HRS cells in most cases of HL, it 
appears that the mechanism of action of anti-PD-1 antibodies in HL does not rely 
on CD8+ cytotoxic T-cell based responses. As expected, response to nivolumab 
and post-nivolumab PFS in patients with rel/ref HL are not associated with the 
presence of MHC-I or B2M expression on HRS cells. Rather, response to 
nivolumab and PFS after nivolumab (in patients more distant from prior autoSCT) 
are associated with at least some degree of expression (positive or decreased vs 
negative) of MHC-II on HRS cells. Given the important prognostic value of antigen 
presentation machinery proteins both as prognostic markers of outcome with 
standard chemotherapy in previously untreated patients it will be important to 
assess the impact of these markers in the setting of BV-AVD. Likewise, it will be 
critical to understand the impact of these molecular derangements in patients 
treated with nivolumab added to standard chemotherapy, and whether these 
tumor-specific features can be utilized to identify patients who are most likely to 
benefit from the N-AVD regimen. 
 
NOTE: Planned integrated biomarker testing of specimens banked for planned 
future research will not occur until an amendment to this protocol (or separate 

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correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
b. 
Cell Free Circulating Tumor DNA in cHL – Planned future integrated translational 
medicine objective 
 
Despite the relative paucity of RS cells in the tumor, the detection of cell free 
circulating tumor DNA (ctDNA) is feasible in cHL. A number of next generation 
sequencing (NGS)-based ctDNA detection methodologies have been studied in 
cHL. NGS-based ctDNA detection performed by NGS of the immunoglobulin (Ig) 
genes can identify ctDNA in the peripheral blood mononuclear cells (PBMC) and 
plasma (cell-free ctDNA) at diagnosis in 73% of patients with cHL. Using a 
separate NGS method, Vandenberghe and colleagues identified cHL-specific 
genomic imbalances in ctDNA at diagnosis that became undetectable after 
treatment. In another study using digital droplet PCR, XPO1 mutations were 
detected at diagnosis in cHL patients and the persistence of this mutation in 
patients with a negative PET scan at the end of treatment showed a possible 
association with relapse. Most recently, using a panel-directed NGS-based 
approach, noninvasive genotyping of cHL was validated in cHL (feasible in 87.5% 
of patients evaluated) and enabled monitoring of clonal evolution in patients with 
treatment failure. Most notably, the presence and rate of ctDNA decline with 
standard treatment as well as with nivolumab treatment was found to be highly 
associated with the presence of active lymphoma and with PFS.  This latter, panel-
directed NGS method has the greatest potential for being the most sensitive and 
specific tool for ctDNA detection in cHL.  The validation of ctDNA in cHL, as a 
sensitive and specific marker of the eradication of the malignant clone, has the 
potential to supplant PET-CT scans as a dynamic disease assessment tool. 
Dynamic response to therapy and the detection of residual cHL are suboptimal 
with PET scans, which are the current gold standard. There remain a high number 
of disease progression events in patients who have negative interim and end of 
treatment PET scans (e.g. 2/3 of the total PFS events in the SWOG S0618 study 
were in PET-negative patients). Furthermore, interpreting PET scans remains 
particularly challenging in the setting of PD-1 inhibition, even requiring a 
modification to the standard lymphoma response assessment criteria (i.e. LYRIC 
criteria). We plan to submit a future revision proposing evaluation of the ability of 
ctDNA assessment to detect 9p24.1 molecular abnormalities, a known 
prognostic/predictive marker that would be advantageous to detect using a non-
invasive method due to the labor intensive methods required for FISH. In addition, 
in order to determine the most sensitive and specific measure of cHL eradication, 
we will compare detection of ctDNA at interim and end of treatment time points to 
PET-CT results to reliably identify disease progression events. 
 
NOTE: Planned integrated biomarker testing of specimens banked for planned 
future research will not occur until an amendment to this protocol (or separate 
correlative science protocol) is reviewed and approved in accordance with National 
Clinical Trials Network (NCTN) policies. 
 
 

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c. 
Quality of Life and PRO-CTCAE Correlatives 
 
Patients with advanced stage HL are at risk for poor quality of life (HRQL) both as 
a result of their underlying disease and its treatment.  While novel therapies, 
including the antibody-drug conjugate Brentuximab vedotin (BV) and anti-PD-1 
antibodies, such as Nivolumab (Nivo) offer the promise of improved disease-free 
and overall survival, these agents, are associated with their own symptom burden, 
such as peripheral neuropathy (BV), rashes, colitis, pneumonitis, and 
endocrinopathies (Nivo). An integrated aim of the trial will be evaluating the impact 
of novel therapy through patient-reported outcomes (PROs) of HRQL in advanced 
stage HL overall and by treatment arms. Adverse symptoms and poor HRQL can 
limit full delivery of novel agents, which in turn, may alter disease outcomes.  
 
In this study we rely on validated measures (PROMIS Global, PROMIS fatigue, 
PRO-CTCAE, and FACT/GOG-Ntx) to be completed by patients in a 15-minute 
period at key clinical time points during the trial.  All of these instruments are 
available for both youth and adult self-report in English, French, and Spanish, 
allowing for broad participation across the age span of the trial population.  Please 
see also Section 18.2. 
 
2.9 
Inclusion of Women and Minorities and Planned Enrollment Report 
 
This study was designed to include women and minorities, but was not designed to 
measure differences of intervention effects.  The anticipated accrual in the ethnicity/race 
and sex categories is shown in the table below.  
 
Adult Patients (age 18 or older) 
 
ADULT (Age 18 or Older): DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
 
Female 
Male 
Female 
Male 
 
American 
Indian/ 
Alaska Native 
5 
10 
5 
9 
29 
Asian 
3 
9 
0 
0 
12 
Native 
Hawaiian 
or 
Other Pacific Islander 
0 
5 
0 
0 
5 
Black 
or 
African 
American 
43 
12 
0 
0 
55 
White 
177 
262 
16 
17 
472 
More Than One Race 
2 
2 
2 
0 
6 
Total 
230 
300 
23 
26 
579 
 
 
 

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ADULT (Age 18 or Older): INTERNATIONAL (including Canadian participants)  
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
 
American 
Indian/ 
Alaska Native 
0 
1 
0 
1 
2 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black 
or 
African 
American 
5 
2 
0 
0 
7 
White 
20 
30 
2 
2 
54 
More Than One Race 
0 
0 
0 
0 
0 
Total 
25 
34 
2 
3 
64 
 
Pediatric Patients (age 12-17) 
 
PEDIATRIC (Age 12-17): DOMESTIC PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
 
American 
Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
1 
7 
0 
0 
8 
Native 
Hawaiian 
or 
Other Pacific Islander 
0 
1 
0 
0 
1 
Black 
or 
African 
American 
20 
18 
3 
2 
43 
White 
104 
102 
24 
31 
261 
More Than One Race 
3 
0 
1 
0 
4 
Total 
128 
128 
28 
33 
317 
 
PEDIATRIC (Age 12-17): INTERNATIONAL (including Canadian participants)  
PLANNED ENROLLMENT REPORT 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or Latino 
Hispanic or Latino 
Female 
Male 
Female 
Male 
 
American 
Indian/ 
Alaska Native 
0 
0 
0 
0 
0 
Asian 
0 
1 
0 
0 
1 
Native 
Hawaiian 
or 
Other Pacific Islander 
0 
0 
0 
0 
0 
Black 
or 
African 
American 
0 
0 
0 
0 
0 
White 
16 
10 
0 
0 
26 
More Than One Race 
0 
0 
0 
0 
0 
Total 
16 
11 
0 
0 
27 
 
 
 

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3.0 
DRUG INFORMATION 
 
Investigator Brochures  
For information regarding Investigator Brochures, please refer to SWOG Policy 15. 
 
For this study, SGN-35 (Brentuximab Vedotin), Doxorubicin hydrochloride, Dacarbazine and 
Vinblastine sulfate are commercially available; therefore, Investigator Brochures are not applicable 
to this/these drug/s.  Information about commercial drugs is publicly available in the prescribing 
information and other resources. 
 
For this study, BMS-936558 (Nivolumab, MDX-1106) is investigational and is being provided under 
an IND held by the National Cancer Institute.  The current version of the Investigator Brochure for 
the agent will be accessible to site investigators and research staff through the PMB Online Agent 
Ordering Processing (OAOP) application  
(http://ctep.cancer.gov/branches/pmb/agent_order_processing.htm).  Access to OAOP requires 
the establishment of a CTEP Identity and Access Managemetn (IAM) account and the maintenance 
of an “active” account status and a “current” password.  Questions about IB access may be directed 
to the PMB IB coordinator via e-mail (IBCoordinator@mail.nih.gov). 
 
IND Exemption 
SGN-35 (Brentuximab Vedotin) (in the U.S. for the pediatric population) is IND exempt as used in 
this trial. This exemption has been determined by attestation that neither the investigator nor 
sponsor intend to seek a new indication for use or to support any other significant change in the 
labeling or product advertising for SGN-35 (Brentuximab Vedotin). This investigation will use an 
approved route of administration and dosage of SGN-35 (Brentuximab Vedotin) and has no factors 
that increase the risk of the product. This investigation will be in compliance with 21CFR parts 56, 
50, and 312.7 and neither the investigator nor the sponsor will promote or represent that SGN-35 
(Brentuximab Vedotin) is safe or effective for the context that is under investigation in this study. 
This investigation will not commercially distribute or test market the study agent and will not 
unnecessarily prolong an investigation. 
 
3.1 
Nivolumab (BMS-936558, MDX1106, Opdivo®) (NSC # 748726) (IND-) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Nivolumab is human monoclonal antibody which targets the 
programmed death–1 (PD-1, cluster of differentiation 279 [CD279]) cell surface 
membrane receptor. PD-1 is a negative regulatory receptor expressed by activated 
T and B lymphocytes. Binding of PD-1 to its ligands, programmed death–ligand 1 
(PD-L1) and 2 (PD-L2), results in the down-regulation of lymphocyte activation. 
Nivolumab inhibits the binding of PD-1 to PD-L1 and PD-L2.  Inhibition of the 
interaction between PD-1 and its ligands promotes immune responses and 
antigen-specific T-cell responses to both foreign antigens as well as self-antigens. 
 
b. 
PHARMACOKINETICS 
 
1. 
Distribution: Nivolumab has linear pharmacokinetics after single and 
multiple dosing within the range 0.1 mg/kg to 10 mg/kg. The volume 
distribution (Vd) is 8L. 
 
2. 
Elimination: Clearance is independent of dose in the range 0.1 mg/kg to 
10 mg/kg. The total body clearance is 9.5 mL/hr, and the elimination half-
life of is approximately 26.7 days. Body weight normalized dosing showed 
approximately constant trough concentrations over a wide range of body 
weights.  
 
 

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c. 
ADVERSE EFFECTS 
 
1. 
Adverse Effects: 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 
2069 patients. Below is the CAEPR for Nivolumab. 
 
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, June 10, 20231 
 
 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS  
 
Anemia 
 
Anemia (Gr 3) 
 
 
Blood and lymphatic 
system 
disorders 
– 
Other 
(lymphatic 
dysfunction) 
 
CARDIAC DISORDERS 
 
 
 
Cardiac disorders - 
Other 
(cardiomyopathy) 
 
 
 
Myocarditis 
 
 
 
Pericardial 
tamponade2 
 
 
 
Pericarditis 
 
ENDOCRINE DISORDERS 
 
 
Adrenal 
insufficiency3 
 
 
 
Hyperthyroidis
m3 
 
 
 
Hypophysitis3  
 
 
Hypothyroidis
m3 
 
 
EYE DISORDERS 
 
 
 
Blurred vision 
 
 
 
Dry eye 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
 
 
Eye disorders - Other 
(diplopia)3 
 
 
 
Eye disorders - Other 
(Graves 
ophthalmopathy)3 
 
 
 
Eye disorders - Other 
(optic 
neuritis 
retrobulbar)3 
 
 
 
Eye disorders - Other 
(Vogt-Koyanagi-
Harada) 
 
 
Uveitis 
 
 
GASTROINTESTINAL DISORDERS 
 
 
Abdominal 
pain 
 
Abdominal pain (Gr 2) 
 
Colitis3 
 
 
 
 
Colonic perforation3 
 
 
Diarrhea 
 
Diarrhea (Gr 3) 
 
Dry mouth 
 
Dry mouth (Gr 2) 
 
 
Enterocolitis 
 
 
 
Gastritis 
 
 
 
Mucositis oral 
 
 
Nausea 
 
Nausea (Gr 2) 
 
Pancreatitis4 
 
 
GENERAL DISORDERS AND ADMINISTRATION 
SITE CONDITIONS 
 
Fatigue 
 
 
Fatigue (Gr 3) 
 
Fever 
 
Fever (Gr 2) 
 
Injection 
site 
reaction 
 
Injection site reaction (Gr 2) 
HEPATOBILIARY DISORDERS 
 
 
 
Hepatobiliary 
disorders 
- 
Other 
(immune-related 
hepatitis) 
 
IMMUNE SYSTEM DISORDERS 
 
 
 
Allergic reaction3 
 
 
 
Autoimmune disorder3  
 
 
Cytokine 
release 
syndrome5 
 
 
 
Immune 
system 
disorders 
- 
Other 
(GVHD in the setting 
of allotransplant)3,6 
 
 
 
Immune 
system 
disorders 
- 
Other 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
(sarcoid 
granuloma, 
sarcoidosis)3 
INJURY, 
POISONING 
AND 
PROCEDURAL 
COMPLICATIONS 
 
 
Infusion 
related 
reaction7 
 
 
INVESTIGATIONS 
 
 
Alanine 
aminotransfer
ase increased3 
 
Alanine 
aminotransferase 
increased3 (Gr 3) 
 
Aspartate 
aminotransfer
ase increased3 
 
Aspartate aminotransferase 
increased3 (Gr 3) 
 
Blood bilirubin 
increased3 
 
Blood bilirubin increased3 
(Gr 2) 
 
CD4 
lymphocytes 
decreased 
 
CD4 lymphocyte decreased 
(Gr 4) 
 
Creatinine 
increased 
 
 
 
Lipase 
increased 
 
 
 
Lymphocyte 
count 
decreased 
 
Lymphocyte 
count 
decreased (Gr 4) 
 
Neutrophil 
count 
decreased 
 
 
 
Platelet count 
decreased 
 
 
 
Serum 
amylase 
increased 
 
 
METABOLISM AND NUTRITION DISORDERS 
 
 
Anorexia 
 
 
 
 
Hyperglycemia 
Hyperglycemia (Gr 2) 
 
 
Metabolism 
and 
nutrition disorders - 
Other 
(diabetes 
mellitus 
with 
ketoacidosis)3 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE 
DISORDERS 
 
 
Arthralgia 
 
 
 
 
Musculoskeletal 
and 
connective 
tissue 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
disorder 
- 
Other 
(polymyositis) 
 
 
Myositis 
 
 
 
Rhabdomyolysis 
 
NERVOUS SYSTEM DISORDERS 
 
 
 
Encephalopathy3 
 
 
 
Facial nerve disorder3  
 
 
Guillain-Barre 
syndrome3 
 
 
 
Myasthenia gravis3 
 
 
 
Nervous 
system 
disorders 
- 
Other 
(demyelination 
myasthenic syndrome) 
 
 
 
Nervous 
system 
disorders 
- 
Other 
(encephalitis)3 
 
 
 
Nervous 
system 
disorders 
- 
Other 
(meningoencephalitis) 
 
 
 
Nervous 
system 
disorders 
- 
Other 
(meningoradiculitis)3 
 
 
 
Nervous 
system 
disorders 
- 
Other 
(myasthenic 
syndrome) 
 
 
 
Peripheral 
motor 
neuropathy 
 
 
 
Peripheral 
sensory 
neuropathy 
 
 
 
Reversible 
posterior 
leukoencephalopathy 
syndrome3 
 
RENAL AND URINARY DISORDERS 
 
 
 
Acute kidney injury3 
 
 
 
Renal 
and 
urinary 
disorders 
- 
Other 
(immune-related 
nephritis) 
 
RESPIRATORY, THORACIC AND MEDIASTINAL 
DISORDERS 
 
 
Pleural 
effusion3 
 
 
 
Pneumonitis3  
 
 
 
Respiratory, 
thoracic 
and 
mediastinal 
 

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 Adverse Events with Possible  
 Relationship to Nivolumab 
 (CTCAE 5.0 Term) 
[n= 2069] 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
 
Likely (>20%) Less Likely 
(<=20%) 
Rare but Serious 
(<3%) 
 
disorders 
- 
Other 
(bronchiolitis 
obliterans 
with 
organizing pneumonia 
(BOOP))3 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS  
 
 
Erythema multiforme3  
 
Pruritus3 
 
Pruritus3 (Gr 2) 
 
Rash maculo-
papular3 
 
Rash maculo-papular3 (Gr 2) 
 
 
Skin 
and 
subcutaneous 
tissue 
disorders 
- 
Other 
(bullous pemphigoid) 
 
 
Skin 
and 
subcutaneous 
tissue 
disorders 
- 
Other (Sweet's 
Syndrome)3 
 
 
 
Skin 
hypopigmenta
tion3 
 
 
 
 
Stevens-Johnson 
syndrome 
 
 
 
Toxic 
epidermal 
necrolysis 
 
1 This 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. 
2 Pericardial tamponade may be related to possible inflammatory reaction 
at tumor site. 
3 Nivolumab being a member of class of agents involved in the inhibition 
of “immune checkpoints”, may result in severe and possibly fatal 
immune-mediated adverse events probably due to T-cell activation and 
proliferation.  This may result in autoimmune disorders that can include 
(but are not limited to) autoimmune hemolytic anemia, acquired anti-
factor VIII immune response, autoimmune aseptic meningitis, 
autoimmune hepatitis, autoimmune nephritis, autoimmune neuropathy, 
autoimmune thyroiditis, bullous pemphigoid, exacerbation of Churg-
Strauss Syndrome, drug rash with eosinophilia systemic symptoms 
[DRESS] syndrome, facial nerve disorder (facial nerve paralysis), limbic 
encephalitis, hepatic failure, pure red cell aplasia, pancreatitis, 
ulcerative and hemorrhagic colitis, endocrine disorders (e.g., 
autoimmune thyroiditis, hyperthyroidism, hypothyroidism, autoimmune 
hypophysitis/hypopituitarism, thyrotoxicosis, and adrenal insufficiency), 

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sarcoid granuloma, myasthenia gravis, polymyositis, and Guillain-Barre 
syndrome. 
4 Pancreatitis may result in increased serum amylase and/or more 
frequently lipase. 
5 Cytokine release syndrome may manifest as hemophagocytic 
lymphohistiocytosis with accompanying fever and pancytopenia. 
6 Complications including hyperacute graft-versus-host disease (GVHD), 
some fatal, have occurred in patients receiving allo stem cell transplant 
(SCT) after receiving Nivolumab.  These complications may occur 
despite intervening therapy between receiving Nivolumab and allo-SCT. 
7 Infusion reactions, including high-grade hypersensitivity reactions which 
have been observed following administration of nivolumab, may 
manifest as fever, chills, shakes, itching, rash, hypertension or 
hypotension, or difficulty breathing during and immediately after 
administration of nivolumab. 
 
Adverse events reported on Nivolumab trials, but for which there is 
insufficient evidence to suggest that there was a reasonable 
possibility that Nivolumab caused the adverse event: 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Leukocytosis 
CARDIAC DISORDERS - Atrial fibrillation; Atrioventricular block 
complete; Heart failure; Ventricular arrhythmia 
EAR AND LABYRINTH DISORDERS - Vestibular disorder 
EYE DISORDERS - Eye disorders - Other (iridocyclitis); Optic nerve 
disorder; Periorbital edema 
GASTROINTESTINAL DISORDERS - Constipation; Duodenal ulcer; 
Flatulence; Gastrointestinal disorders - Other (mouth sores); Vomiting 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - 
Chills; Edema limbs; Malaise; Pain 
HEPATOBILIARY DISORDERS - Bile duct stenosis 
IMMUNE SYSTEM DISORDERS - Anaphylaxis; Immune system 
disorders - Other (autoimmune thrombotic microangiopathy); Immune 
system disorders - Other (limbic encephalitis) 
INFECTIONS AND INFESTATIONS - Bronchial infection; Lung infection; 
Sepsis; Upper respiratory infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; GGT 
increased; Investigations - Other (protein total decreased); Lymphocyte 
count increased; Weight loss 
METABOLISM 
AND 
NUTRITION 
DISORDERS 
- 
Dehydration; 
Hyperuricemia; 
Hypoalbuminemia; 
Hypocalcemia; 
Hyponatremia; 
Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - 
Back pain; Musculoskeletal and connective tissue disorder - Other 
(musculoskeletal pain); Musculoskeletal and connective tissue disorder - 
Other (polymyalgia rheumatica); Myalgia; Pain in extremity 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL 
CYSTS AND POLYPS) - Neoplasms benign, malignant and unspecified 
(incl cysts and polyps) - Other (Histiocytic necrotizing lymphadenitis) 
NERVOUS SYSTEM DISORDERS - Dizziness; Headache; Intracranial 
hemorrhage 
PSYCHIATRIC DISORDERS - Insomnia 
RENAL AND URINARY DISORDERS - Hematuria; Renal and urinary 
disorders - Other (tubulointerstitial nephritis) 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS - 
Bronchospasm; Cough; Dyspnea; Hypoxia 

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SKIN AND SUBCUTANEOUS TISSUE DISORDERS - Alopecia; Dry skin; 
Hyperhidrosis; Pain of skin; Photosensitivity; Rash acneiform; Skin and 
subcutaneous tissue disorders - Other (rosacea) 
VASCULAR DISORDERS - Flushing; Hypertension; Hypotension; 
Vasculitis 
 
Note: Nivolumab 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. 
 
2. 
Pregnancy and Lactation: 
 
Pregnancy: Adverse events were observed in animal reproduction studies. 
Nivolumab may be expected to cross the placenta; effects to the fetus may 
be greater in the second and third trimesters. Based on its mechanism of 
action, nivolumab is expected to cause fetal harm if used during 
pregnancy. Women of reproductive potential should use highly-effective 
contraception during therapy and for at least 23 weeks after treatment has 
been discontinued. Men receiving nivolumab and who are sexually active 
with women of child bearing potential should adhere to contraception for a 
period of 31 weeks after the last dose of nivolumab. 
 
Lactation: It is not known if nivolumab is excreted into breast milk. Due to 
the potential for serious adverse reactions in the nursing infant, the 
manufacturer recommends women to discontinue breastfeeding during 
treatment with nivolumab. 
 
3. 
Drug Interactions: Nivolumab is not expected to have any effect on 
cytochrome P450 or other drug metabolizing enzymes in terms of 
inhibition or induction, and is, therefore, not expected to induce these 
types of PK-based drug interactions. No incompatibilities between 
nivolumab injection and polyvinyl chloride (PVC), non-PVC/non-DEHP 
(di(2-ethylhexyl)phthalate) IV components, or glass bottles have been 
observed. 
 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan 
 
Nivolumab injection is to be administered as a 30 minute IV infusion through a 0.2 
micron to 1.2 micron pore size, low-protein binding membrane in-line filter. DO 
NOT administer as IV push or bolus injection. Do not administer other medications 
through the same IV line. Flush IV line at the end of the infusion. 
 
e. 
HOW SUPPLIED 
 
1. 
Nivolumab Injection is a clear to opalescent, colorless to pale yellow liquid; 
light (few) particulates may be present. The drug product is a sterile, 
nonpyrogenic, single-use, isotonic aqueous  solution formulated in sodium 
citrate, sodium chloride, mannitol, diethylenetriaminepentacetic acid 
(pentetic acid) and polysorbate 80 (Tween® 80), and water for injection.  
Dilute solutions of hydrochloric acid and/or sodium hydroxide may be used 
for pH adjustment (pH 5.5-6.5). 
 

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2. 
Nivolumab is supplied by Bristol-Myers Squibb and distributed by the 
Pharmaceutical Management Branch, CTEP/DCTD/NCI.  Nivolumab will 
be supplied as 100 mg vials (10 mg/mL) with a 0.7mL overfill.  It is supplied 
in 10 mL type I flint glass vials, with fluoropolymer film-laminated rubber 
stoppers and aluminum seals. 
 
f. 
STORAGE, PREPARATION & STABILITY 
 
1. 
Vials of nivolumab injection must be stored at 2°-8°C (36°-46°F) and 
protected from light, freezing and shaking.  The unopened vials can be 
stored at room temperature (up to 25°C, 77°F) and room light for up to 48 
hours. 
 
2. 
Nivolumab injection can be infused undiluted (10 mg/mL) or diluted with 
0.9% Sodium Chloride Injection, USP or 5% Dextrose, USP to drug 
concentrations no less than 0.35 mg/mL. When the dose is fixed (eg, 240 
mg, 360 mg, or 480 mg flat dose), nivolumab injection can be infused 
undiluted or diluted so as not to exceed a total infusion volume of 160 mL.  
For patients weighing less than 40 kilograms (kg), the total volume of 
infusion must not exceed 4 mL per kg of patient weight. Note: Mix gently. 
Do not shake. 
 
3. 
Nivolumab infusions are compatible with polyvinyl chloride (PVC) or 
polyolefin containers and infusion sets, and glass bottles. 
 
4. 
Stability: Shelf-life stabilitiy studies of the intact vials are ongoing. 
 
The administration of undiluted and diluted solutions of nivolumab must be 
completed within 24 hours of preparation.  If not used immediately, the 
infusion solution may be stored up to 24 hours in a refrigerator at 2°-8°C 
(36°-46°F) and a maximum of 8 hours of the total 24 hours can be at room 
temperature (20°-25°C, 68°-77°F) and room light.  The maximum 8-hour 
period under room temperature and room light conditions includes the 
product administration period.  
 
CAUTION: The single-use dosage form contains no antibacterial 
preservative or bacteriostatic agent.  Therefore, it is advised that the 
product be discarded 8 hours after initial entry. 
 
g. 
DRUG ORDERING & ACCOUNTABILITY 
 
1. 
Drug ordering: NCI-supplied agents may be requested by the Principal 
Investigator (or their authorized designee) at each participating institution.  
Pharmaceutical Management Branch (PMB) policy requires that agent be 
shipped directly to the institution where the patient is to be treated.  PMB 
does not permit the transfer of agents between institutions (unless prior 
approval from PMB is obtained).  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), 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 investigator at 
that institution. 
 
Starter supplies will not be provided.  Order initial supplies once a patient 
is randomized to the nivolumab arm.  If expedited shipment is required, 

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sites should provide an express courier account through the Online Agent 
Order Processing (OAOP) application. 
 
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, 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. 
 
2. 
Drug Handling and Accountability (NCI logs or other) 
 
a. 
Drug Accountability:  The investigator, or a responsible party 
designated by the investigator, must maintain a careful record of 
the receipt, disposition, and return of all drugs received from the 
PMB using the Drug Accountability Record Form available on the 
NCI home page (http://ctep.cancer.gov). Store and maintain 
separate NCI Investigational Agent Accountability Records for 
each ordering investigator on this protocol. 
 
b. 
Electronic logs are allowed as long as a print version of the log 
process is the exact same appearance as the current NCI DARF. 
If the trial is a placebo control trial – indicate that separate DARFs 
are needed for each patient to also include the placebo drug 
supply. 
 
3. 
Drug return and/or disposition instruction  
 
a. 
All unused drug supplies must be returned to the PMB.  When it 
is necessary to return study drug (e.g., sealed bottles remaining 
when PMB sends a stock recovery letter), investigators should 
return the study drug to the PMB using the NCI Return Agent Form 
available on the NCI home page (http://ctep.cancer.gov). 
 
b. 
Drug expiration:  (If packaging does not have expiration date, 
check with drug ordering designee and/or PI at site to confirm 
receipt of ongoing stability testing letter from NCI when internal 
drug audits are being performed on a quarterly basis. If packaging 
has expiration date, indicate drug expiration date on the DARF 
under Manufacturer and Lot # and use the drug lots with shorter 
expiration date first). 
 
4. 
Useful Links and Contacts 
 
x 
CTEP Forms, Templates, Documents:  http://ctep.cancer.gov/forms/  
x 
NCI CTEP Investigator Registration:  RCRHelpDesk@nih.gov  
x 
PMB policies and guidelines: 
http://ctep.cancer.gov/branches/pmb/agent_management.htm   
x 
PMB 
Online 
Agent 
Order 
Processing 
(OAOP) 
application: 
https://ctepcore.nci.nih.gov/OAOP/  
x 
CTEP 
Identity 
and 
Access 
Management 
(IAM) 
account: 
https://ctepcore.nci.nih.gov/iam/     
x 
CTEP IAM account help:  ctepreghelp@ctep.nci.nih.gov   
x 
IB Coordinator: IBCoordinator@mail.nih.gov  
x 
PMB email:  PMBAfterHours@mail.nih.gov 
x 
PMB phone and hours of service: (240) 276-6575 Monday through 
Friday between 8:30 am and 4:30 pm (ET). 

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3.2 
Brentuximab vedotin (SGN-35, ADCETRIS®) – COMMERCIALLY AVAILABLE FOR U.S. 
SITES – SUPPLIED BY SEATTLE GENETICS FOR SITES IN CANADA  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Mechanism of Action: SGN-35 (Brentuximab Vedotin) is a 
CD-30 directed antibody-drug conjugate (ADC) consisting of 3 components: (1) 
the chimeric IgG1 antibody cA10, specific for human CD30, (2) the microtubule 
disrupting agent monomethyl auristatin E (MMAE), and (3) a protease-cleavable 
linker that covalently attaches MMAE to cA10.  Its cytotoxic activity occurs when 
ACD binds to the CD-30 expressing cell, forming an ADC-CD30 complex 
compound and releasing MMAEs via proteolytic cleavage.  Subsequently, MMAE 
binds to tubulin to disrupt the microtubule network within the cells, resulting in cell 
cycle arrest and apoptosis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: Maximum concentrations of antibody drug conjugate (ADC) 
were typically observed close to the end of infusion. 
 
2. 
Distribution: The mean steady state volume of distribution was 
approximately 6–10 L for ADC.  In vitro, the binding of MMAE to human 
plasma proteins ranged from 68–82%.  
 
3. 
Metabolism: MMAE: Minimal, primarily hepatic via oxidation by CYP3A4/5.   
MMAE is not likely to displace or to be displaced by highly protein-bound 
drugs. In vitro, MMAE was a substrate of P-gp and was not a potent 
inhibitor of P-gp. 
 
4. 
Elimination:  The elimination half-life of ADC is 4 to 6 days.  The 
microtubule disrupting agent cleaved from brentuximab vedotin (MMAE), 
3 to 4 days.  
 
c. 
ADVERSE EFFECTS 
 
1. 
Possible Side Effects of Brentuximab vedotin: 
 
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).  
 
 
Version 2.5, February 13, 20191 

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 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious (<3%) 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
 
Anemia 
 
 
 
Febrile neutropenia 
GASTROINTESTINAL DISORDERS 
 
Abdominal pain 
 
 
 
 Colitis2 
 
Constipation 
 
Diarrhea 
 
 
 
 
 Enterocolitis 
 
 
Gastrointestinal 
hemorrhage3 
 
 
Gastrointestinal 
obstruction4 
 
 
Gastrointestinal 
perforation5 
 
 
Gastrointestinal ulcer6 
 
 
Ileus 
Nausea 
 
 
 
 
Pancreatitis 
 
Vomiting 
 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
 
Chills 
 
 
Edema limbs 
 
Fatigue 
 
 
 
Fever 
 
 
Pain 
 
HEPATOBILIARY DISORDERS 
 
Hepatobiliary 
disorders - Other 
(hepatotoxicity)7 
 
 
IMMUNE SYSTEM DISORDERS 
 
 
Anaphylaxis 
 
INFECTIONS AND INFESTATIONS 
 
Lung infection 
 
  
Upper respiratory 
infection 
 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
 
 
Infusion related reaction 
 
INVESTIGATIONS 
 
Alanine 
aminotransferase 
increased 
 

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 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious (<3%) 
 
Aspartate 
aminotransferase 
increased 
 
Neutrophil count 
decreased 
 
 
 
Platelet count 
decreased 
 
 
Weight loss 
 
 
White blood cell 
decreased 
 
METABOLISM AND NUTRITION DISORDERS 
 
Anorexia 
 
 
Hyperglycemia 
 
 
 
Tumor lysis syndrome 
 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
 
Arthralgia 
 
 
Back pain 
 
 
Muscle cramp 
 
 
Myalgia 
 
 
Pain in extremity 
 
NERVOUS SYSTEM DISORDERS 
 
Dizziness 
 
 
Headache 
 
 
 
Nervous system 
disorders - Other 
(progressive multifocal 
leukoencephalopathy) 
 
Paresthesia 
 
 
Peripheral 
motor 
neuropathy 
 
Peripheral 
sensory 
neuropathy 
 
 
PSYCHIATRIC DISORDERS 
 
Anxiety 
 
 
Insomnia 
 
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
 
Cough 
 
 
Dyspnea 
 
 
Oropharyngeal pain  
 
 
Respiratory, thoracic 
and mediastinal 
disorders - Other 
(pulmonary toxicity)8 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
 
Alopecia 
 

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 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
Likely (>20%) 
Less Likely 
(<=20%) 
Rare but Serious (<3%) 
 
Hyperhidrosis 
 
 
Pruritus 
 
 
Rash maculo-
papular 
 
 
 
Stevens-Johnson 
syndrome 
 
 
Toxic epidermal 
necrolysis 
1 This 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. 
2 Colitis may also include the term neutropenic colitis. 
3 Fatal 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. 
4 Fatal 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. 
5 Fatal 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. 
6 Fatal 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. 
7 Hepatotoxicity may manifest as increased ALT/AST, bilirubin, alkaline 
phosphatase, and/or GGT. 
8 Pulmonary 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. Concomitant use of bleomycin 
with brentuximab vedotin is contraindicated.  

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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. 
 
2. 
Pregnancy and Lactation:  
Pregnancy:  Based on animal studies, brentuximab vedotin causes 
miscarriages, birth defects, and affects the testes. Advise men and women 
of childbearing potential to use effective contraception during the study 
and 6 months after last dose of brentuximab vedotin.   
 
Lactation:  It is not known whether brentuximab vedotin excretes in breast 
milk.  Because of the potential risk to harm a nursing baby, breastfeeding 
is not allowed while receiving brentuximab vedotin. 
 

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3. 
Drug Interactions:  
In vitro data indicate that brentuximab vedotin is oxidized primarily via 
CYP3A4/5. Co-administration of brentuximab vedotin with a strong 
CYP3A4 inhibitor such as ketoconazole resulted in moderately increased 
monomethyl auristatin E (MMAE) exposure by approximately 34%.  
Therefore, patients who are receiving strong or moderate CYP3A4 
inhibitors concomitantly with brentuximab vedotin must be closely 
monitored for adverse reactions.  Co-administration of brentuximab 
vedotin with a strong CYP3A4 inducer such as rifampin has the potential 
to affect the exposure to MMAE, moderately reducing MMAE exposure by 
approximately 46%.   
 
In vitro studies show that MMAE is not a substrate of BCRP, MRP2, 
OATP1B1, OATP1B3, OAT1, OAT3 or OCT2 transporters. However, in 
vitro data indicate that MMAE is a substrate of the efflux transporter P-
glycoprotein (P-gp).  Co-administration of brentuximab vedotin with P-gp 
inhibitors may increase exposure to MMAE. Patients should be closely 
monitored for adverse reactions when concomitantly administered P-gp 
inhibitor with brentuximab vedotin. 
 
Brentuximab vedotin (MMAE) inhibits CYP3A4/5 with an IC50 of 10 μM, 
and its level peaks to about 7 nM after receiving a dose of 1.8 mg/kg.  Co-
administration of brentuximab vedotin with midazolam, a CYP3A4 
substrate did not affect the exposure of midazolam. SGN-35 is not 
expected to alter the exposure to drugs that are metabolized by CYP3A4. 
 
Refer to package insert or manufacturer website for the most complete 
and up to date information.  Due to potential drug interactions, a complete 
patient medication list, including brentuximab vedotin, should be screened 
prior to, initiation of, and during treatment with brentuximab vedotin. See 
Section 8.0 Toxicities to be Monitored and Dosage Modifications. 
d. 
DOSING & ADMINISTRATION 
 
See Section 7.0 Treatment Plan. 
 
e. 
STORAGE & STABILITY 
 
Please refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
f. 
HOW SUPPLIED 
 
Brentuximab vedotin is commercially available and will not be supplied. Refer to 
the current FDA-approved package insert for the most comprehensive and up to 
date information. 
 
3.3 
Doxorubicin (Adriamycin ®) (NSC-123127) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Doxorubicin is an anthracycline, topoisomerase II inhibitor.  
It is isolated from cultures of Streptomyces peucetius var. caesius. The cytotoxic 
effect of doxorubicin is related to nucleotide base intercalation and cell membrane 
lipid binding activities.  It blocks nucleotide replication and the action of DNA and 
RNA polymerases.  The interaction between doxorubicin and topoisomerase II to 
form DNA-cleavable complexes appears to be an important mechanism of its 
cytocidal activity. 
 

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b. 
PHARMACOKINETICS 
 
1. 
Absorption: N/A   
 
2. 
Distribution: Steady-state volume of distribution: 809-1214 L/m2; protein 
binding: 74-76%; doxorubicin does not cross the blood brain barrier. 
 
3. 
Metabolism: Primarily hepatic 
 
4. 
Elimination:  Half-life for distribution is approximately 5 minutes.  The 
terminal half-life is 20-48 hours.   
 
c. 
ADVERSE EFFECTS 
 
1. 
Refer to package insert or manufacturer website for the most complete 
and up to date information on contraindications, warnings and precautions, 
and adverse reactions. 
 
 
The listed black box warning include: cardiomyopathy, secondary 
malignancies, 
extravasation 
and 
tissue 
necrosis, 
and 
severe 
myelosuppression.  The most common reported adverse events of 
doxorubicin are nausea, vomiting, and alopecia.  
 
2. 
Pregnancy and Lactation: Pregnancy Category D. Doxorubicin HCl can 
cause fetal harm when administered to a pregnant woman. Doxorubicin 
HCl was teratogenic and embryotoxic in rats and rabbits at doses 
approximately 0.07 times (based on body surface area) the recommended 
human dose of 60 mg/m2. If this drug is used during pregnancy, or if the 
patient becomes pregnant while taking this drug, apprise the patient of the 
potential hazard to a fetus. 
  
Doxorubicin has been detected in the milk of at least one lactating patient.  
Nursing is not recommended while receiving doxorubicin therapy because 
of the potential for adverse events in a nursing child. 
 
3. 
Drug Interactions: Refer to package insert or manufacturer website for the 
most complete and up to date information. 
 
Due to potential drug interactions, a complete patient medication list, 
including doxorubicin, should be screened prior to initiation of doxorubicin.  
Of note, doxorubicin is a substrate for CYP2D6, CYP3A4, and P-
glycoprotein.  
 
d. 
DOSING & ADMINISTRATION 
 
Dosing – See Section 7.0 Treatment Plan 
 
Refer to FDA-approved package insert for drug administration 
 
e. 
STORAGE & STABILITY 
 
Please refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
f. 
HOW SUPPLIED 
 
Doxorubicin is commercially available and will not be supplied. Please refer to the 
current FDA-approved package insert for additional information. 

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3.4 
Dacarbazine (NSC- 45388) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Dacarbazine is an alkylating agent which is converted to the 
active 
alkylating 
metabolite 
MTIC 
[(methyl-triazene-1-yl)-imidazole-4-
carboxamide] via the cytochrome P450 system. MTIC alkylates DNA leading to 
DNA double strand breaks and apoptosis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Distribution: Exceeds total body water; suggesting binding to some tissue 
(probably liver) 
 
2. 
Metabolism: Extensively hepatic to the active metabolite MTIC [(methyl-
triazene-1-yl)-imidazole-4-carboxamide]  
 
3. 
Elimination: Half-life elimination is biphasic. Initial: 19 minutes, 55 minutes 
(renal and hepatic dysfunction); Terminal: 5 hours, 7.2 hours (renal and 
hepatic dysfunction). Excreted in the urine (~40%, as unchanged drug) 
 
c. 
ADVERSE EFFECTS 
 
1. 
Possible Side Effects of Dacarbazine: 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Adverse effects reported in > 20% of subjects treated with dacarbazine 
include: hypotension, headache, nausea, vomiting, anorexia, muscle 
weakness, flu-like symptoms, alopecia. 
 
Adverse effects reported in 4% to 20% of subjects include: cerebral 
hemorrhage, seizure, venous thromboembolism, infection, bone marrow 
depression, anemia, increased liver enzymes, anaphylaxis, infusion-site 
pain. 
 
Serious adverse effects reported in ≤ 3% of subjects include: skin 
photosensitivity. 
 
2. 
Pregnancy and Lactation: Studies have demonstrated dacarbazine to be 
carcinogenic and/or teratogenic when used in animals. Women of 
reproductive potential should avoid becoming pregnant during treatment.  
 
It is not known if dacarbazine is present in breast milk. Due to the potential 
for serious adverse reactions in the breasted infant, a decision should be 
made to discontinue dacarbazine or to discontinue breastfeeding.  
 
3. 
Drug Interactions: Dacarbazine is a major substrate of CYP1A2 and a 
minor substrate of CYP2E1. 
 
Due to potential drug interactions, a complete patient medication list, 
including dacarbazine, should be screened prior to initiation of and during 
treatment with dacarbazine. See Section 8.0 Toxicities to be Monitored 
and Dosage Modifications.  
 
d. 
DOSING & ADMINISTRATION 
 

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Dosing – See Section 7.0 Treatment Plan 
 
Refer to FDA-approved package insert for drug administration 
 
 

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e. 
STORAGE & STABILITY 
 
Please refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
 
f. 
HOW SUPPLIED 
 
Dacarbazine is commercially available and will not be supplied. Please refer to the 
current FDA-approved package insert for additional information. 
 
3.5 
Vinblastine sulfate (NSC- 49842)  
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Vinblastine sulfate is an alkaloidal antineoplastic agent that 
inhibits microtubule formation in the mitotic spindle resulting in an arrest of dividing 
cells at the metaphase stage. It may also interfere in cell-energy production in 
mitosis and nucleic acid synthesis. 
 
b. 
PHARMACOKINETICS 
 
1. 
Distribution: Volume of distribution: 70% of body weight. Protein binding: 
98 - 99.7%. Vinblastine blinds extensively to tissues. It does not penetrate 
CNS or other fatty tissues.  
 
2. 
Metabolism: Vinblastine sulfate is metabolized by hepatic cytochrome 
P450 isoenzymes in the CYP 3A subfamily to an active metabolite, 
deacetylvinblastine. 
 
3. 
Elimination: After rapid IV administration, a triphasic serum decay pattern 
followed.  The respective half-lives were 3-7 minutes, 1.6 hours, and 24.8 
hours. About 13.6 to 23.3% of the administered dose was excreted in urine 
and 10% in the feces, the remaining activity was not accounted for.  
 
c. 
ADVERSE EFFECTS 
 
1. 
Possible Side Effects of vinblastine 
 
Refer to the current FDA-approved package insert for the most 
comprehensive and up to date information on adverse reactions. 
 
Commonly reported adverse events include: myelosuppression, diarrhea 
or constipation, and peripheral neuropathy (e.g. jaw pain). 
 
CAUTION: Vinblastine sulfate injection is for intravenous use only. The 
intrathecal administration of vinblastine, a vesicant, can results in death. 
Syringes containing vinblastine sulfate should be labeled, “FATAL IF 
GIVEN INTRATHECALLY. FOR INTRAVENOUSLY USE ONLY.”  
 
2. 
Pregnancy and Lactation: Pregnancy category D Information on the use 
of vinblastine sulfate during human pregnancy is very limited. Animal 
studies suggest that teratogenic effects may occur. Women of childbearing 
potential should be advised to avoid becoming pregnant. 
 
Aspermia has been reported in man. Animal studies show metaphase 
arrest and degenerative changes in germ cells.  
 

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It is not known whether vinblastine is excreted in human milk. Because 
many drugs are excreted in human milk and because of the potential for 
serious adverse reactions from vinblastine sulfate in nursing infants, a 
decision should be made whether  
 
3. 
Drug Interactions: 
 
Refer to the current FDA-approved package insert. 
 
Concurrent oral or intravenous administration of phenytoin and 
antineoplastic chemotherapy combinations that included vinblastine 
sulfate has been reported to have reduced blood levels of the 
anticonvulsant and to have increase seizure activity. The contribution of 
vinblastine sulfate to this interaction is not certain. Dosing adjustment of 
phenytoin should be based on serial blood level monitoring. 
 
Caution should be exercised in patients concurrently taking drugs known to 
inhibit drug metabolism by hepatic cytochrome P450 isoenzymes in the 
CYP3A subfamily, or in patients with hepatic dysfunction. An earlier onset 
and/or an increased severity of side effects of vinblastine can occur.  
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan. 
 
2. 
Refer to FDA-approved package insert for drug administration. 
 
e. 
STORAGE & STABILITY 
 
Please refer to the current FDA-approved package insert for storage, stability and 
special handling information. 
 
 
f. 
HOW SUPPLIED 
 
Vinblastine sulfate is commercially available and will not be supplied. Please refer 
to the current FDA-approved package insert for additional information. 
 
3.6 
Filgrastim (r-metHuG-CSF) (Neupogen®) (NSC 614629) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Filgrastim stimulates the production, maturation, and 
activation of neutrophils; filgrastim activates neutrophils to increase both their 
migration and cytotoxicity. 
 
b. 
PHARMACOKINETICS 
 
1. 
Absorption: First-order pharmacokinetic modeling with maximum serum 
concentration reached within 2 to 8 hours after subcutaneous injection. 
 
2. 
Distribution: Average Vd 150 mL/kg. 
 
3. 
Metabolism: Unknown. 
 
4. 
Elimination:  Renal and neutrophil receptor-mediated, elimination half-life 
is approximately 3.5 hours. 
 
 

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c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Filgrastim: Refer to the current FDA-approved 
package insert for the most comprehensive and up to date information on 
adverse reactions. 
 
Most frequent adverse reactions reported are skeletal pain (> 20%). 
 
2. 
Pregnancy and Lactation: Category C, filgrastim should be used during 
pregnancy only if the potential benefit justifies the potential risk to the 
fetus.  Animal studies have demonstrated adverse effects and fetal loss.  
Filgrastim has been shown to cross the placenta in humans.  There are no 
adequate and well-controlled studies in pregnant women. Excretion in 
breast milk unknown/use caution. 
 
3. 
Drug Interactions: Drug interactions between filgrastim and other drugs 
have not been fully evaluated.  Drugs which may potentiate the release of 
neutrophils‚ such as lithium‚ should be used with caution. 
 
Increased hematopoietic activity of the bone marrow in response to growth 
factor   therapy has been associated with transient positive bone-imaging 
changes. This should be considered when interpreting bone-imaging 
results. 
 
Filgrastim should not be administered on the same day with anticancer 
chemotherapeutic agent(s) with leukocyte suppressive properties.  
 
Filgrastim is contraindicated in patients with hypersensitivity to E.coli-
derived proteins, filgrastim, or any component of the product. 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan.  
 
2. 
Refer to the current FDA-approved package insert for drug administration.  
 
e. 
STORAGE & STABILITY 
 
Refer to the current FDA-approved package insert for storage, stability and special 
handling information. 
 
f. 
HOW SUPPLIED  
 
Filgrastim is commercially available and will not be supplied. Refer to the current 
FDA-approved package insert. 
 
3.7 
Pegfilgrastim (Neulasta™) (NSC 725961) 
 
a. 
PHARMACOLOGY 
 
Mechanism of Action: Similar to filgrastim, pegfilgrastim is a colony-stimulating 
factor that acts on hematopoietic cells by binding to specific cell surface receptors, 
thereby stimulating proliferation, differentiation, commitment, and end-cell 
functional activation. Studies on cellular proliferation, receptor binding, and 
neutrophil function demonstrate that filgrastim and pegfilgrastim have the same 
mechanism of action. 
 

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b. 
PHARMACOKINETICS 
 
1. 
Absorption: Similar to filgrastim, first-order pharmacokinetic modeling is 
expected with maximum serum concentration reached within 2 to 8 hours 
after subcutaneous injection. 
 
2. 
Distribution: Similar to filgrastim, volume of distribution of averaged at 150 
mL/kg. 
 
3. 
Metabolism: Unknown. 
 
4. 
Elimination:  Neutrophil receptor binding is an important component of the 
clearance of pegfilgrastim, and serum clearance is directly related to the 
number of neutrophils. Pegfilgrastim has reduced renal clearance and 
prolonged persistence in vivo as compared with filgrastim. The half-life of 
pegfilgrastim ranges from 15 to 80 hours after subcutaneous injection. 
 
c. 
ADVERSE EFFECTS  
 
1. 
Possible Side Effects of Pegfilgrastim: Refer to the current FDA-approved 
package insert for the most comprehensive and up to date information on 
adverse reactions. Most frequent adverse reactions are skeletal pain (< 
20%). 
 
2. 
Pregnancy and Lactation: Category C, pegfilgrastim should be used during 
pregnancy only if the potential benefit justifies the potential risk to the 
fetus.  Animal studies have demonstrated adverse effects and fetal loss.  
Pegfilgrastim has been shown to cross the placenta in humans.  There are 
no adequate and well-controlled studies in pregnant women. Excretion in 
breast milk unknown/use caution. 
 
3. 
Drug Interactions: Drug interactions between filgrastim and other drugs 
have not been fully evaluated.  Drugs such as lithium may potentiate the 
release of neutrophils; ensure that patients receiving lithium and 
pegfilgrastim have more frequent monitoring of neutrophil counts. 
Pegfilgrastim should not be administered on the same day with anticancer 
chemotherapeutic agent(s) with leukocyte suppressive properties.  
Pegfilgrastim is contraindicated in patients with hypersensitivity to E.coli-
derived proteins, filgrastim, or any component of the product 
 
d. 
DOSING & ADMINISTRATION 
 
1. 
Dosing – See Section 7.0 Treatment Plan.  
 
2. 
Refer to the current FDA-approved package insert for drug administration.  
 
e. 
PREPARATION, STORAGE & STABILITY 
 
Refer to the current FDA-approved package insert for storage, stability and special 
handling information. 
 
f. 
HOW SUPPLIED  
 
Pegfilgrastim is commercially available and will not be supplied. Refer to the 
current FDA-approved package insert. 
 
 

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4.0 
STAGING CRITERIA 
 
4.1 
Diagnostic Criteria 
The Ann Arbor staging criteria will be used. Stage is based on extent of disease at the time 
of diagnosis. Only patients with Stage III or IV disease are eligible for this protocol. 
 
4.2 
Staging Criteria 
 
STAGE III  
Involvement of lymph node regions on both sides of the diaphragm (III), 
which may be accompanied by localized involvement of an associated 
extralymphatic organ or site (IIIE) or spleen (IIIS) or both (IIISE). 
 
STAGE IV  
Diffuse or disseminated involvement of one or more extra lymphatic 
organs with or without associated lymph node involvement, or isolated 
extralymphatic organ involvement with distant (non-regional) nodal 
involvement). 
 
International Prognostic Score (IPS) (95) 
 
The IPS, developed by Hansclever and colleagues, assesses the total score of several 
individual risk factors (each assigned a value of 1 point) present in a patient. The IPS score 
is associated with prognosis following standard therapy for HL.  A total score of 0 
represents the most favorable risk with increasing scores associated with lower freedom 
from progression and survival. 
 
Age 
≥ 45 years 
Gender 
Male 
Stage 
IV   
Note:  Stage IV is defined as diffuse or disseminated 
involvement of one or more extra lymphatic organs or tissues, 
with or without associated lymph node involvement. 
Hemoglobin 
< 105 g/L 
Albumin, serum < 40 g/L 
WBC 
≥ 15.0 x 109/L 
Lymphocytes 
Count < 0.6 x 109/L or percent < 8% of WBC 
 
 
 

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5.0 
ELIGIBILITY CRITERIA 
 
Each of the criteria in the following section must be met in order for a patient to be considered 
eligible for registration.  For each criterion requiring test results and dates, please record this 
information on the Onstudy Form and submit via Medidata Rave® (see Section 14.0).  Any potential 
eligibility issues should be addressed to the SWOG Statistics and Data Management Center in 
Seattle at 206/652-2267 or lymphomaquestion@crab.org prior to registration. NCI policy does not 
allow for waiver of any eligibility criterion  
(http://ctep.cancer.gov/protocolDevelopment/policies_deviations.htm). 
 
In calculating days of tests and measurements, the day a test or measurement is done is 
considered Day 0.  Therefore, if a test is done on a Monday, the Monday 4 weeks later would be 
considered Day 28.  This allows for efficient patient scheduling without exceeding the guidelines.  
If Day 14, 28 or 42 falls on a weekend or holiday, the limit may be extended to the next 
working day. 
 
5.1 
Disease Related Criteria 
 
a. 
All patients must have histologically confirmed newly diagnosed, previously 
untreated Stage III or IV classical Hodgkin lymphoma (nodular sclerosing, mixed 
cellularity, lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified 
(NOS)).  Nodular lymphocyte predominant Hodgkin Lymphoma is not eligible.  
 
b. 
Patients must have bidimensionally measurable disease (at least one lesion with 
longest diameter ≥ 1.5 cm) documented on the Lymphoma Baseline Tumor 
Assessment Form in Rave. 
 
c. 
Patients must have a whole body or limited whole body PET-CT scan performed 
within 42 days prior to registration. (A contrast-enhanced (diagnostic) CT, MRI or 
MR-PET is acceptable in event that PET-CT is contra-indicated, however if it is 
later possible to administer a PET-CT, then PET-CT is strongly preferred for the 
interim scan (after Cycle 2) (if performed) and the EOT assessment. Otherwise, if 
PET-CT is not subsequently possible, then the same modality as baseline must be 
used throughout the trial.)  NOTE: All images from PET-CT, CT, MRI or MR-PET 
scans performed as standard of care to assess disease (within 42 days prior to 
registration) must be submitted as indicated in Section 15.4 and associated 
radiology reports must be submitted as indicated in Section 14.4a. 
 
5.2 
Age criteria: Patients must be ≥ 12 years of age. 
 
5.3 
Prior/Concurrent Therapy Criteria 
 
a. 
Patients must not have received any prior chemotherapy, radiation, or antibody-
based treatment for classical Hodgkin lymphoma. Steroid pre-treatment is 
permitted as outlined in Section 5.4k 
 
b. 
Patients must not have had prior solid organ transplant. 
 
c. 
Patients must not have had prior allogeneic stem cell transplantation. 
 
d. 
Patients must not have received a live vaccine within 30 days prior to planned Day 
1 of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies, 
BCG, oral polio vaccine, and oral typhoid). 
 
 

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e. 
At registration, investigator must declare intent-to-treat with Residual PET 
Radiation Therapy  (Residual PET RT- RPRT) to be administered after patient 
completes 6 cycles of therapy if, after end of treatment, the patient meets 
criteria specified in Section 7.5 for receiving RT). Patients will be stratified by 
investigator’s intent-to-treat with Residual PET RT. 
x 
All pediatric patients (< 18 years of age) will be considered intent-to-treat 
with Residual PET RT at time of registration. 
 
5.4 
Clinical/Laboratory Criteria 
 
Please note that eligibility criteria and the timing of documentation prior to 
registration differ by age. 
 
a. 
Patients must have a performance status corresponding to Zubrod scores of 0, 1 
or 2. Use Lansky for patients ≤ 17 years of age. *The conversion of the Lansky to 
ECOG scales is intended for NCI reporting purposes only. See Sections 10.3 and 
18.4. 
 
b. 
Patients must have adequate renal function as indicated below: 
 
Adults (age 18 or older):  
 
x 
Creatinine clearance ≥ 30 mL/min, as estimated by the Cockcroft and 
Gault formula. The creatinine value used in the calculation must have been 
obtained within 28 days prior to to registration. Estimated creatinine 
clearance is based on actual body weight. 
 
Estimated creatinine clearance =       (140 - age) x weight in kg † 
72 x creatinine* (mg/dl) 
 
Multiply this number by 0.85 if the participant is a female.  
 
† 
The kilogram weight is the participant weight with an upper limit of 
140% of the ideal body weight (IBW). 
* 
Actual lab serum creatinine value with a minimum of 0.7 mg/dL. 
 
Pediatric Patients (age 12-17): 
 
The following must have been obtained within 14 days prior to registration:  
 
x 
Measured or calculated* creatinine clearance or radioisotope GFR   ≥ 70 
ml/min/1.73 m2, or  
 
x 
Serum creatinine ≤ 1.5 x institutional upper limit of normal (IULN), or a 
serum creatinine based on age/gender as follows:  
 
Age 
Maximum Serum Creatinine (mg/dL) 
 
Male 
Female 
 < 13 years 
1.2 
1.2 
13 to < 16 years 
1.5 
1.4 
16 -17 years 
1.7 
1.4 
The threshold creatinine values in this Table were derived from the 
Schwartz formula for estimating GFR (96) utilizing child length and stature 
data published by the CDC. 
*calculated based on institutional standard 
 

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c. 
Patients must have adequate hepatic function, evidenced by the following*:  
x 
Total bilirubin ≤ 2 x IULN, and  
x 
AST and ALT ≤ 3 x IULN  
* unless due to Gilbert’s disease, lymphomatous involvement of liver or 
vanishing bile duct syndrome 
 
For adults (age 18 or older), above hepatic function must be documented 
within 28 days prior to registration.  
 
For pediatric Patients (age 12-17), above hepatic function must be 
documented within 14 days prior to registration. 
 
d. 
Patients must have adequate cardiac function defined as follows: 
 
Patients must have an echocardiogram (ECHO),  MUGA, or functional cardiac 
imaging scan with a left ventricular ejection (LVEF) fraction ≥ 50% or a shortening 
fraction of t 27%. For all patients, the ECHO, MUGA, or functional cardiac 
imaging scan must be performed within 42 days prior to registration. 
 
e. 
Patients with known human immunodeficiency virus (HIV) infection must be 
receiving anti-retroviral therapy and have an undetectable or unquantifiable viral 
load at their most recent viral load test within 6 months prior to registration. 
 
f. 
Patients must not have known active Hepatitis B (HBV) or Hepatitis C Virus (HCV) 
at date of registration. Patients with previously treated HBV or HCV that have an 
undetectable viral load within 6 months prior to registration and no residual hepatic 
impairment are eligible.  
 
g. 
Patients must not have any known central nervous system lymphoma. 
 
h. 
Patients must not have a history of or active interstitial pneumonitis or interstitial 
lung disease. 
 
i. 
Patients must not have had a diagnosis of inherited or acquired immunodeficiency 
(unless allowed under Section 5.4e). 
 
j. 
Patients must not have any known uncontrolled intercurrent illness including, but 
not limited to symptomatic congestive heart failure, unstable angina pectoris, 
hemodynamically unstable cardiac arrhythmia, or psychiatric illness/social 
situations that would limit compliance with study requirements.  
 
k. 
Patients must not have a condition requiring systemic treatment with either 
corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive 
medications within 14 days prior to registration. Inhaled or topical steroids, and 
adrenal replacement doses >10 mg daily prednisone equivalents are permitted in 
the absence of active autoimmune disease. Steroid use for the control of Hodgkin 
lymphoma symptoms is allowable, but must be discontinued prior to Cycle1, Day1. 
 
l. 
Patients with peripheral neuropathy must have < Grade 2 at date of registration. 
 
 

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m. 
Patients must not have active autoimmune disease that has required systemic 
treatment in past 2 years (i.e., with use of disease modifying agents, 
immunosuppressive drugs, or corticosteroids with doses higher than prednisone 
10 mg or equivalent). Autoimmune diseases include but are not limited to 
autoimmune hepatitis, inflammatory bowel disease (including ulcerative colitis and 
Crohn’s disease), as well as symptomatic disease (e.g.: rheumatoid arthritis, 
systemic progressive sclerosis [scleroderma], systemic lupus erythematosus, 
autoimmune vasculitis [e.g., Wegener’s Granulomatosis]); CNS or motor 
neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and 
Myasthenia Gravis, multiple sclerosis or glomerulonephritis). Vitiligo, alopecia, 
hypothyroidism on stable doses of thyroid replacement therapy, psoriasis not 
requiring systemic therapy within the past 2 years are permitted. 
 
n. 
No second prior malignancy is allowed except for adequately treated basal (or 
squamous cell) skin cancer, any in situ cancer or other cancer for which the patient 
has been disease free for two years. 
 
o. 
Females of childbearing potential must not be pregnant or nursing, and have a 
negative pregnancy test within 28 days prior to registration. Women/men of 
reproductive potential must have agreed to use an effective contraceptive method 
while receiving study drug and for women until 6 months after receiving the last 
dose of study drug or, for men, until 7 months after receiving the last dose of study 
drug.  A woman is considered to be of "reproductive potential" if she has had 
menses at any time in the preceding 12 consecutive months.  In addition to routine 
contraceptive methods, "effective contraception" also includes heterosexual 
celibacy and surgery intended to prevent pregnancy (or with a side-effect of 
pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or 
bilateral tubal ligation.  However, if at any point a previously celibate patient 
chooses to become heterosexually active during the time period for use of 
contraceptive measures outlined in the protocol, he/she is responsible for 
beginning contraceptive measures. 
 
5.5 
Specimen Submission Criteria 
 
a. 
Patients must have one formalin-fixed paraffin embedded (FFPE) diagnostic tumor 
block or at least 1 diagnostic, 4-5 micron, H&E slide collected prior to registration 
and available for submission, as outlined in Sections 12.1 and 15.1a. 
 
b. 
Patients must be offered participation in banking for planned translational medicine 
and future research, as outlined in Section 15.2. With patient consent, any 
residuals from the mandatory tissue submission will also be banked for future 
research.  
 
Note: Streck tubes must be ordered in advance, as indicated in Section 
15.2c. Allow 5-7 days for shipment of the collection kits. 
 
5.6 
Patient-reported outcomes and PRO-CTCAE criteria 
 
a. 
Patients who can complete Patient-Reported Outcome instruments in English, 
Spanish, or French must complete the PROMIS Fatigue, the FACT/GOG-Ntx, and 
the PROMIS Global prior to registration. Patients who do not complete PRO 
instruments prior to registration but are otherwise eligible will remain 
eligible for the primary analysis and other secondary analyses. 
 
b. 
Patients who can complete Patient-Reported Outcome instruments in English, 
Spanish, or French must also agree to complete the PROMIS Fatigue, the 

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FACT/GOG-Ntx, the PROMIS Global, and the PRO-CTCAE (or Ped PRO-CTCAE) 
at the scheduled on-study assessment timepoints. 
 
5.7 
Regulatory Criteria 
 
a. 
Patients must be informed of the investigational nature of this study and all 
patients and/or their parents or legal guardians (for patients <18 years of age) must 
sign and give informed consent and assent (where appropriate) in accordance with 
institutional and federal guidelines. For participants with impaired decision-making 
capabilities, legally authorized representatives may sign and give informed 
consent on behalf of study participants in accordance with applicable federal, local, 
and CIRB regulations. 
 
Note: As a part of the OPEN registration process (see Section 13.4 for OPEN access 
instructions) the treating institution's identity is provided in order to ensure that the 
current (within 365 days) date of institutional review board approval for this study has been 
entered in the system. 
 
 
6.0 
STRATIFICATION FACTORS 
 
Patients will be randomized between Arm 1 – nivolumab + AVD and Arm 2 – brentuximab vedotin 
+ AVD in a 1:1 fashion using a randomized dynamic balancing algorithm with stratification based 
on: 
 
a. 
Age (years): age 12-17 vs. age 18-60 vs. age > 60 
 
b. 
International prognostic score: 0-3 vs. 4-7 
 
c. 
Pre-specified plan to use Residual PET Radiation Therapy (Residual PET RT)*: 
yes vs. no 
* See Section 7.5.   
 
 
7.0 
TREATMENT PLAN 
 
For treatment or dose modification questions, please contact:  
 
x 
Adults: E-mail: S1826USAdults@swog.org or call: Dr. Alex Herrera (SWOG) at Phone: 
626/256-4673 ext. 62405 or Dr. Sarah Rutherford (Alliance) at Phone: 646/962-2064 
or Dr. Andrew Evens (ECOG-ACRIN) at Phone: 732-235-9289. 
 
x 
Pediatrics: E-mail: S1826pediatrics@swog.org  or call: Dr. Sharon Castellino at Phone: 
404/785-3616 or Dr. Angela Punnett at: Phone: 416/813-5394. 
 
x 
CCTG Adults: Dr. Kelly Davison at: E-mail: kelly.davison@mcgill.ca  or Phone: 
514/934-1934, ext 31558. Dr. Michael Crump at: Michael.Crump@uhn.ca or Phone: 
416/946-4567.   
For dosing principles or questions, please consult the SWOG Policy #38 "Dosing Principles for 
Patients on Clinical Trials" at https://www.swog.org/sites/default/files/docs/2017-11/Policy38.pdf. 
 
Initiation of treatment must be planned to start no more than 14 calendar days after registration.   
 
 

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7.1 
General Treatment Information  
 
a. 
Treatment Plan Overview 
 
This is a multicenter, randomized, open-label Phase III clinical trial for participants 
with previously untreated advanced stage (III-IV) classical Hodgkin lymphoma.  
 
Once a patient meets eligibility criteria, the patient will be randomized to either Arm 
1 (N+AVD) or Arm 2 (BV+AVD).  
 
The planned therapy duration is 6 x 28 day cycles, with study treatment 
administered on Days 1 and 15 of each cycle. See Section 7.3 below for specific 
details about treatment regimen for each arm.   
 
b. 
Guidance for trial conduct during the COVID-19 pandemic (and other extenuating 
circumstances) 
 
1. 
In order to provide participating sites flexibility in treatment participant 
population, it is the intent of the S1826 protocol to allow for laboratory and 
imaging assessments to be drawn and resulted by local healthcare 
providers (with appropriate oversight by the Responsible Investigator 
(local treating investigator)), where administration of the assessment at an 
off-site facility is in the best interest of the patient and provides for 
continuity of patient care. Utilization of offsite / local healthcare resources 
for conduct of participant’s laboratory and imaging assessments does not 
need to be documented as a deviation due to COVID-19 pandemic or 
other extenuating circumstances, however participating sites must 
document procedures for oversight (by the Responsible Investigator) of 
assessments performed offsite. 
 
2. 
In addition to continuity of care options above, follow-up visits may also be 
delayed if in the judgment of the Responsible Investigator the benefit of 
delay of a visit outweighs the risks of exposure of the patient to the virus 
by coming in for an in-person visit and an alternative method (phone or 
virtual visit) is not possible.  
 
3. 
Participating sites are requested to carefully consider each participant’s 
ability to come into the clinic for planned treatments (with respect to the 
local COVID-19 situation) prior to enrollment.  Every effort should be made 
to avoid treatment delays. 
 
a. Since S1826 is conducted under an IND, nivolumab must be 
administered at an approved/NCI-registered site participating in the 
S1826 protocol.  Total treatment delays (of all components of the study 
regimen) of up to 4 weeks / 28 days are allowable per protocol, with 
documented reason for delay. Total treatment delays (of all 
components of a study regimen) of longer than 4 weeks (for any 
reason) will require the patient to be removed from protocol treatment 
permanently (Section 7.8).  
 
b. For patients declared at time of registration as intent-to-treat with 
residual PET radiation therapy (RPRT), the EOT PET-CT scan must 
be submitted for review and approval by IROC RI one week prior to 
the planned start of RPRT. RPRT may not begin until subsequent 
IROC RI review and approval (See protocol Sections 12.3 and 7.5b). 
 

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c. FFPE diagnostic tumor tissue is required per protocol and must be 
submitted to the SWOG Biospecimen Bank, as indicated in protocol 
Section 15.1.  
 
d. PRO (QOL and PRO-CTCAE) assessments are required at applicable 
timepoints. Please see Sections 15.5c.4 and 15.6c.5 for instructions 
on questionnaire administration via phone (with provision of a copy via 
email or mail) in event that COVID-19 extenuating circumstances 
preclude on-site administration of the questionnaires within the 
protocol allowable windows. Assessments completed via phone or 
telehealth (videoconference) visits must still be submitted within 
allowable windows at time of collection. See Section 14.4.  
 
e. Following are extended windows for protocol assessments in event of 
a COVID-19 or related extenuating circumstance. The Responsible 
Investigator rationale for utilization of the extended windows outlined 
below must be carefully documented in the patient chart as resultant 
from the COVID-19 pandemic and extenuating circumstance. Please 
note the allowable windows indicated in Sections 7.5, 9.0, and 15.0 
remain applicable for all patients, where there is not a COVID-19 
pandemic-related extenuating circumstance.                
 
4. 
Extended Radiation Therapy window 
 
A pause of RT timing beyond the allowable 72 hours specified in Section 
7.5a.2 due to COVID-19 extenuating circumstances, or the need to stop 
RT in a patient due to COVID-19 positive status are permitted at the 
discretion of the investigator. Variances due to COVID-19 extenuating 
circumstances or patient’s COVID-19-positive status must be thoroughly 
documented and discussed with the S1826 Study Chairs and Radiation 
Oncology Chair for guidance. Contact the study-specific email listed on 
the S1826 Protocol Contact Information page.  
 
5. 
Extended window for peripheral blood sample collection 
 
To provide additional flexibility, the best practices window for the Cycle 3, 
Day 1  peripheral blood sample collection is being extended to +/- 14 days, 
and the window for the End of Cycle 6 (or time of off-protocol) and Time 
of Progression peripheral blood sample collection is being extended to +/-
30 days. See Section 15.2. 
 
6. 
Extended window for patient follow-up in event of COVID-19 or related 
extenuating circumstances  
 
To provide additional flexibility, the best practices windows for follow-up 
visits (both prior to and after progression), which are to occur every 3 
months for the first year, then every 6 months for the second and third 
years, and then annually until 10 years from the date of registration, are 
being extended to +/- 30 days, where the Responsible Investigator 
determines that the delayed assessment helps to assure the safety of the 
patient, with consideration for the COVID-19 pandemic and related 
extenuating circumstances. 
 
 
 
 

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Off-treatment follow-up CT scans should be conducted as close to the 
protocol timepoint as is reasonably possible, in the judgment of the 
Responsible Investigator.  
 
To provide additional flexibility, the best practices window for follow-up CT 
scans at 12- and 24-months after time of registration, is being extended 
+/- 90 days, where the Responsible Investigator determines that the 
delayed assessment helps to assure the safety of the patient, with 
consideration for the COVID-19 pandemic and related extenuating 
circumstances. 
 
7.2 
Pre-medication, Concomitant Therapy, and Supportive Care Guidelines 
 
a. 
Pre-medication: Pre-medications including antiemetics and steroids can be 
administered per institutional practice. 
 
b. 
Concomitant Therapy 
 
1. 
Required concomitant medications: 
The use of granulocyte-colony stimulating factor (G-CSF) is required for 
patients receiving BV + AVD.  G-CSF is optional for patients receiving N + 
AVD. See Section 7.3 for G-CSF dose and scheduling. 
 
2. 
Permitted concomitant medications: 
Dexrazoxane use is allowed concomitant with doxorubicin as a cardiac 
protectant per investigator choice and must be captured on study CRFs if 
used. Since there may be an increased risk of typhlitis associated with 
myelosuppression with the use of dexrazoxane, treating investigators are 
cautioned that evaluation for typhlitis should be kept in mind for patients 
presenting with severe abdominal pain. 
 
The use of topical, inhalational and ophthalmic steroids is permitted. 
Corticosteroids are permitted as part of a chemotherapy premedication 
regimen per institutional standards. In addition, a brief course of 
corticosteroids for prophylaxis (e.g,: contrast dye allergy) or for treatment 
of non-autoimmune conditions (e.g,: delayed-type hypersensitivity 
reaction caused by contact allergen) is permitted. 
 
Patients may receive hormonal contraceptives. 
 
 

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3. 
Prohibited concomitant medications:  
x 
Any investigational agents other than nivolumab. 
x 
Any concurrent antineoplastic therapy other than AVD, brentuximab 
vedotin, or nivolumab (i.e.: chemotherapy, hormonal therapy, 
immunotherapy, radiation therapy except for those subjects planned 
to receive radiation as specified in Section 7.5). 
x 
Immunosuppressive agents (except to treat a drug-related AE). 
x 
Systemic corticosteroids (defined as equivalent to > 10 mg daily 
prednisone) except as pre-medications, antiemetics, for prophylaxis, 
or treatment of non-autoimmune conditions for brief course as noted 
in preceding section, and as stated in Section 18.3 to treat a drug-
related AE).   
x 
Replacement therapy (e.g., thyroxine, insulin, or physiologic 
corticosteroid 
replacement 
therapy 
for 
adrenal 
or 
pituitary 
insufficiency, etc.) is not considered a form of systemic treatment. 
Short-term steroid premedication for contrast allergy is also permitted.  
x 
Use of ritonavir or HIV therapy that uses pharmacologic boosters,  
such as cobicistat in the control arm for HIV+ patients or HIV, is 
prohibited. 
 
4. 
Cautionary concomitant medications:  
x 
The use of strong inhibitors or inducers of CYP1A2 (dacarbazine 
interaction) or CYP3A4 (doxorubicin, brentuximab vedotin, vinblastine 
interactions) should be avoided.   See Section 18.9. 
x 
Multiple CYP3A4 interacting agents of moderate or strong effect in the 
HIV+ patients should not be used.  This includes most HIV protease 
inhibitors.   
 
c. 
Supportive Care Guidelines 
 
1. 
Infusion-related reactions: 
 
All infusions should be administered at a site properly equipped and 
staffed for anaphylaxis should it occur.  
 
Medications for treatment of hypersensitivity reactions, such as 
epinephrine, antihistamines, and steroids, should be available for 
immediate use in the event of a reaction during administration.  
 
See Section 8.2c.2 for dose modification guidelines. 
 
2. 
Nausea and/or vomiting: 
 
Although the study does not require prophylactic antiemetics, there is no 
prohibition against their use. Treating investigators should follow 
institutional guidelines for administration of antiemetics. 
 
3. 
Suspected Progressive Multifocal Leukoencephalopathy (PML):  
 
Signs and symptoms of PML may include altered mental status; motor 
deficits, such as hemiparesis or ataxia; visual disturbances; or higher 
cortical dysfunction, such as dysphasia or agnosia. Seizures have also 
been reported in patients with PML (approximately 20%). The onset of 
neurological deficits may occur over weeks to months.  
 
See Section 8.2b for dose modification guidelines. 
 

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4. 
Suspected immune reaction to nivolumab:  
 
See Section 8.2c.2 for dose modification guidelines and Section 18.3 for 
detailed algorithms for Immuno-Oncology management of the following 
groups of AEs: 
 
x 
Gastrointestinal 
x 
Renal 
x 
Pulmonary 
x 
Hepatic 
x 
Endocrinopathies 
x 
Skin 
x 
Neurological 
 
5. 
Antimicrobial prophylaxis 
 
Pneumocystis pneumonia (PCP) is known to occur in patients with 
compromised immune systems and has been reported in patients 
receiving ABVD-based therapy, including BV+AVD. PCP prophylaxis 
should be considered at the discretion of the treating investigator for both 
arms, particularly in patients treated on Arm 2 (BV+AVD). 
 
Antimicrobial prophylaxis (such as fluconazole, acyclovir, levofloxacin) is 
allowed at the discretion of the treating investigator and should be 
administered per standard of care and institutional procedures. 
 
6. 
Additional monitoring recommended for patients with pericardial effusion 
at time of registration 
 
It has been noted that exacerbation of pericardial effusion/pericarditis may 
occur in patients with a pre-existing pericardial effusion. Treating 
investigators should carefully monitor patients who have pericardial 
effusion at time of enrollment for worsening pericardial effusion and for 
pericarditis. 
 
Pericarditis adverse events can be managed according to the “Other 
treatment-related adverse events” category specified at the end of the 
dose modifications table in Section 8.2c.2. 
 
 

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7.3 
Protocol Treatment 
a. 
Arm 1 – Nivolumab + AVD a 
AGENT  
Age/Weight 
DOSE 
ROUTE 
DAY 
SCHEDULE 
a, b, c 
Doxorubicin d, g, h 
All patients 
25 mg/m2 
IV 
Days 1 
and 15 
Every cycle 
x 6 cycles 
Vinblastine d, h 
All patients 
6 mg/m2 
IV 
Days 1 
and 15 
Every cycle 
x 6 cycles 
Dacarbazine d, h 
All patients 
375 mg/m2 
IV 
Days 1 
and 15 
Every cycle 
x 6 cycles 
Nivolumab e 
Age 18  
or older 
240 mg 
IV 
Days 1 
and 15 
Every cycle 
x 6 cycles 
Nivolumab e, h 
Age 12-17 f 
3 mg/kg (up to 
240 mg max) 
IV 
Days 1 
and 15 
Every cycle 
x 6 cycles 
a N-AVD combination therapy should be administered after all procedures and 
assessments have been completed. Treatment may be administered up to 3 days before 
or after the protocol-specified days due to administrative reasons. Treatment delay (≤ 4 
weeks) or dose reduction due to adverse events/toxicity is allowed, as indicated in 
Sections 8.2a and 8.2c. 
b  One cycle = 28 days. 
c  G-CSF administration is allowable, in accordance with institutional procedure.  
x If G-CSF is given, it should begin no sooner than 24 hours after completion of 
chemotherapy. 
x Pegfilgrastim:  
x For adult patients and pediatric patients ≥ 45kg: 6mg subcutaneously on Days 2 and 
16. (On-body injector kit is allowable).  
x For pediatric patients < 45kg: 0.1 mg/kg subcutaneously on Days 2 and 16 (On-body 
injector kit is allowable) or dose per institutional standards. 
x For all patients: Biosimilars are also allowable. 
x Filgrastim:  
x Suggested to administer 5mcg/kg per day for 5 days (e.g.: Days 6-10 and Days 21-
25) but can be adjusted if more or less is needed, should be no less than 2 days 
between study treatment days, or in accordance with institutional procedure.  
x Filgrastim should be stopped 24 hours prior to Day 15 treatment and may resume 24 
hours after the Day 15 treatment.  
x Biosimilar forms of recombinant filgrastim (tbo-filgrastim or filgrastim-sndz) are 
permitted at institutional discretion. 
d AVD is to be administered prior to nivolumab per institutional guidelines. Administration 
method and sequence of each component of AVD (doxorubicin, vinblastine, and 
dacarbazine) will be according to local and institutional standards.  
e  Nivolumab will be administered after AVD. Nivolumab infusion should start after the 
conclusion of the dacarbazine. Nivolumab will be administered intravenously over 
approximately 30 minutes. 
f  Age at date of registration. Patients who turn 18 while on protocol but do not reach max 
weight, will remain on the 3 mg/kg dose for the duration of protocol treatment. 
g Dexrazoxane use is allowed concomitant with doxorubicin as a cardiac protectant per 
investigator choice and must be captured on the S1826 Concomitant Medication Form, if 
used. See also Section 7.2b.2. 
h  For dosing based upon the patients’ weight, dosing calculations should be based on the 
body surface area (BSA) and calculated using the body weight for the first dose. However, 
if the patient’s weight later changes by ≥ 10% from the previous weight used to calculate 
BSA, then BSA should be recalculated and next dose corrected accordingly. All doses 
should be rounded in accordance with institutional procedure. 
 
Recommended Cardiac Monitoring 
Patients who have evidence of CHF, MI, cardiomyopathy, or myositis cardiac 
evaluation (NYHA I/II) (subsequent to the start of protocol therapy) should have 
additional consult by a cardiologist, including review of EKG, CPK, troponin, 
echocardiogram, as clinically indicated, prior to start of each cycle. 

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b. 
Arm 2 – Brentuximab Vedotin + AVD a 
AGENT 
DOSE 
ROUTE 
DAY 
SCHEDULE a, b 
Doxorubicin  
c, g, h 
25 mg/m2 
IV 
Days 1 
and 15 
Every cycle  
x  6 cycles 
Vinblastine  
c, h 
6 mg/m2 
IV 
Days 1 
and 15 
Every cycle  
x  6 cycles 
Dacarbazine  
c, h 
375 mg/m2 
IV 
Days 1 
and 15 
Every cycle  
x  6 cycles 
Brentuximab 
vedotin d, h  
1.2 mg/kg  
(max dose 120 mg) 
IV 
Days 1 
and 15 
Every cycle  
x  6 cycles 
G-CSF: e, h 
Pegfilgrastim 
OR 
Filgrastim 
 
Pegfilgrastim: 
Adults 
or 
pediatric
patients ≥ 45 kg:  
6 mg  
Pediatric patients  
< 45 kg: 0.1 mg/kg or
dose per institutional 
standards 
OR 
Filgrastim: 
5mcg/kg per day 
Pegfilgra-
stim: 
SubQ 
OR 
Filgrastim: 
SubQ or IV 
* For patients
age 
12-17:
SubQ 
is
preferred.  
Pegfilgra-
stim: 
All patients:  
D2 & D16.  
On-body 
injector kit is 
allowable.  
OR 
Filgrastim: 
See  
Footnote (e) 
Every cycle  
x  6 cycles 
 
See  
Footnote (e) 
a  BV-AVD combination therapy should be administered after all procedures and 
assessments have been completed. Treatment may be administered up to 3 days before 
or after the protocol-specified days due to administrative reasons. Treatment delay (≤ 4 
weeks) or dose reduction due to adverse events/toxicity is allowed, as indicated in 
Sections 8.2a and 8.2d. If BV is discontinued due to toxicity, G-CSF is no longer required. 
b  One cycle = 28 days. 
c AVD is to be administered first per institutional guidelines. Administration method and 
sequence of each component of AVD (doxorubicin, vinblastine, and dacarbazine) will be 
according to local and institutional standards.  
d Brentuximab vedotin is to be administered after AVD. BV infusion should start after the 
conclusion of the dacarbazine. BV will be administered intravenously over approximately 
30 minutes.  
e G-CSF administration is required unless BV is discontinued due to toxicity.  
x Begin G-CSF no sooner than 24 hours after completion of chemotherapy. 
x Pegfilgrastim:  
x For adult patients and pediatric patients ≥ 45kg: 6mg subcutaneously on Days 2 and 
16. (On-body injector kit is allowable).  
x For pediatric patients < 45kg: 0.1 mg/kg subcutaneously on Days 2 and 16 (On-body 
injector kit is allowable) or dose per institutional standards. 
x For all patients: FDA-approved biosimilars are also allowable. 
x Filgrastim:  
x Suggested to administer 5mcg/kg per day for 5 days (e.g.: Days 6-10 and Days 21-
25) but can be adjusted if more or less is needed, should be no less than 2 days 
between study treatment days, or in accordance with institutional procedure.  
x Filgrastim should be stopped 24 hours prior to Day 15 treatment and may resume 24 
hours after the Day 15 treatment.  
x FDA-approved biosimilar forms of recombinant filgrastim (tbo-filgrastim or filgrastim-
sndz) are permitted at institutional discretion. 
g Dexrazoxane use is allowed concomitant with doxorubicin as a cardiac protectant per 
investigator choice and must be captured on the S1826 Concomitant Medication Form, if 
used. See also Section 7.2b.2. 
h  For dosing based upon the patients’ weight, dosing calculations should be based on the 
body surface area (BSA) and calculated using the body weight for the first dose. However, 
if the patient’s weight later changes by >/= 10% from the previous weight used to calculate 
BSA, then BSA should be recalculated and next dose corrected accordingly. For BV, 
actual weight will be used except for patients weighing greater than 100kg; dose will be 
calculated based on 100kg for these individuals. All doses should be rounded in 
accordance with institutional procedure. 

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7.4 
PET-CT response assessment 
 
Primary response assessment by PET-CT must occur 4-8 weeks after the last dose of 
study drug. 
 
Responses will be assessed based on the local radiology review according to the 
2014 Lugano classification using the 5-point Deauville score (See Section 10.1).  
 
Central review of PET scans will not be performed in real time; therefore, therapy should 
proceed as per the initial randomization arm without awaiting central review results. This 
is not PET response adapted therapy. 
 
For patients who do undergo interim PET-CT scanning as part of standard of care testing, 
or because they have been declared eligible for radiation, specific guidelines are provided 
below, pertaining to each study arm about management and decision-making.   
 
a. 
Baseline 
 
Per Section 12.0, unless otherwise contraindicated, patients must receive a 
baseline PET-CT scan.  While a contrast-enhanced (diagnostic) CT, MRI or MR-
PET is acceptable in event that PET-CT is contra-indicated, if it is later possible to 
administer a PET-CT, then PET-CT is strongly preferred for the interim scan (after 
Cycle 2) (if performed) and the EOT assessment. Otherwise, if PET-CT is not 
subsequently possible, then the same modality as baseline must be used 
throughout the trial.   
 
NOTE: All images from PET-CT, CT, MRI or MR-PET scans performed as 
standard of care to assess disease (within 42 days prior to registration) must 
be submitted as indicated in Section 15.4 and associated radiology reports must 
be submitted as indicated in Section 14.4a. 
 
b. 
Interim PET-CT Scans 
 
If PET-CT is contra-indicated at baseline, and it is later possible to administer a 
PET-CT, then PET-CT is strongly preferred for the interim scan (after Cycle 2) (if 
performed) and the EOT assessment. Otherwise, the same modality as baseline 
must be used throughout the trial. 
 
Although it has been a standard of care to perform interim PET-CT scans (e.g. 
after Cycle 2), in patients with HL undergoing initial treatment, S1826 protocol 
treatment is NOT intended to be PET response-adapted therapy.  
 
Since the historical standard indication for radiation use in pediatric patients 
includes criteria regarding interim response, the study team intends to collect 
interim PET-CT data in patients who are declared at time of patient registration as 
intent-to-treat with radiation therapy accordinto to protocol guidelines. Interim PET-
CT data are not intended for use in real-time treatment decision making (see 
Sections 7.4b.1 and 7.4b.2 for guidance on interim PET-CT information according 
to treatment arm). Integrated imaging objectives are planned for incorporation into 
the protocol with a future protocol revision. For this reason, interim PET-CT scans 
are not required per protocol unless the investigator declared (at the time of 
patient registration) intent-to-treat with radiation therapy according to protocol 
guidelines.  
 
For patients who are declared a intent-to-treat with radiation therapy, interim 
PET-CT must be performed after 2 cycles of therapy (Day 53 ± 3 days) and prior 
to start of Cycle 3. Images must be submitted, as indicated in Section 15.3. (See 
also Sections 7.5, and 12.0). The interim PET-CT data will allow future analysis of 
the impact of narrowing the RT indications. 

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1. 
Arm 1: N+AVD 
 
Due to the often indeterminate PET-CT results observed in patients with 
HL treated with PD-1 blockade, N+AVD treatment is not intended to be 
PET-response adapted.  
 
A treatment change based on interim PET-CT in the absence of 
formal disease progression defined in Section 10.1b.4 is not 
recommended and will be considered a protocol violation.  
 
If a therapy switch is planned based on interim scanning (i.e. Deauville 4 
or 5 in the absence of formal disease progression), biopsy confirmation of 
active lymphoma is required to avoid a protocol violation (as long as the 
biopsy is safe/feasible). If biopsy is not feasible, contact the Study Chair 
for guidance. 
 
2. 
Arm 2: BV+AVD 
 
BV+AVD therapy is not intended to be response-adapted, and interim 
PET-CT scanning is not a protocol-specified study activity.   
 
If interim PET-CT is performed and treatment is changed based on interim 
PET-CT results in the absence of disease progression (i.e. Deauville 4 or 
5 in the absence of formal disease progression), this will not be counted 
as an PFS event.  
 
However, if a therapy switch is planned, biopsy confirmation of active 
lymphoma is strongly encouraged (as long as the biopsy is safe/feasible).  
 
If biopsy is not feasible, contact the Study Chair for guidance. 
 
c. 
End-of-Treatment Assessments 
 
If PET-CT was previously contra-indicated for the patient, and it is later possible to 
administer a PET-CT, then PET-CT is strongly preferred for the EOT assessment. 
Otherwise, the same modality as baseline must be used throughout the trial. 
 
Interpretation of PET-CT in patients with HL treated with PD-1 blockade can 
be challenging due to the indeterminate PET-CT results that are often 
observed. In the CheckMate 205 study, only 2 out of 12 patients who were not in 
CR at the end of N+AVD by independent review were treated with subsequent 
salvage therapy.  
 
Moreover, the positive predictive value for end-of-treatment PET-CT scans (in the 
setting of nivolumab) is unknown. When interpreting interim and EOT PET-CT 
results for patients in Arm 1, treating investigators should take into 
consideration that the false positive rate may be high. 
 
It is generally good clinical practice to confirm the presence of relapsed or 
refractory HL prior to initiating second line therapy. Especially because of these 
challenges with PET-CT interpretation in patients with HL treated with PD-1 
blockade, in the absence of a formal disease progression event (and even in the 
setting of PD), it is strongly recommended that patients undergo biopsy 
confirmation of residual HL (as long as the biopsy is safe/feasible) at the end 
of treatment (or thereafter) prior to the initiation of second line therapy for 
suspected relapsed or refractory HL. 
 

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In the event of indeterminate PET-CT results at the end of treatment (see 
LYRIC criteria, Section 18.1), the patient should be observed without additional 
treatment and repeat imaging should be performed after an additional 12 weeks 
(or sooner if clinically indicated) to determine whether there is true progressive 
disease. Biopsy confirmation should be sought (if safe/feasible) prior to initiation 
of second line therapy if repeat imaging is concerning for relapsed or refractory 
HL. 
 
Please see also Section 9.1 for required laboratory assessments to be performed 
at the EOT visit. Peripheral blood must be submitted, with patient’s consent, as 
indicated in Section 15.2. 
 
7.5 
Radiotherapy Indications, Dosage, Timing and Credentialing 
 
End-of-treatment Residual PET Radiation Therapy may be administered at the 
discretion of the treating physician, provided that the intent to deliver RT was declared 
at study enrollment and the criteria below are met. Of note, as described above, 
indeterminate PET-CT scan findings are common with nivolumab treatment.  
 
Patients who are declared eligible for RT are not required to receive RT - if the treating 
physician feels like residual PET-avid lesions are consistent with indeterminate response 
(see LYRIC criteria, Section 18.1), it is allowable to observe the patient without additional 
treatment and perform repeat imaging after an additional 12 weeks (or sooner if clinically 
indicated) to determine whether there is true progressive disease. 
 
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) in patients who have a complete response to systemic therapy (defined 
as Deauville 1-3 after six cycles of systemic therapy), and 2) limiting the volume of RT 
among patients who receive this treatment only to residual PET+ lesions. 
 
a. 
Eligibility for protocol-specified radiation therapy Residual PET RT  
 
1. 
The treating investigator must have declared intent for use of Residual 
PET RT at the date of registration to the protocol (and patient must meet 
criteria for RT indications in Section 7.5b).      
 
2. 
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).  
 
See also Section 7.1b for extended allowable windows in event of COVID-
19 extenuating circumstance. 
 
 
 
 
 

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3. 
All investigators registering pediatric patients are required to agree to 
intent to apply RT per the disease and response characteristics defined 
below.  Investigators at all other (non-COG) participating institutions will 
be required to have declared their intent to apply RT prior to patient 
registration and randomization (per Section 5.3e). 
 
4. 
IROC Rhode Island will verify patient eligibility for protocol-specified RT. 
To allow for IROC Rhode Island review prior to RT, images must be 
submitted to IROC Ohio (via TRIAD preferred) as indicated in Sections 
12.3 and 15.4. 
 
b. 
Indications for Radiotherapy  
 
1. 
The indication for RT will be based on the end-of-treatment imaging 
evaluation performed upon completion of 6 cycles of systemic therapy (4-
8 weeks after the last dose of study drug). In general terms, RT will be 
delivered when patients have 1-2 sites initially involved with HL that 
achieve only a partial response. Specifically, RT will be indicated when the 
patient has persistent sites upon completion of 6 cycles of systemic 
therapy that meet all of the following criteria:  
 
a. 
Residual nodal mass ≥ 2.5cm in axial diameter, or residual 
extranodal lesion >1cm in axial diameter (e.g. lung nodule or 
splenic nodule), and  
 
b. 
Deauville score = 4 or 5 (See Section 10.1a), and   
 
c. 
≥ 30% reduction in maximal transverse diameter compared to pre-
treatment imaging. 
 
2. 
RT may be given to one or two nodal sites.  RT to more than two nodal 
sites is not allowed. 
 
c. 
Contraindications for RT: 
 
1. 
Deauville score 5 due to development of new PET avid sites during 
systemic therapy. 
 
2. 
Three or more persistent PET-avid (Deauville score 4-5) sites at 
completion of systemic therapy. 
 
3. 
An end-of-treatment PET-avid lesion contained within a mass that is 
measurable by CT scan and has not achieved at least 30% reduction in 
transverse diameter since initiation of therapy. 
 
Patients with the above features are unlikely to be cured with RT, and 
biopsy with alternative management should be considered. 
 
d. 
Radiotherapy Dose and Schedule for SRL Lesions    
 
Radiotherapy will consist of 3000-3600 cGy in fractions of 150-200 cGy per day.  
 
1. 
The treatment will be given 5 days per week.  
 
2. 
All fields should be treated once each day.  
 
3. 
The total elapsed treatment time will be approximately 4 weeks. 
 

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e. 
Timing of Radiotherapy and Starting Criteria  
 
Treatment should begin 5-12 weeks from Cycle 6, Day 15 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.  
 
f. 
Credentialing Requirements  
 
See Section 18.6d for credentialing requirements. 
 
7.6 
Follow-up and Disease Evaluation Off-Protocol Treatment 
 
The last dose of protocol therapy is defined as either the last dose of study drug or the last 
dose of radiation therapy (administered per protocol), whichever is later. 
 
The End-of-Treatment assessment is defined as the visit occurring 4-8 weeks after the last 
dose of study drug. 
 
The End-of-RT assessment is defined as the visit occurring after the last dose of radiation 
therapy, for patients who were registered with intent-to-treat with RPRT and go on to 
receive RT per protocol.  
 
a. 
Prior to Progression 
 
All patients will have the following every 3 months for the first year after registration, 
then every 6 months for years 2 and 3, then annually until 10 years after 
registration. 
 
x 
History and Targeted Physical exam 
x 
Toxicity notation 
x 
Completion of QOL Questionnaires at 4-8 weeks after the last dose of 
protocol therapy (following last dose of study drug or radiation therapy, 
whichever is later), 1 year after registration and 3 years after registration. 
x 
Completion of the PRO-CTCAE Questionnaire after last dose of study 
drug, after last dose of radiation therapy (if applicable), and then 3-6 (if off-
treatment early), 9, 12, 18, 24, 30, and 36 months (after date of 
registration) visits. 
 
All patients will have a contrast-enhanced CT scan of chest, abdomen and pelvis 
(+ neck or other involved areas, if involvement at baseline) (or if contra-indicated, 
PET-CT, CT, MRI, or MR-PET) at 1 and 2 years after registration. 
 
b. 
For patients receiving residual PET Radiation Therapy 
 
Patients must have a PET-CT (or if contra-indicated, CT, MRI, or MR-PET) within 
8-12 weeks after completion of radiation therapy.  
 
c. 
Time of Progression 
 
FDG-PET-CT scan:  Patients who are removed from protocol treatment must 
receive a PET-CT scan before starting subsequent therapy. 
 
For patients contra-indicated for FDG-PET-CT, a MRI, MR-PET or a contrast-
enhanced CT scan of chest, abdomen, and pelvis (+ neck, if involvement at 
baseline) is allowable. 
 

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d. 
Follow-up After Progression 
 
Following disease progression, patients will be followed annually for survival and 
note of subsequent therapy which is typically performed by medical record review. 
 
7.7 
Patient-Reported Outcomes  
 
a. 
Quality of  Life Assessments  
 
Patients who can complete Patient-Reported Outcome instruments in English, 
Spanish, or French must complete the baseline PROMIS Fatigue questionnaire, 
FACT/GOG-Ntx, and the PROMIS Global. The PROMIS Fatigue questionnaire, 
FACT/GOG-Ntx, PROMIS Global questionnaires will also be administered to these 
patients at Day 56 (corresponding to the beginning of cycle 3), 4-8 weeks after the 
last dose of protocol therapy (following last dose of study drug or radiation therapy, 
whichever is later), and at years 1 and 3 after randomization. The scheduled follow-
up PRO assessments should be completed even if the patient goes off protocol 
treatment early for any reason (including progression). The S1826 PRO Cover 
Sheet for Patient Questionnaires is required to be submitted at each PRO 
assessment time.  See Section 15.5 for PRO (QOL) administration procedures. 
PRO assessments at baseline and follow-up should be completed even if a patient 
is later deemed clinically ineligible after enrollment. If a patient is removed from 
protocol therapy prior to an indicated administration timepoint, the indicated 
assessment tools should still be administered at that timepoint. It will take 
approximately 15 minutes for the patient to complete the questionnaires at each 
time point. 
 
b. 
PRO-CTCAE Assessments 
 
Adult patients who can complete PRO-CTCAE instrument in English, Spanish, or 
French and Pediatric patients who can complete the PRO-CTCAE instrument in 
English must complete the PRO-CTCAE questions at the beginning of treatment 
and weekly during radiation treatment, corresponding to the following time points 
indicated in Section 15.6a. The administration timing of the PRO-CTCAE 
questionnaire should coincide with the physician-directed toxicity assessment for 
the respective visit. If a patient is removed from protocol therapy prior to an 
indicated administration timepoint, the scheduled PRO-CTCAE assessments must 
continue to be administered until such time that the patient starts a subsequent 
non-protocol systemic anti-cancer therapy. See Section 15.6 for PRO-CTCAE 
questionnaire administration procedures. 
 
7.8 
Criteria for Removal from Protocol Treatment 
 
a. 
Completion of protocol treatment (ether completion of 6 cycles of study drug or 
(where applicable) completion of radiation therapy, whichever is later). 
 
b. 
Progression of disease or symptomatic deterioration (as defined in Section 10.1). 
 
c. 
Unacceptable toxicity per treating physician or study chair recommendation.  
 
d. 
Treatment delay of all components of study regimen (BV or nivolumab AND AVD) 
for any reason > 28 days.  
 
e. 
Unplanned radiation therapy (that was not declared as intent-to-treat with Residual 
PET RT at date of registration and/or does not meet criteria in Section 7.5). 
 
f. 
The patient may withdraw from the protocol treatment at any time for any reason. 

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7.9
Discontinuation of Treatment
All reasons for discontinuation of treatment must be documented in the Off Treatment 
Notice.
7.10
Follow-Up Period
All patients will be followed until death or 10 years after registration, whichever occurs first.
8.0
TOXICITIES TO BE MONITORED AND DOSE MODIFICATIONS
8.1
NCI Common Terminology Criteria for Adverse Events
This study will utilize the CTCAE (NCI Common Terminology Criteria for Adverse Events) 
Version 5.0 for toxicity and Serious Adverse Event reporting.  A copy of the CTCAE Version 
5.0 can be downloaded from the CTEP home page (http://ctep.cancer.gov).  All appropriate 
treatment areas should have access to a copy of the CTCAE Version 5.0.
8.2
Dose Modifications
NOTE: PRO-CTCAE data should not be used for determining dose delays or dose 
modifications or any other protocol directed action.
a.
Dose interruption or delay is permitted for toxicity or administrative reasons.   If 
toxicity is deemed attributable to any single agent, then dose delay or missed dose 
of any single agent is allowable (ie, nivolumab, BV, A, V, or D alone may be 
delayed or missed or the entire regimen (N-AVD or B-AVD) may be delayed or 
missed at the discretion of the treating investigator.
If all drugs are held > 3 and ≤28 days after the protocol-scheduled date, 
the total treatment is considered delayed. 
a.
The next treatment after a delayed dose should occur as soon as 
possible (per the treatment schedule) once all toxicities resolve 
per the adverse event tables below or once the administrative 
delay is addressed.  
b.
The reason for delay must be documented. 
c.
When treatment is resumed, the treatment should be counted as 
the treatment cycle that was originally due at the earlier protocol-
scheduled date, and the calendar will reset for subsequent visits. 
x
For example, if C2/D15 dose is delayed by 10 days and is 
administered on D25 of Cycle 2, then the calendar will reset 
on Day 25 and the next scheduled dose will be scheduled to 
be administered 14 days later on what would have originally 
been Cycle 3/Day 11 (and will be counted as C3/D1).

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If an individual drug is held for >3 days, then respective dose of the 
individual drug (e.g. vinblastine) will be considered a missed dose, and 
when the individual drug is resumed (once all toxicities have improved per 
the adverse event tables), it will be counted as the next scheduled dose.  
a.
Missed doses may not be made up. 
b.
Data submission for the missed dose will reflect the reason for 
missed dose.  
A total treatment interruption [i.e. stopping all study drugs nivolumab and
AVD or BV and AVD) of > 28 days will require the patient to go off-protocol 
therapy].
b.
Hematologic Toxicity:
Although it has been common practice in adult oncology settings in the United 
States to attenuate doses or delay treatment due to cytopenias alone, recent 
studies have shown that this policy is unneccessary and inadvisable for patients 
receiving ABVD and results in suboptimal treatment outcomes.  (97,98) Patients 
should receive full doses of AVD on schedule on Days 1 and 15 of each 28 day 
cycle without treatment delays, unless neutropenic fever or documented infections 
are present.  In nearly all cases, counts will recover despite administration of the 
next course of full dose chemotherapy administered on time. (99, 100)
c.
Arm 1: N-AVD 
The following tables summarize the criteria for nivolumab dose delays. The dose 
of nivolumab should not be modified. If dose delay criteria are met, the entire dose 
of nivolumab is held until the patient meets criteria for nivolumab re-initiation and 
then the patient should resume full dose nivolumab. In the event of a nivolumab-
related AE that requires hold or discontinuation of nivolumab, AVD may be 
continued (dose reductions may be necessary according to Section 8.2 above). If 
nivolumab is withheld for > 6 weeks due to nivolumab-related toxicity, nivolumab 
should be permanently discontinued.
If patient is unable to receive ALL components of study therapy (i.e: Nivolumab as 
well as A, V, and D) > 4 weeks (for any reason), then patient must go off protocol
treatment. 
Dose Modification and Management for Myocarditis
x
Nivolumab will be held for Grade 2 cardiac dysfunction pending 
evaluation.
x
Nivolumab will be permanently discontinued for Grade 3 or 4 cardiac 
dysfunction and Grade 2 events that do not recover to normal 
parameters or that reoccur.
x
Treatment with steroids as clinically indicated.
x
For cardiomyopathy without evidence of myocarditis, please call the 
Study Chair to determine management (e.g. doxorubicin dose 
modification).

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Cardiac a, c 
Management/Next Dose for BMS-936558 
(Nivolumab) Cardiac Toxicities 
Grade 1 
Hold nivolumab pending evaluation and observation.b  
Evaluate for signs and symptoms of CHF, ischemia, 
arrhythmia or myositis.  Obtain history EKG, CK (for 
concomitant myositis), CK-MB.  Repeat troponin, CK 
and EKG 2-3 days.  If troponin and labs normalize 
may resume therapy.  If labs worsen or symptoms 
develop then treat as below. 
Grade >2 with 
suspected 
myocarditis 
Hold nivolumab.b  Admit to hospital.  Cardiology 
consult.  Rule out MI or other causes of cardiac 
disease.  Cardiac Monitoring.  Cardiac Echo.  
Consider cardiac MRI and cardiac biopsy.  Initiate 
high dose methylprednisolone.  If no improvement 
within 24 hours, add either infliximab, antithymocyte 
globulin (ATG) or tacrolimus. Resume therapy if there 
is a return to baseline and myocarditis is excluded or 
considered unlikely. 
Grade >2 with 
confirmed 
myocarditis 
Discontinue nivolumab.  Admit to CCU (consider 
transfer to nearest Cardiac Transplant Unit, if 
appropriate).  Treat as above.  Consider high dose 
methylprednisolone.   
Add ATG or tacrolimus if no improvement.  Off 
protocol treatment. 
a      Including CHF, LV systolic dysfunction, Myocarditis, CPK, and 
troponin.  
b      Patients with evidence of myositis without myocarditis may be 
treated according as “other event”. See “All other treatment-
related events” in Section 8.2c.2. 
c       Pericarditis events should be managed according to the “Other 
treatment-related adverse events” category at the end of the 
table in Section 8.2c.2. 
 
Note:  The optimal treatment regimen for immune mediated myocarditis 
has not been established.  Since this toxicity has caused patient 
deaths, an aggressive approach is recommended.   
 
 
 

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Dose Modification and Management for all other Adverse Events
Treatment-
related Adverse 
Event
Grade of 
Event
Management for Nivolumab 
Nephritis
≤ Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2.  
Grade 3
Hold nivolumab until < Grade 2.  
Grade 4
Permanently discontinue nivolumab.
See also: Section 18.3 for Renal Adverse Event 
Management Algorithm.
Diarrhea 
(immune-related 
enterocolitis)
≤ Grade 1
No change.
Grade 2
Hold nivolumab until < Grade 2
Grade 3
Hold nivolumab until < Grade 2.  
Grade 4
Permanently discontinue nivolumab.
See also: Section 18.3 for GI Adverse Event 
Management Algorithm.
Endo-
crinopathy 
(hypophysitis, 
adrenal 
insufficiency, 
Type 1 diabetes 
≤ Grade 1
No change.
Grade 2
Hold until < Grade 2. 
Grade 3
Hold until < Grade 2.  
Grade 4
Permanently discontinue nivolumab.
Note: Asymptomatic hypothyroidism does not 
require dose modification. See also: Section 18.3
for Endocrinopathy Management Algorithm.
Pneumonitis,
broncho-spasm, 
pulmonary 
toxicity or 
interstitial lung 
disease
≤ Grade 1
No change.
Grade 2
Hold nivolumab until event resolves to 
baseline.  
Grade 3
Permanently discontinue nivolumab.
Grade 4
Permanently discontinue nivolumab.
Above does not include infusion reactions. See also:
Section 
18.3
for 
Pulmonary 
Adverse 
Event 
Management Algorithm.
Neurologic 
(encephalitis, 
encephalopathy
, seizure, 
Guillain-Barre 
syndrome, 
myelitis,
excludes 
peripheral 
neuropathy)
≤ Grade 1
No change.
Grade 2
Hold nivolumab until event resolves to 
baseline. If event is felt to represent 
immune-related neurologic toxicity, the 
Study Chair should be consulted before 
re-initiation of nivolumab.    
Grade 3
Permanently discontinue nivolumab.
Grade 4
Permanently discontinue nivolumab.
See also: Section 18.3 for Neurological Adverse 
Event Management Algorithm.
Peripheral 
Neuropathy
Grade 1-2
No change.
Grade 3
• Reduce the dose of vinblastine by 
50% for all further cycles of AVD.
• If nivolumab-related, hold nivolumab 
until improves to Grade 2
Grade 4
• Vinblastine will be omitted from all 
future cycles of AVD.
• If 
nivolumab-related, 
discontinue 
nivolumab permanently
See also: Section 18.3 for Neurological Adverse 
Event Management Algorithm.

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Treatment-
related Adverse 
Event 
Grade of 
Event 
Management for Nivolumab  
Skin drug-
related AE 
≤ Grade 1 No change. 
Grade 2 
No change. 
Grade 3 
Hold nivolumab until < Grade 3.   
Grade 4 
Permanently discontinue nivolumab. 
See also: Section 18.3 for Skin Adverse Event 
Management Algorithm. 
Ocular toxicities 
(uveitis, iritis) 
≤ Grade 1 No change. 
Grade 2 
• Consider holding nivolumab, treat with 
topical 
steroids 
such 
as 
1%  
prednisolone acetate suspension.  
• Evaluation 
by 
ophthalmologist 
strongly recommended.   
Grade 3 
• Hold nivolumab. 
• Treat with systemic corticosteroids 
such as 1-2mg/kg of prednisone. 
• Evaluation 
by 
ophthalmologist 
strongly recommended.   
Grade 4 
• Permanently discontinue nivolumab.  
• Treat with systemic corticosteroids 
such as 1-2mg/kg of prednisone. 
Abnormal liver 
function 
(AST/ALT, Total 
bilirubin, 
immune-related 
hepatitis) 
≤ Grade 1 No change. 
Grade 2 
• Nivolumab 
management: 
hold 
nivolumab until < Grade 2 or baseline. 
• AVD management: If the bilirubin rises 
to > 2 x ULN (but ≤ 5 x ULN), the 
doxorubicin and vinblastine doses 
must be reduced by 50% of last dose 
received to avoid undue hepatic 
toxicity. Full doses should be given 
once the bilirubin is ≤ 2 x ULN.   
Grade 3 
• AVD management: If the bilirubin rises 
to ≥ 5x ULN, then hold doxorubicin 
and vinblastine.  
• Nivolumab 
management: 
hold 
nivolumab until < Grade 2 or baseline. 
If AST/ALT>8x ULN or bilirubin >5x 
ULN, 
permanently 
discontinue 
nivolumab. 
Grade 4 
Permanently discontinue nivolumab. 
If patient has concurrent AST or ALT > 3 x ULN and 
total bilirubin > 2 x ULN, then permanently 
discontinue nivolumab. 
See also Section 18.3 for Hepatic Adverse Event 
Management Algorithm. 

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Treatment-
related Adverse 
Event 
Grade of 
Event 
Management for Nivolumab  
Amylase or 
lipase, 
associated with 
GI symptoms 
≤ Grade 1 No change. 
Grade 2 
No change. 
Grade 3 
No change if asymptomatic.  If GI 
symptoms, 
hold 
nivolumab 
until 
asymptomatic and < Grade 3. 
Grade 4 
Permanently discontinue nivolumab. 
Note: Isolated Grade 4 abnormalities 
that are not associated with symptoms 
or clinical manifestations of pancreatitis 
may not require nivolumab delay or 
discontinuation, but there should be 
discussion with the Study Chair1 
1 Contact the Study Chair for consultation on 
asymptomatic Grade 4 amylase or lipase 
abnormalities.  
See also: Section 18.3 for GI Adverse Event 
Management Algorithm. 
Infusion / 
hypersensitivity 
reactions 
(manifestation 
may include: 
fever, chills, 
rigors, headache, 
rash, pruritus, 
arthralgia, 
hypotension, 
hypertension, 
bronchospasm) 
≤ Grade 
1 
• Remain at bedside and monitor 
subject 
until 
recovery 
from 
symptoms.  
• Following 
prophylactic 
premedication is recommended for 
future infusions:  
• Diphenhydramine 50 mg (1 mg/kg 
up to 50 mg in pediatric patients) 
PO/IV or equivalent  
and/or  
• Acetaminophen/ paracetamol 325 
to 1000 mg (10-15 mg/kg up to 650 
mg in pediatric patients) PO at 
least 30 minutes before additional 
administration.  
• No change in dose for future 
administration. 
 
 
 
 
 
 
 
 
 
 
 

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Treatment-
related Adverse 
Event 
Grade of 
Event 
Management for Nivolumab  
Infusion / 
hypersensitivity 
reactions 
(manifestation 
may include: 
fever, chills, 
rigors, headache, 
rash, pruritus, 
arthralgia, 
hypotension, 
hypertension, 
bronchospasm) 
Grade 2 
• Stop infusion, begin an IV infusion of 
normal saline, and treat the subject 
with diphenhydramine 50 mg IV (1 
mg/kg up to 50 mg in pediatric 
patients) PO/IV or equivalent and/or 
acetaminophen /paracetamol 325 to 
1000 mg (10-15 mg/kg up to 650 mg 
in pediatric patients) PO; remain at 
bedside and monitor subject until 
resolution 
of 
symptoms. 
Corticosteroid (e.g. hydrocortisone 
50-100 mg IV (1-2 mg/kg up to 100 
mg in pediatric patients)) and/or 
bronchodilator therapy may also be 
administered 
as 
appropriate 
if 
reaction is severe or patient not 
responding to diphenhydramine or 
acetaminophen.  
• If the infusion is interrupted, then 
restart the infusion at 50% of the 
original infusion rate when symptoms 
resolve; if no further complications 
ensue after 30 minutes, the rate may 
be increased to 100% of the original 
infusion rate.  
• Monitor subject closely. If symptoms 
recur, then no further drug will be 
administered at that visit.  
• Administer diphenhydramine 50 mg 
IV, (1 mg/kg up to 50 mg in pediatric 
patients) and remain at bedside and 
monitor the subject until resolution of 
symptoms. The amount of study drug 
infused must be recorded on the 
electronic case report form (eCRF). 
• For 
future 
infusions, 
following 
prophylactic 
pre-medications 
are 
recommended: diphenhydramine 50 
mg (1 mg/kg up to 50 mg in pediatric 
patients) 
or 
equivalent 
and/or 
acetaminophen /paracetamol 325 to 
1000 mg (10-15 mg/kg up to 650 mg 
in pediatric patients) should be 
administered at least 30 minutes 
before 
nivolumab 
infusions. 
If 
necessary, corticosteroids (up to 25 
mg 
of 
methylprednisolone 
or 
equivalent) 
may 
be 
used 
if 
premedication with diphenhydramine 
and acetaminophen is not sufficient 
to prevent infusion reactions. 

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Treatment-
related Adverse 
Event 
Grade of 
Event 
Management for Nivolumab  
Infusion / 
hypersensitivity 
reactions 
 
(manifestation 
may include: 
fever, chills, 
rigors, headache, 
rash, pruritus, 
arthralgia, 
hypotension, 
hypertension, 
bronchospasm) 
Grade 3 
or  
Grade 4 
• Immediately 
discontinue 
infusion.  
Begin an IV infusion of normal saline 
and treat the subject as follows:  
• Recommend 
bronchodilators, 
epinephrine 0.2 to 1 mg of a 1 
mg/mL solution for subcutaneous 
administration (pediatric patients: 
0.01 mg/kg [0.01 mL/kg/dose of 1 
mg/mL solution]. 
• IM also allowed per institutional 
standards.  
• SubQ not to exceed 0.5 mg/dose) or 
0.1 to 0.25 mg of a 0.1 mg/mL 
solution injected slowly for IV 
administration in adults, and/or 
diphenhydramine 50 mg IV (1 mg/kg 
up to 50 mg in pediatric patients) 
with methylprednisolone 100 mg IV 
(1 mg/kg up to 100 mg in pediatric 
patients) (or equivalent), as needed.  
• Subject should be monitored until 
the investigator is comfortable that 
the symptoms will not recur.  
• For Grade 3, rechallenge of nivolumab 
can be considered with approval of the 
Study 
Chair 
via 
email 
to: 
S1826pediatrics@swog.org 
(for 
pediatric 
patients) 
or 
to: 
S1826USAdults@swog.org (for adult 
patients). 
• For Grade 4, permanently discontinue 
drug. Investigators should follow their 
institutional 
guidelines 
for 
the 
treatment of anaphylaxis. Remain at 
bedside and monitor subject until 
recovery of the symptoms. 
• In 
case 
of 
late-occurring 
hypersensitivity 
symptoms, 
symptomatic treatment may be given 
(e.g., 
oral 
antihistamine 
or 
corticosteroids). 
Note: Treatment guidelines may be modified based 
upon local SOPs, as appropriate. See also: Section 
18.3 for Skin Adverse Event Management Algorithm. 

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Treatment-
related Adverse 
Event 
Grade of 
Event 
Management for Nivolumab  
Hematologic 
(excluding 
lymphopenia) 
 
Grade 1-2 No change. 
Grade 3-4 • No change required 
• G-CSF use for subsequent cycles is 
recommended. If already using daily 
filgrastim, additional doses should be 
considered. 
• For anemia, manage per institutional 
guidelines. Erythrocyte transfusion is 
allowable. 
• For 
thrombocytopenia, 
consider 
platelet transfusion and/or manage 
per institutional guidelines. Delay of 
nivolumab 
for 
Grade 
4 
thrombocytopenia may be considered 
at the investigator’s discretion. 
Febrile 
Neutropenia, 
Sepsis, 
infections, or 
Infestations 
Grade  
1-2  
No change. 
(only pertains to infection/infestation) 
Grade  
3-4 
• Hold protocol therapy until ≤ Grade 2. 
• After recovery to ≤ Grade 2, continue 
N-AVD at same dose level. 
• Must use G-CSF with subsequent
cycles. 
• Consider 
prophylaxis 
with 
antibacterial therapy for subsequent 
cycles. 
• For repeated occurrences, it is 
allowable to decrease the doses of 
vinblastine and doxorubicin to 75% of 
the last dose received for the next 
cycle.  Re-escalation is at the 
discretion of the treating physician. 
Any other 
laboratory 
abnormality 
(except 
AST/ALT, Total 
bilirubin, 
thrombocyte-
penia, 
neutropenia, 
lymphopenia)  
≤ Grade 1 • No change. 
Grade 2 
No change. 
Grade 3 
If clinically significant, hold nivolumab 
until < Grade 2.  If not clinically 
significant, no change. 
Grade 4 
Hold nivolumab. If clinically significant, 
nivolumab may need to be discontinued. 
Consult with Study Chair to discuss 
restarting nivolumab. If not clinically 
significant, hold nivolumab until < Grade 
2. 1, 2, 3 
1  Grade 4 lymphopenia or leukopenia or does not 
require drug discontinuation. 
2  Resolved, 
well-controlled, 
or 
asymptomatic 
hypothyroidism does not require approval by Study 
Chairs prior to restarting therapy. 
3  Patients who develop Grade 3 or 4 electrolyte 
laboratory abnormalities may continue study 
treatment without interruption.   

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Treatment-
related Adverse 
Event 
Grade of 
Event 
Management for Nivolumab  
All other 
treatment-
related events 
≤ Grade 1 No change. 
Grade 2 
No change. 
Grade 3 
Hold nivolumab until < Grade 2.  
Grade 4 
Permanently discontinue nivolumab. 1 
1  With exception of laboratory abnormalities, as 
noted above. 
See also: Section 18.3 for Skin Adverse Event 
Management Algorithm. 
 
 
d. 
Arm 2: BV 
 
Dose delay or modification is allowable for toxicities related to brentuximab therapy 
if it is determined by the treating physician that it is in the best interest of the patient 
for safety reasons taking into consideration the overall clinical status of the subject.  
In the event of a BV-related AE that requires hold or discontinuation of BV, AVD 
may be continued (dose reductions may be necessary according to Section 8.2 
above).  If patient is unable to recieve ALL components of study therapy (i.e: BV 
as well as A, V, and D) > 4 weeks (for any reason), then patient must go off protocol 
treatment. 
  
For toxicity-related modifications beyond Cycle 1, suggested dose modifications of 
brentuximab vedotin are as follows: 
 
Intrapatient Dose Modification for Brentuximab 
Dose Level 
Brentuximab vedotin Dose 
  1 
1.2 mg/kg (max 120 mg) 
–1 
0.9 mg/kg (max 90 mg) 
 
Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may 
continue study treatment without interruption.  For toxicities that can be treated or 
prevented, such as nausea, vomiting, diarrhea and neutropenia, treatment may be 
resumed at the previous dose once supportive measures have been instituted and 
toxicity recovers to Grade 2 or less.    
 
For additional information on dose management, please see also Dosing and 
Administration 
Guide 
for 
brentuximab 
vedotin 
in 
cHL 
at: 
http://www.seattlegenetics.com/application/files/6515/4238/3292/adcetris_USPI.p
df.   
 
 

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The following table summarizes brentuximab vedotin dose modifications. 
 
Treatment-
related 
Adverse 
Event 
Grade of 
Event 
Management for Brentuximab vedotin 
Allergic 
reactions   
  
or   
  
Acute 
infusional 
reactions/ 
cytokine 
release 
syndrome 
Grade 1-2 
For first reaction:  
x 
Hold the infusion and wait 30 to 60 minutes 
(depending upon the reaction severity).  
x 
Treat reactions with 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) IV, or 
other systemic corticosteroid per institutional 
standard,  should be used.   
x 
Upon resolution of the symptoms, at the 
physician’s discretion, it may be possible to 
resume treatment by administering an H2 
blocker approximately 30 minutes before 
restarting the infusion.  Acetaminophen can also 
be considered.  Dosing of brentuximab vedotin 
should be administered at half of the previously 
administered rate.  
 
For subsequent doses:   
x 
Utilize 
diphenhydramine 
with 
or 
without 
acetaminophen 
as 
pretreatment 
for 
all 
subsequent infusions.    
x 
Dosing should be administered over the shortest 
period that was well tolerated.  
 
If Grade 1-2 infusion reactions recur despite the 
above measures, either during re-challenge or 
subsequent treatments:  
x 
Take the measures outlined above.  
x 
With subsequent dosing, add dexamethasone 
0.2 mg/kg (max 10mg) IV or equivalent to 
medications above prior to infusion. 
 
 
 
 
 

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Treatment-
related 
Adverse 
Event 
Grade of 
Event 
Management for Brentuximab vedotin 
Allergic 
reactions   
  
or   
  
Acute 
infusional 
reactions/ 
cytokine 
release 
syndrome 
 
Grade 3 
x 
Stop infusion immediately.  
x 
Administer diphenhydramine hydrochloride 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.  
x 
Once symptoms recover, brentuximab vedotin 
should not be resumed for that course. 
x 
Subsequent courses of brentuximab vedotin 
may be considered at physicians’ discretion, 
after approval by the Study Chair. 
x 
All subsequent infusions should use the 
following pre-medications prior to infusion, 
diphenhydramine hydrochloride 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. 
If 
necessary, 
corticosteroids 
(up 
to 
25 
mg 
of 
methylprednisolone or equivalent) may be used 
if premedication with diphenhydramine and 
acetaminophen is not sufficient to prevent 
infusion reactions. 
Grade 4 
x 
Stop infusion immediately.  
x 
Administer diphenhydramine hydrochloride 1 
mg/kg (max 50 mg) IV, dexamethasone 0.2 
mg/kg (max 10 mg) IV (or equivalent), and other 
anaphylaxis medications as indicated. 
x 
Epinephrine or bronchodilators should be 
administered as indicated.  
x 
Hospital admission for observation may be 
indicated.  
x 
Discontinue brentuximab vedotin. 
Anaphylaxis 
Any 
Grade  
If anaphylaxis occurs, immediately and permanently 
discontinue administration of brentuximab vedotin 
and administer appropriate medical therapy. 
Peripheral 
Neuropathy 
Grade 1 
No change. 
Grade 2 
x 
Reduce dose to 0.9mg/kg (max 90 mg) and 
resume treatment; if already at 0.9mg/kg 
continue dosing at that level. 

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Treatment-
related 
Adverse 
Event 
Grade of 
Event 
Management for Brentuximab vedotin 
Peripheral 
Neuropathy 
Grade 3 
x 
Treatment should be delayed until neuropathy 
improves to Grade 2 or lower.  
x 
Once improved to grade 2 or lower, brentuximab 
vedotin should be reduced to 0.9mg/kg and 
treatment should be resumed. 
x 
Patients who develop grade 3 neuropathy after 
dose reduction of brentuximab vedotin to 
0.9mg/kg should have brentuximab vedotin 
discontinued. 
x 
In the setting of Grade 3 peripheral neuropathy 
(e.g., 
obstipation, 
weakness), 
that 
persists/occurs despite discontinuation of BV, 
the dose of vinblastine will be reduced by 50% 
for all further cycles of AVD  
Grade 4 
x 
Discontinue brentuximab vedotin. 
x 
In the setting of Grade 4 peripheral neuropathy 
(e.g., 
obstipation, 
weakness), 
that 
persists/occurs despite discontinuation of BV, 
vinblastine will be omitted from all future cycles 
of AVD. 
Pneumonitis 
 
Grade 1 
No change. 
Grade 2 
If suspected, strongly consider administration of 100 
mg of oral or intravenous prednisolone 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. Upon occurrence of 
pneumonitis, study therapy should be held, and 
notify the Study Chair within 48 hours. 
Grade 3-4 
If suspected, strongly consider administration of 100 
mg 
of 
oral 
prednisone 
or 
intravenous 
methylprednisolone (1 mg/kg IV every 12 hours) 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. 
Upon occurrence of pneumonitis, study therapy 
should be held, and notify the Study Chair within 48 
hours. 
Abnormal 
liver 
function 
(AST/ALT, 
Total 
bilirubin, 
immune-
related 
hepatitis) 
≤ Grade 1  No change. 
Grade 2 
x 
If the bilirubin rises to > 2 x ULN (but ≤ 5 x ULN), 
the doxorubicin and vinblastine doses must be 
reduced by 50% of last dose received to avoid 
undue hepatic toxicity. Full doses should be 
given once the bilirubin is ≤ 2 x ULN.   

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Treatment-
related 
Adverse 
Event 
Grade of 
Event 
Management for Brentuximab vedotin 
Abnormal 
liver 
function 
(AST/ALT, 
Total 
bilirubin, 
immune-
related 
hepatitis) 
Grade  
3-4 
x 
AVD management: If the bilirubin rises to ≥ 5x 
ULN, then hold doxorubicin and vinblastine.  
x 
Withhold doxorubicin and vinblastine dose until ≤ 
Grade 2 or has returned to baseline.  
x 
BV management: Dose reduction of brentuximab 
vedotin to 0.9mg/kg can be considered.  
x 
If recurs after BV dose reduction, discontinuation 
of brentuximab vedotin can be considered. 
Progressive 
Multifocal 
Leukoence-
phalopathy 
(PML) 
Any 
Grade 
If PML is suspected, a diagnostic work-up should be 
performed.  The workup may include, but is not 
limited to the following:  
x 
Neurologic 
examinations 
and 
neurology 
consultation, as warranted. · 
x 
Brain MRI.  Features suggestive of PML include 
presence of unifocal or multifocal lesions, mainly 
of the white matter, which are typically non-
enhancing and do not have mass effect. 
x 
PCR analysis. JCV DNA, detectable in CSF or 
in a brain biopsy, is suggestive of PML. 
Brentuximab vedotin dosing should be held if 
PML is suspected.  If PML is confirmed, 
brentuximab vedotin should be permanently 
discontinued. 
Febrile 
Neutropenia, 
Sepsis, 
Infections or 
infestations 
Grade 1-2 
(only 
pertains to 
infection/in
festation) 
No change. 
Grade 3 
x 
Hold protocol therapy until ≤ Grade 2. 
x 
If using daily filgrastim (rather than pegfilgrastim),
additional doses beyond days 6-10 should be
administered in subsequent cycles. 
x 
Consider prophylaxis with antibacterial therapy
for subsequent cycles. 
x 
First occurrence - continue at same dose level. 
x 
Second occurrence – Consider dose reduction to
0.9mg/kg (max 90 mg) of brentuximab vedotin. 
x 
Additional occurrence – – If brentuximab vedotin
has already been dose reduced, consider
discontinuation of brentuximab vedotin. 
x 
If febrile neutropenia recurs despite brentuximab
vedotin dose reduction or discontinuation, it is
allowable to decrease the doses of vinblastine
and doxorubicin to 75% of the last dose received
for the next cycle. Re-escalation is at the
discretion of the treating physician.  
x 
 

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Treatment-
related 
Adverse 
Event 
Grade of 
Event 
Management for Brentuximab vedotin 
Febrile 
Neutropenia, 
Sepsis, 
Infections or 
infestations 
Grade 4 
x 
Hold protocol therapy until ≤ Grade 2. 
x 
If 
using 
daily 
filgrastim 
(rather 
than 
pegfilgrastim), additional doses beyond days 6-
10 should be administered. 
x 
Consider prophylaxis with antibacterial therapy 
for subsequent cycles. 
x 
First occurrence - consider dose reduction to 
0.9mg/kg (max 90 mg) of brentuximab vedotin. 
x 
Second/repeated occurrence – if brentuximab 
vedotin has already been dose reduced, 
discontinuation of brentuximab vedotin is 
recommended. 
x 
If 
febrile 
neutropenia 
recurs 
despite 
brentuximab 
vedotin 
dose 
reduction 
or 
discontinuation, it is allowable to decrease the 
doses of vinblastine and doxorubicin to 75% of 
the last dose received for the next cycle. Re-
escalation is at the discretion of the treating 
physician.  
Hematol-
ogic 
(excluding 
lympho-
penia) 
Grade 1-2 
No change. 
Grade 3-4  x 
No change required. 
x 
For neutropenia, if using daily filgrastim (rather 
than pegfilgrastim), additional doses beyond 
days 6-10 and 21-25 can be considered. 
x 
For anemia, manage per institutional guidelines. 
Erythrocyte transfusion is allowable. 
x 
For 
thrombocytopenia, 
consider 
platelet 
transfusion and/or manage per institutional 
guidelines. Delay of brentuximab vedotin for 
Grade 4 thrombocytopenia may be considered 
at the investigator’s discretion. 
 
Non-
hematol-
ogic 
events  
(not 
including 
electrolyte 
abnormaliti
es or others 
not 
specifically 
outline 
above, e.g. 
neuropathy) 
Grade 1-2 
No change. 
Grade 3-4  x 
Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline.  
x 
Dose reduction of brentuximab vedotin to 
0.9mg/kg (max 90 mg) can be considered.  
x 
If non-hematological Grade 3-4 toxicity recurs 
after one dose reduction, discontinuation of 
brentuximab vedotin should be considered. 

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Treatment-
related 
Adverse 
Event 
Grade of 
Event 
Management for Brentuximab vedotin 
Electrolyte 
abnormal-
ities 
Grade 1-4 
x 
Continue at same dose level, provided 
electrolyte 
toxicity 
is 
not 
medically 
consequential and has been readily corrected.  
x 
If 
electrolyte 
abnormality 
is 
medically 
consequential, refer to guidelines above for non-
hematologic events. 
Patients who develop Grade 3 or 4 electrolyte 
laboratory 
abnormalities 
may 
continue 
study 
treatment without interruption but should receive 
appropriate medical therapy. 
 
8.3 
Dose Modification Contacts 
 
For treatment or dose modification questions, please contact:  
 
x 
Adults: E-mail: S1826USAdults@swog.org or call: Dr. Alex Herrera (SWOG) at 
Phone: 626/256-4673 ext. 62405 or Dr. Sarah Rutherford (Alliance) at Phone: 
646/962-2064 or Dr. Andrew Evens (ECOG-ACRIN) at Phone: 732-235-9289. 
 
x 
Pediatrics: E-mail: S1826pediatrics@swog.org. or call: Dr. Sharon Castellino at 
Phone: 404/785-3616 or Dr. Angela Punnett at: Phone: 416/813-5394. 
 
x 
CCTG Adults: Dr. Kelly Davison at: E-mail: kelly.davison@mcgill.ca or Phone: 
514/934-1934, ext 31558 or Dr. Michael Crump at: Michael.Crump@uhn.ca or 
Phone: 416/946-4567.   
 
8.4 
Adverse Event Reporting /Serious Adverse Event Reporting Guidance 
 
Please Note:  This protocol utilizes Rave® / Cancer Therapy Evaluation Program Adverse 
Event Reporting System (CTEP-AERS) integration for expedited reporting of serious 
adverse events. The CTEP-AERS integration enables evaluation of post-baseline Adverse 
Events (AE) entered in Rave to determine whether they require expedited reporting.  
 
All AEs that occur after baseline are collected in Medidata Rave using the Adverse Event 
form, which is available for entry at each treatment or reporting period, and used to collect 
AEs that start during the period or persist from the previous reporting period. The Clinical 
Research Associate (CRA) will enter AEs that occur prior to the start of treatment on a 
baseline form that is not included in the Rave-CTEP-AERS integration. AEs that occur prior 
to enrollment must begin and end on the baseline Adverse Events form and should not be 
included on the standard Adverse Events form that is available at treatment unless there 
has been an increase in grade. 
 
Prior to sending AEs through the rules evaluation process, site staff should verify the 
following on the Adverse Event form in Rave: 
 
x 
The reporting period (course/cycle) is correct; and 
 
x 
AEs are recorded and complete (no missing fields) and the form is query free 
(fields added to the form during study build do not need to be query free for the 
integration call with CTEP-AERS to be a success). 
 

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The CRA reports AEs in Rave at the time the Investigator learns of the event. If the CRA 
modifies an AE, it must be re-submitted for rules evaluation. 
 
Upon completion of AE entry in Medidata Rave, the CRA submits the AE for rules 
evaluation by completing the Expedited Reporting Evaluation form. Both NCI and protocol-
specific reporting rules evaluate the AEs submitted for expedited reporting. A report is 
initiated in CTEP-AERS using information entered in Medidata Rave for AEs that meet 
reporting requirements. The CRA completes the report by accessing CTEP-AERS via a 
direct link on the Medidata Rave Expedited Reporting Evaluation form. 
 
In the rare event when internet connectivity is disrupted a 24-hour notification is made to 
CTEP by telephone at 301-897-7497. Once Internet connectivity is restored, the 24-hour 
notification that was phoned in must be entered immediately into CTEP-AERS using the 
deep link from Medidata Rave. 
 
Additional information about the CTEP-AERS integration is available on the CTSU website: 
x 
Study specific documents: Protocols > Documents> Education and Promotion; and   
 
x 
Expedited Safety Reporting Rules Evaluation user guide: Resources > CTSU 
Operations Information> User Guides. 
 
NCI requirements for SAE reporting are available on the CTEP website:  
x 
NCI Guidelines for Investigators: Adverse Event Reporting Requirements is 
available 
at 
https://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguid
elines.pdf. 
 
If you have questions about this process, please contact the SAE Program Manager 210-
614-8808 or email  adr@swog.org.  
 
The CTEP-AERS electronic reporting system “Help” feature has detailed instructions in the 
section "Submitting Reports for RAVE Users". 
 
8.5 
COVID-19 Adverse Event Reporting Requirements:  
 
Per the NCI “Guidance for Collection of Adverse Events Related to COVID-19 Infection,” 
accessible from: https://ctep.cancer.gov/content/docs/Adverse_Event_Guidance_COVID-
19_Final_3-25-20.pdf, any known COVID-19 infection should be reported as an adverse 
event (and if applicable via CTEP-AERS). 
 
8.6 
Serious Adverse Event Reporting Requirements  
 
a. 
Purpose 
 
Definition:  Adverse event means any untoward medical occurrence associated 
with the use of a drug in humans, whether or not considered drug related. (FDA, 
21 CFR 312.32). See Table 8.1 for definition of a Serious Adverse Event (SAE) 
and reporting requirements. 
 
Adverse event 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. Adverse events are 
reported in a routine manner at scheduled times during a trial. (Directions for 
routine reporting are provided in Section 14.0.) Additionally, certain adverse events 
must be reported in an expedited manner to allow for more timely monitoring of 
patient safety and care. The following guidelines prescribe expedited adverse 
event reporting for this protocol.  
 

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b. 
Reporting method 
 
This study requires that expedited adverse events be reported to the SWOG 
Operations Office using the Cancer Therapy Evaluation Program Adverse Event 
Reporting System (CTEP-AERS).  CTEP's guidelines for CTEP-AERS can be 
found at http://ctep.cancer.gov. A CTEP-AERS report must be submitted to the 
SWOG Operations Office electronically via the CTEP-AERS Web-based 
application 
located 
at: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/adverse_eve
nts.htm. 
 
NOTE: For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is entered 
into RAVE, the Rules Engine will confirm whether or not the adverse event 
requires expedited reporting.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website.  Sites are encouraged to 
confirm the Expedited Reporting Evaluation Recommendation with the 
reporting criteria outlined in Table 8.1. 
 
c. 
When to report an event in an expedited manner 
 
Some adverse events require 24-hour notification (refer to Table 8.1) via CTEP-
AERS.  
 
In the rare event when internet connectivity is disrupted a 24-hour notification is 
made to NCI by telephone at 301-897-7497.  An electronic report MUST be 
submitted immediately upon re-establishment of internet connection. 
 
When the adverse event requires expedited reporting, submit the report via  CTEP-
ARS within the number of calendar days of learning of the event specified in Table 
8.1.  
 
Some adverse events require 24-hour notification (refer to Table 8.1) via CTEP-
AERS.  
 
Any supporting documentation requested by CTEP should be submitted in 
accordance with instructions provided by the CTEP-AERS system. 
 
PRO-CTCAE is not intended for expedited reporting, real time review or safety 
reporting. 
 
d. 
Other recipients of adverse event reports 
 
CTEP will forward reports and documentation to the appropriate regulatory 
agencies and drug companies as required. 
 
Adverse events determined to be reportable to the Institutional Review Board 
responsible for oversight of the patient must be reported according to local policy 
and procedures. 
 
 

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e. 
Expedited reporting for investigational agents 
 
Expedited reporting is required if the patient has received at least one dose of the 
investigational agent(s) as part of the trial. Reporting requirements are provided in 
Table 8.1.  
 
The investigational agent used in Arm 1 of this study is Nivolumab (BMS-936558, 
MDX1106, Opdivo®).  
 
If there is any question about the reportability of an adverse event or if internet 
connectivity  is disrupted, please telephone or email the SAE Program Manager at 
the Operations Office, 210/614-8808 or adr@swog.org, before preparing the 
report. 
 
NOTE: For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is entered 
into RAVE, the Rules Engine will confirm whether or not the adverse event 
requires expedited reporting.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website.  Sites are encouraged to 
confirm the Expedited Reporting Evaluation Recommendation with the 
reporting criteria outlined in Table 8.1. 
 
 
 

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Table 8.1: 
Late Phase 2 and Phase 3 Studies:  Expedited Reporting Requirements for Adverse Events that 
Occur on Studies under a CTEP IND within 30 Days of the Last Administration of the Investigational 
Agent/Intervention1 [Nivolumab (BMS-936558, MDX1106, Opdivo®)] [Arm 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) An adverse event that results in inpatient hospitalization or prolongation of existing 
hospitalization for ≥ 24 hours  
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 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting 
in 
Hospitalization  
≥ 24 hrs 
Not required 
10 Calendar Days 
NOTE:  Protocol specific exceptions to expedited reporting of serious adverse events are found 
in Section 8.6f. 
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 AE, followed by a complete expedited report within 5 calendar 
days of the initial 24-hour report. 
 
o “10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 
calendar days of learning of the AE. 
1Serious adverse events 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: 
x All Grade 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
x Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization  
x Grade 3 adverse events 
 
May 5, 2011 
 
 

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f. 
Additional Instructions or Exceptions to CTEP-AERS Expedited Reporting 
Requirements for Late Phase 2 and Phase 3 Studies Utilizing an Agent under 
a CTEP IND: 
 
1. 
Group-specific instructions 
 
Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements.  In addition, 
you may be asked to submit supporting clinical data to the SWOG 
Operations Offices in order to complete the evaluation of the event.  If 
requested by the SAE Program Manager, the supporting data should be 
sent within 5 calendar days by fax to 210-614-0006.   
 
2. 
PRO-CTCAE 
 
Clinician-graded CTCAE is the AE safety standard. PRO-CTCAE items 
are to complement CTCAE reporting. Patients will respond to PRO-
CTCAE items, but no protocol directed action will be taken. The study-
specific S1826 PRO-CTCAE items can be found on the forms section of 
the CTSU S1826 protocol webpage. 
 
g. 
Expedited reporting for commercial agents 
 
Commercial reporting requirements are provided in Table 8.2. The commercial 
agent(s) used in Arms 1 and 2 of this study are Doxorubicin hydrochloride, 
Dacarbazine and Vinblastine sulfate.  
 
The commercial agents used in Arm 2 of this study are filgrastim, pegfilgrastim, 
and SGN-35 (brentuximab vedotin).  
 
If there is any question about the reportability of an adverse event or if on-line 
CTEP-AERS cannot be used, please telephone or email the SAE Program at the 
Operations Office, 210/614-8808 or adr@swog.org, before preparing the report. 
 
NOTE: For this study, all adverse events requiring expedited reporting must 
initially be reported on the Adverse Event Form in the appropriated 
Treatment Cycle folder in Medidata Rave.  Once the adverse event is entered 
into RAVE, the Rules Engine will confirm whether or not the adverse event 
requires expedited reporting.  The CTEP-AERS report must then be initiated 
directly from the Adverse Event Form in Medidata Rave.  Do not initiate the 
CTEP-AERS report via the CTEP-AERS website.  Sites are encouraged to 
confirm the Expedited Reporting Evaluation Recommendation with the 
reporting criteria outlined in Table 8.2. 
 
 

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Table 8.2. Expedited reporting requirements for adverse events experienced 
by patients on study Arm 1 and Arm 2 who have received the commercial 
drug(s) listed in Section 8.6g above within 30 days of the last administration 
of the commercial agent(s). 
Attribution 
 
Grade 4 
 
Grade 5
a 
Unexpected 
Expected 
Unexpected 
Expected 
Unrelated 
or Unlikely 
 
 
CTEP-AERS 
CTEP-AERS 
Possible, 
Probable, 
Definite 
CTEP-AERS 
 
CTEP-AERS 
CTEP-AERS 
CTEP-AERS:  Indicates an expedited report is to be submitted via CTEP-
AERS within 10 calendar days of learning of the event b. 
 
a This includes all deaths within 30 days of the last dose of treatment with a 
commercial agent(s), regardless of attribution.  Any death that occurs more 
than 30 days after the last dose of treatment with a commercial agent(s) 
and is attributed (possibly, probably, or definitely) to the agent(s) and is not 
due to cancer recurrence must be reported according to the instructions 
above. 
b Submission of the on-line CTEP-AERS report plus any necessary 
amendments generally completes the reporting requirements. You may, 
however, be asked to submit supporting clinical data to the Operations 
Office in order to complete the evaluation of the event. If requested, the 
specified data should be sent within 5 calendar days by fax to 210-614-
0006.  
 
h. 
Reporting Secondary Malignancy, including AML/ALL/MDS 
 
1. 
A secondary malignancy is a cancer caused by treatment for a previous 
malignancy (e.g., treatment with investigational agent/intervention, 
radiation or chemotherapy).  A secondary malignancy is not considered a 
metastasis of the initial neoplasm. 
 
CTEP requires all secondary malignancies that occur following treatment 
with an agent under an NCI IND to be reported via CTEP-AERS.  Three 
options are available to describe the event. 
x 
Leukemia secondary to oncology chemotherapy (e.g., Acute 
Myelocytic Leukemia [AML]) 
x 
Myelodysplastic syndrome (MDS) 
x 
Treatment-related secondary malignancy 
 
Any malignancy possibly related to cancer treatment (including AML/MDS) 
should also be reported via the routine reporting mechanisms outlined in 
each protocol. 
 
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. 
 
For more information see: 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/
aeguidelines.pdf. 
 

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2. 
Supporting documentation should be submitted to CTEP by fax at 301-
897-7404 in accordance with instructions provided by the CTEP-AERS 
system.  Supporting documentation must also be submitted to SWOG 
Operations Office by fax to 210-614-0006.  
 
NOTE: If a patient has been enrolled in more than one NCI-sponsored 
study, the report must be submitted for the most recent trial. 
 
i. 
Reporting Pregnancy, Pregnancy Loss, and Death Neonatal 
 
1. 
Pregnancy.   Study participants who become pregnant while on study; 
that pregnancy should 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.   
 
Additionally, the pregnancy outcome for patients on study should be 
reported via CTEP-AERS at the time the outcome becomes known, 
accompanied by the same Pregnancy Report Form used for the initial 
report. 
 
2. 
Pregnancy Loss.   Pregnancy Loss is defined in CTCAE as “Death in 
utero.” Pregnancy loss should be reported expeditiously as Grade 4 
“Pregnancy Loss” under the Pregnancy, puerperium and perinatal 
conditions SOC.  
 
A Pregnancy loss should NOT be reported as a Grade 5 event under the 
Pregnancy, puerperium and perinatal conditions SOC, as currently CTEP-
AERS recognizes this event as a patient death. 
 
3. 
Death Neonatal.   Death neonatal is defined in CTCAE as “Newborn death 
occurring during the first 28 days after birth. A neonatal death should be 
reported expeditiously as Grade 4 “Death neonatal” under the General 
disorders and administration SOC.   
 
Neonatal death should NOT be reported as a Grade 5 event under the 
General disorders and administration SOC as currently CTEP-AERS 
recognizes this event as a patient death 
 
NOTE:  When submitting CTEP-AERS reports for “Pregnancy, “Pregnancy loss”, 
or “Neonatal loss”, the Pregnancy Information Form should also be completed and 
faxed with any additional medical information to 301-897-7404.  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.  
 
The Pregnancy Information Form is available at:  
http://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm.

 
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9.0 
STUDY CALENDAR 
9.1 
Treatment Calendar 
REQUIRED STUDIES 
PRE 
REG 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5 
Cycle 6 
After 
last 
dose 
of 
study 
drug  
m 
End of Tx 
Assess 
4-8 wks 
after last 
dose of 
study drug 
4-8 wks after 
either the 
last dose of 
study drug or 
last dose RT, 
whichever is 
later 
D1 D15 D1 
D15 
D1 
D15 
D1 
D15 
D1 D15 D1 D15 
History 
and 
Targeted 
Physical p (including wt.) 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Performance Status 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
Disease Assessment 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Toxicity Notation q 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
PRO-CTCAE a 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
LABORATORY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
TSH b 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
 
X 
 
CBC/Differential/Platelet c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
CMP d 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Pregnancy Test  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) o 
 
HIV viral load and CD4 count 
e 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET-CT f   
X 
 
 
 
 
(X)i 
 
 
 
 
 
 
 
 
X 
 
ECHO, MUGA, or functional 
cardiac imaging scan g   
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
IMAGING SUBMISSION  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PET-CT h   
X 
 
 
 
 
(X)i 
 
 
 
 
 
 
 
 
X 
 
SPECIMEN SUBMISSION  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FFPE diagnostic tissue j 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Peripheral Blood (Streck) k 
 
X 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
 
QOL SUBMISSION l 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PROMIS-Global 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
PROMIS-Fatigue 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
FACT/GOG-Ntx 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
TREATMENT n 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ARM 1: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Nivolumab  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AVD 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
ARM 2: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Brentuximab Vedotin 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
AVD 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Click here for footnotes. 

 
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NOTE: Forms are found on the protocol-specific page of the CTSU website (www.ctsu.org).  Forms submission guidelines are found in Section 14.0. 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous 
treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in the SWOG Best 
Practices document accessible from the “Best Practices” link at: https://www.swog.org/clinical-trials/protocol-workbench. 
a  
PRO-CTCAE or Ped PRO-CTCAE questionnaire, based on patient age with adult ≥ 18 and pediatric 12-17 years, must be completed on Day 1, prior 
to beginning treatment (for English-, Spanish- and French- speaking adult and English-speaking pediatric patients). All subsequent PRO-CTCAE 
questionnaires must be completed within a +/- 7-day window of the indicated timepoint. See also Section 15.6 for administration instructions.  
b  
For patients randomized to Arm 1 (N-AVD), TSH must be performed at baseline and then every 4-8 weeks prior to the start of the cycle, as clinically 
indicated. Results of the baseline TSH test does not determine eligibility but is performed prior to initiating treatment for Arm 1 patients only, in order 
to obtain baseline measurements. 
c 
Allowable window for CBC with differential is within 3 days prior to start of Cycles 1-6 and must include: WBC count, hemoglobin, absolute neutrophil 
count (ANC), and absolute lymphocyte count (ALC). See also Section 7.1b for extended allowable windows in event of COVID-19 extenuating 
circumstance. 
d  
Allowable window for CMP is within 3 days prior to start of Cycles 1-6 and must include: electrolytes (sodium, potassium, chloride, bicarbonate (CO2)), 
albumin, serum or plasma creatinine or calculated creatinine clearance, and liver function tests (total bilirubin, SGOT [AST], SGPT [ALT], alkaline 
phosphatase). See also Section 7.1b for extended allowable windows in event of COVID-19 extenuating circumstance. 
e  
Required within 6 months prior to registration for patients who are known to be HIV-positive. 
f  
A contrast-enhanced (diagnostic) CT, MRI or MR-PET is acceptable in event that PET-CT is contra-indicated, however if it is later possible to administer 
a PET-CT, then PET-CT is strongly preferred for the interim scan (after Cycle 2) (if performed) and the EOT assessment. Otherwise, if PET-CT is not 
subsequently possible, then the same modality as baseline must be used throughout the trial.  
g  
For Patients Randomized to Arm1 (N-AVD): Recommended cardiac monitoring includes: EKG, ECHO, CPK & Troponins to be done within 3 days prior 
to Day 1 of each Cycle, as clinically indicated for patients who: 1) develop CHF, 2) are deemed at risk because of underlying cardiovascular disease 
or exposure to cardiotoxic drugs, or 3) have evidence of CHF or MI, cardiomyopathy, or myositis cardiac evaluation (NYHA I/II). See also Section 7.3a. 
h  
See also: Sections 14.4 and 15.4. NOTE: If patient goes off protocol treatment early the EOT PET-CT must still be collected/submitted at 4-8 wks after 
the last dose of study drug. 
i 
All pediatric patients and all patients who were declared (at date of registration) intent to treat with EOT Residual PET RT must have a standard of care 
PET-CT on Day 53 (+/-3 days) (after Cycle 2/Day 15 and prior to the start of Cycle 3). 
j  
1 FFPE block or 1 H&E slide required per Section 15.1 for pathology review. At same timepoint, with patient’s consent, tissue must be collected for 
banking per Section 15.2. 
k  
With patient’s consent, peripheral blood must be collected per Section 15.2. 
l  
Patient-reported outcome instruments are required at Baseline for patients who can complete the forms in English, Spanish, or French and must also 
be administered to these patients at the required follow-up time points (timing based on registration date). If a patient refuses or cannot complete the 
patient questionnaires at any time point, he or she should be asked to do so at the next scheduled assessment time. Note that there are two age-based 
versions of the PROMIS measures for adults 18+ and for pediatric patients age 12-17 years. See also Sections 14.4 for data submission and 15.5 for 
administration instructions. 
m 
If patient goes on to receive RT, then toxicity and PRO-CTCAE assessments must be performed after administration of both the last dose of study drug 
and after last dose of radiation therapy.  
n  
End of treatment Residual PET RT is allowable for eligible patients, as indicated in Section 7.5. 
o 
Females of childbearing potential who will receive radiation therapy per protocol must have a standard of care pregnancy test, prior to start of radiation 
therapy. 
p 
Targeted H&P with systems examined as per the treating physician discretion (must include weight). 
q 
See Section 8.6 for SAE reporting requirements. Note: If a patient experienced a severe (Grade ≥3) adverse event that is possibly, probably or definitely 
related to protocol treatment that was not previously reported in RAVE, report SAE on the S1826 Late Adverse Events Form (Section 14.4). 

 
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9.2 
Follow-up After Off-Protocol Treatment 
REQUIRED STUDIES 
Follow-up Prior to Progression a 
At Prog 
FUP  
 Post-Prog 
3-6 mos  
after reg (if 
off-Tx early) 
9 mos 
after reg 
End of 
RT 
12 mos 
after reg 
18 mos 
after reg 
24 mos 
after reg 
30 mos 
after reg 
36 mos 
after reg 
Y4 - 
Y10 
 
 
History and Targeted Physical 
Exam b (including weight) 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Performance Status 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
Disease Assessment 
 
 
 
X 
 
X 
 
 
 
 
X 
Toxicity Notation c 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
PRO-CTCAE d 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X-RAYS AND SCANS 
 
 
 
 
 
 
 
 
 
 
 
PET-CT  
 
 
(X) h 
 
 
 
 
 
 
X 
 
CT (or MRI) e 
 
 
 
X 
 
X 
 
 
 
 
 
SPECIMEN SUBMISSION  
 
 
 
 
 
 
 
 
 
 
 
FFPE diagnostic tissue f 
 
 
 
 
 
 
 
 
 
X 
 
Peripheral Blood (Streck) f 
 
 
 
 
 
 
 
 
 
X 
 
QOL SUBMISSION g 
 
 
 
 
 
 
 
 
 
 
 
PROMIS-Global 
 
 
 
X 
 
 
 
X 
 
 
 
PROMIS-Fatigue 
 
 
 
X 
 
 
 
X 
 
 
 
FACT/GOG-Ntx  
 
 
 
X 
 
 
 
X 
 
 
 
NOTE: Forms are found on the protocol-specific page of the CTSU website (www.ctsu.org).  Forms submission guidelines are found in Section 14.0. 
NOTE: Unless indicated otherwise in the protocol, scheduled procedures and assessments (treatment administration, toxicity assessment for continuous 
treatment, disease assessment, specimen collection and follow-up activities) must follow the established SWOG guidelines as outlined in the SWOG Best 
Practices document accessible from the “Best Practices” link at: https://www.swog.org/clinical-trials/protocol-workbench. 
a  
Every 3 months (+/- 7 days) for the first year, then every 6 months (+/- 7 days) for the second and third year, then annually (+/-14 days) until 10 years 
from the date of registration or until time of progression. See also Section 7.1b for extended allowable windows in event of COVID-19 extenuating 
circumstance. 
b  
Targeted H&P with systems examined as per the treating physician discretion. 
c  
See Section 8.6 for SAE reporting requirements. Note: If a patient experienced a severe (Grade ≥3) adverse event that is possibly, probably or definitely 
related to protocol treatment that was not previously reported in RAVE, report SAE on the S1826 Late Adverse Events Form (Section 14.4). 
d  
PRO-CTCAE assesssments must be collected within +/- 7 days of timepoints indicated above. The scheduled follow-up PRO-CTCAE assessments 
should coincide with the physician-directed toxicity assessment and must be completed even if the patient goes off protocol treatment early 
for any reason or if a patient is deemed ineligible for any reason until such time that the patient starts a subsequent non-protocol anti-cancer 
therapy.  See also Section 15.6 for administration instructions. 
e 
All patients must have a contrast-enhanced CT scan of chest, abdomen and pelvis (+ neck or other involved areas, if involvement at baseline) (or if 
contra-indicated, CT, MRI, or MR-PET) at 1 and 2 years after registration (+/- 14 days). See also Section 7.1b for extended allowable windows in event 
of COVID-19 extenuating circumstance. 
f 
With patient’s consent, peripheral blood and tissue must be collected per Section 15.2. 
g 
The scheduled follow-up PRO assessments must be completed even if the patient goes off protocol treatment early for any reason or the 
patient progressed or if a patient is deemed ineligible for any reason. If a patient refuses or cannot complete the patient questionnaires at any 
time point, he or she should be asked to do so at the next scheduled assessment time. See also Sections 14.4 for data submission and 15.5 for 
administration instructions. 
h  
Patients who receive Residual PET RT, per Section 7.5, (ONLY) must have a PET-CT (or if contra-indicated, CT, MRI, or MR-PET) within 8-12 weeks 
after completion of radiation therapy.  

 
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10.0 
CRITERIA FOR EVALUATION AND ENDPOINT ANALYSIS 
 
Response and progression will be evaluated in this study using the revised international working 
group guidelines (Lugano classification) (101). 
10.1 
Measurement of Treatment/Intervention Effect 
 
a. 
Target Lesions & Target Lymph Nodes 
 
FDG avid lesions: Up to five of the largest dominant nodes, nodal masses, and 
extranodal lesions selected to be clearly FDG avid. Nodes should preferably be 
from disparate regions of the body and should include, where applicable, 
mediastinal and retroperitoneal areas. Non-nodal lesions include those in solid 
organs (e.g., liver, spleen, kidneys, lungs), GI involvement, cutaneous lesions, or 
those noted on palpation. 
 
PET 5-Point Scale / Deauville score:  
x 
1, no FDG uptake above background;  
x 
2, FDG uptake ≤ mediastinum;  
x 
3, FDG uptake > mediastinum but ≤ liver;  
x 
4, FDG uptake moderately >liver;  
x 
5, FDG uptake markedly higher than liver and/or new lesions;  
x 
X, new areas of uptake unlikely to be related to lymphoma. 
 
b. 
Metabolic Response at the end of Cycle 6 or end of treatment.  
 
1. 
Complete Metabolic Response (CR) (as defined by all the following): 
 
a. 
Deauville Score of 1, 2, or 3 with or without a residual mass or 
nodal lesion: 
 
x 
1, no FDG uptake above background; 
x 
2, FDG uptake ≤ mediastinum; 
x 
3, FDG uptake > mediastinum but ≤ liver. 
 
b. 
In Waldeyer’s ring or extranodal sites with high physiologic uptake 
or with activation within spleen or marrow (e.g., with 
chemotherapy or myeloid colony-stimulating factors), uptake may 
be greater than normal mediastinum and/or liver.  In this 
circumstance, complete metabolic response may be inferred if 
uptake at sites of initial involvement is no greater than surrounding 
normal tissue even if the tissue has high physiologic uptake. 
 
c. 
No new lesions. 
 
d. 
No evidence of FDG avid disease in marrow unless as noted in 
Section 10.1b.1b. 
 
e. 
In the event that a bone marrow biopsy is performed at baseline 
and the patient had evidence of marrow involvement by bone 
marrow biopsy at baseline, a repeat marrow will be required to 
confirm CR. A sample that is negative by immunohistochemistry 
but that demonstrates a small population of clonal lymphocytes by 
flow cytometry will be considered a CR. 
 
 

 
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2. 
Partial Metabolic Response (PR) (as defined by all the following): 
 
a. 
Deauville Score of 4 or 5 with reduced uptake compared to 
baseline and residual mass(es) of any size. 
 
b. 
No new lesions. 
 
c. 
In the event that a bone marrow biopsy is performed at baseline: 
Residual marrow uptake higher than uptake in normal marrow but 
reduced compared with baseline (diffuse uptake compatible with 
reactive changes from chemotherapy allowed). If there are 
persistent focal changes in the marrow in the context of a nodal 
response, consideration should be given to further evaluation with 
a BM biopsy. 
 
3. 
No Metabolic Response (SD) (as defined by all the following): 
 
a. 
Deauville Score 4 or 5 with no significant change in FDG uptake 
from baseline at interim or end of treatment. 
 
b. 
No new lesions. 
 
c. 
No change in marrow uptake from baseline. 
 
4. 
Progressive Metabolic Disease (PD) (as defined by any of the following): 
 
a. 
Deauville Score 4 or 5 with an increase in intensity of uptake from 
baseline.  
 
b. 
New FDG-avid foci consistent with lymphoma. 
 
c. 
New or recurrent FDG-avid foci in the bone marrow. 
 
* 
For patients who are contra-indicated for PET-CT, see Section 18.7 
for Measurement-based Response Assessment According to the 
Lugano Classification. 
 
10.2 
Best Response: 
 
a. 
CR: One objective status of CR documented before relapse. 
 
b. 
PR: One objective status of PR documented before progression but not qualifying 
as a CR. 
 
c. 
Stable: At least one objective status of stable documented at least 6 weeks after 
registration, not qualifying as anything else above. 
 
d. 
Increasing Disease: Objective status of progression. 
 
e. 
Inadequate assessment, response unknown: No other response category applies. 
 
 

 
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10.3 
Performance Status   
 
See also Section 18.4. 
 
a. 
Patients ≥ 18 years of age will be graded according to the Zubrod 
performance status scale: 
 
GRADE 
SCALE 
 
0 
Fully active; able to carry on all pre-disease activities 
without restriction.   
 
1 
Restricted in physically strenuous activity but ambulatory 
and able to carry out work of a light or sedentary nature, 
e.g., light housework, office work.   
 
2 
Ambulatory and capable of all self-care but unable to 
carry out any work activities; up and about more than 
50% of waking hours.   
 
3 
Capable of only limited self-care; confined to bed or chair 
more than 50% of waking hours.   
 
4 
Completely disabled; cannot carry on any self-care; 
totally confined to bed or chair.   
 
b. 
Patients ≤ 17 years of age will be graded according to the Lansky play-performance 
scale for pediatric patients. *The conversion of the Lansky to Zubrod scale is 
intended for NCI reporting purposes only. See Section 18.4. 
 
This scale is rated by parents based on their child's activity over the past week. 
Parents fill out the assessment based on the directions on the form, and the form 
is re-administered over time to assess for changes in performance status. 
 
An excerpt of the relevant directions for parents is as follows: 
 
"Think about your child's play and activity over the past week. Think about both 
good days and bad days. Average out this period. Now read the descriptions and 
pick the one that best describes your child's play during the past week." 
 
RATING 
DESCRIPTION 
100 
Fully active, normal 
90 
Minor restrictions with strenuous physical activity 
80 
Active, but gets tired more quickly 
70 
Both greater restriction of, and less time spent in, active play 
60 
 
Up and around, but minimal active play; keeps busy with quieter
activities 
50 
Lying around much of the day, but gets dressed; no active play; 
participates in all quiet play and activities 
40 
Mostly in bed; participates in quiet activities 
30 
Stuck in bed; needs help even for quiet play 
20 
Often sleeping; play is entirely limited to very passive activities 
10 
Does not play nor get out of bed 
0 
Unresponsive 
 
 

 
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10.4 
Progression Free Survival (PFS) 
 
From date of registration to date of first observation of progressive disease according to 
the 2014 Lugano classification, or death due to any cause.  Patients last known to be alive 
and without report of progression are censored at date of last contact. See Sections 
10.1b.4 and 18.7 for definition of progressive disease according to 2014 Lugano 
classification. 
 
10.5 
Event Free Survival (EFS) 
 
From date of registration to date of first occurrence of EFS event. Patients last known to 
be alive and without EFS event are censored at date of last contact. 
  
EFS Events are defined as: 
 
x 
Disease progression/relapse 
x 
Administration of non-protocol specified systemic anti-lymphoma therapy (i.e. 
salvage therapy) at any time after initiation of protocol therapy. 
o 
Administration of non-protocol specified systemic anti-lymphoma therapy 
for residual or relapsed Hodgkin lymphoma (whether or not confirmed by 
biopsy) in the absence of formal progression of disease according to the 
Lugano classification  
 
x 
Administration of any non-protocol specified radiation therapy at any time after 
initiation of protocol therapy: 
o 
Administration of radiation therapy in a patient who was not declared 
eligible for radiation therapy at registration 
o 
Administration of radiation in a patient who was declared eligible for 
radiation therapy but does not meet protocol-specified criteria for use of 
radiation (refer to Section 7.5). 
 
10.6 
Time to Death 
 
From date of registration to date of death due to any cause.  Patients last known to be alive 
are censored at date of last contact. 
 
 
11.0 
STATISTICAL CONSIDERATIONS 
 
11.1 
Primary Analysis and Power Justification 
 
The primary endpoint is progression free survival (PFS). 
 
Based on previous data, the 2-year PFS for the control arm (Arm 2) is estimated to be 
approximately 84%.  Prior PFS data in patients with advanced stage Hodgkin lymphoma 
indicates that a proportion of patients may be long-term non-progressing patients. An 
exponential cure rate model is assumed for both arms with 70% long term non-progressing 
patients on the control arm (Arm 2) and 74% on the experimental arm (Arm 1). In addition, 
among the fraction of patients with disease progression, a hazard ratio of 1.67 is assumed 
between the arms.  The BV-AVD control arm (Arm 2) PFS model is written that the PFS at 
year t is equal to 0.70+0.30*exp(-0.38t) and .74+ .26*exp (-.38t/1.67) for the N-AVD 
experimental arm (Arm 1).  The power calculations are based on the log-rank based testing 
on simulated data sets from the survival cure models described above.  At the end of study, 
this corresponds to an average hazard ratio (based on 10,000 simulated hazard ratios from 
the Cox model) of 1.58. 
 
 
 

 
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940 eligible patients are expected to be accrued over 4 years with a total of 987 patients 
assuming an expected ineligible rate of 5% (6% of enrolled patients deemed ineligible due 
to central pathology review on S0816). The analysis is event-based and planned after 
achieving 179 events across arms, that will be reached at approximately 2 additional years 
of follow-up. The power to detect a change in time-to-event PFS outcomes corresponds to 
a 2-year PFS in the control arm (Arm 2) of 84%  and a 2-year PFS of 90% in the 
experimental arm (Arm 1) of 86%.  The power calculations assume uniform patient entry 
and a one-sided stratified log-rank test at 2.5% significance level. 
 
Sensitivity analyses of above will be performed where PFS is censored/not-censored at 
the time of start of non-protocol therapy.  
 
11.2 
Interim Analysis 
 
For early reporting, interim analyses will be conducted when 25%, 50% and 75% of 
anticipated progressions or deaths in the pooled across arms have been observed. This 
under the alternative hypothesis this approximately corresponds to 58%, 85% of accrual 
and six months after completing full accrual. Evidence suggesting early termination for of 
the study would be if the alternative hypothesis of a greater than average hazard ratio 
control vs. experimental hazard ratio of 1.58 is rejected at a one-sided .5% level at the first 
interim analysis, and 1% level at second or later of the interim analyses.  At the second 
interim analysis testing would approximately correspond to observing a hazard ratio 
favoring the control of approximately .96. The conservative first interim analysis 
acknowledges the potential late therapeutic effect of the experimental arm relative to the 
control arm. The timing of interim analyses will be based the combined number of PFS 
events across arms. At full information or the time of primary analysis will occur when 179 
PFS events have been observed. 
 
Interim Analysis 
Information 
One-sided Futility 
p-value 
One-sided superiority P-
value 
1 
25% 
.002 
NA 
2 
50% 
.01 
.005 
3 
75% 
.01 
.005 
 
At the second two interim analyses superiority testing will be conducted at the .5% level.   
 
Final Analysis Plan: If the trial is not stopped early, the final analysis will test the null 
hypothesis (HR=1) for PFS using stratified log-rank test with a one-sided alpha of 0.021.  
The strata used in the stratified log-rank test are those defined and coded as in Section 6.0 
in the dynamic balancing randomization scheme utilized for the study. The variables 
include: Age (years): age 12-17 vs. age 18-60 vs. age > 60, International prognostic score: 
0-3 vs. 4-7 and Pre-specified plan to use Residual PET Radiation Therapy (Residual PET 
RT)*: yes vs. no. The analysis will be based on modified intent-to-treat and will include all 
eligible patients as randomized regardless of treatment received.  The one-sided alpha of 
.021 will control of the overall type-one error of the study (including the 2 interim superiority 
analyses) to be less than .025.  The final analysis type-1 error calculations were based 
simulation studies using the information times specified in the interim analysis schedule 
and interim analysis specified superiority p-value testing.  
 
 
 

 
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RT monitoring: The use of RT will almost exclusively be on the pediatric population, but 
due to the concern appropriate use in N-AVD arm given the potential of false progressions, 
it will be monitored closely throughout the study.  The DSMB will be provided rates of 
radiotherapy used in each arm (and within the 12-17 years and ≥ 18 years age groups in 
each arm) for each meeting. The committee will monitor the rate of radiotherapy in both 
arms and by age group to ensure that there is no overuse in the experimental arm (Arm 1). 
Due to variability in early event calculations focus on this analysis will not commence until 
after 30 patients have completed RT.  At that point, if there is greater than 15% difference 
between arms, then the additional communication to NCI and study team for protocol 
amendment would be considered. This substantive threshold for action in rates is 
motivated by limited sample sizes and by a slightly higher expected baseline rate of RT 
use in the N-AVD arm based on the ECHELON-1 and CheckMate 205 studies.  If after 75 
patients have received RT, then a smaller difference (10%) would be considered a concern 
and warrant additional discussion with NCI and the study team. We will apply the same 
rules to RT differences within each age group in each arm.  
 
11.3 
Analysis of Secondary Endpoints 
 
Secondary endpoints include overall survival (OS), event-free survival (EFS), metabolic 
complete response (CR) rate, safety and tolerability. 
 
A key secondary endpoint for the study is OS. Based on previous data, the estimated 2-
year OS in the control arm (Arm 2) was 96%. We assume that overall survival in the 
experimental arm (Arm 1) will follow an exponential distribution, with 4 years of accrual, 2 
additional years of follow-up, a stratified log-rank test at two-sided alpha level of .05 will 
have 90% power to detect a hazard ratio of 2.8 (corresponds to an improvement of OS 
from 96% in the control arm (Arm 2) to 98.5% in the experimental arm (Arm 1)). A total of 
61 OS events (deaths) are required for the final analysis. 
 
Event free survival (EFS) will be estimated using Kaplan-Meier method and compared 
between treatment arms using cox regression model. Based on the estimated 2-year 
modified PFS of 82% in the control arm (Arm 2), and the average hazard ratio 1.54, we 
anticipate at least 195 events under the alternative hypothesis. With 940 eligible patients, 
the hazard ratio can be estimated to within ±0.28 (95% confidence). 
 
Metabolic complete response is defined using 2014 Lugano classification.  In the previous 
study, the CR rate was 86% at the end of frontline therapy for BV-AVD, but the estimate 
might include BEACOPP and/or radiation therapy. We assume that the CR rate is 83% for 
BV-AVD alone, with 940 eligible patients, a binomial test at one-sided alpha level of .025 
will have 92% power to detect an increase in CR rate from 83% in the control arm (Arm 2) 
to 90% in the experimental arm (Arm 1). 
 
Toxicity will be evaluated using the CTCAE Version 5 items.  Eligible patients receiving at 
least one dose of drug will be included in the assessment of adverse events by treatment 
arms. The maximum Grade for each toxicity will be recorded for each patient, and 
frequency tables will be reviewed to determine toxicity patterns. With 470 eligible patients 
in each arm, any toxicity with at least 4% prevalence has at least a 90% chance of occurring 
within an arm. Toxicity rates in each arm can be estimated to within at least ± 4.5% with 
95% confidence. Treatment-related toxicities between arms will be compared using 
Fisher’s exact test stratified by age groups. 
 
Targeted patient-reported toxicities also will be collected at each time point (see Sections 
9.1 and 9.2), using the PRO-CTCAE for patients 18 years and older and from youth 12-17 
years, using the Ped PRO-CTCAE.  
 
 
 

 
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Safety Monitoring:  The CTEP IDB Drug Monitor, S1826 study chairs, statisticians and data 
coordinator(s) will review aggregate adverse event rates by arms on a monthly basis, and 
serious adverse events immediately after receiving notification.  Additionally, special 
summary reports will be run more frequently to evaluate adverse events in both arms for 
the first six weeks of the treatment regimen to ensure that there is no significant increase 
in adverse events in the combination arm of chemotherapy and immunotherapy.  
Conference calls will be scheduled to discuss these data as needed. 
 
11.4 
Interim Safety Analysis 
 
In addition to ongoing toxicity monitoring and every DSMC meeting, after 6 months after 
approximately 125 patients have been registered to each arm and again concurrently with 
each interim efficacy analyses, there will be an additional interim assessment death or 
discontinuation of all components of BV+AVD or N+AVD prior to the protocol-specified 
completion of all components of BV+AVD or N+AVD due to an adverse event. If there is 
an absolute difference of a 5% rate of death or complete discontinuation of all components 
of BV+AVD or N+AVD  due to adverse events in the experimental arm (Arm 1) versus Arm 
2, then the consideration of temporarily closing the study to accrual pending a decision by 
the DSMC as to whether to continue accrual. We note that we will also present data on 
deaths separate to treatment discontinuation to the DSMC. We will present all deaths to 
treatment, and deaths within 30 days of completing therapy.  If the decision is to re-open 
accrual, this will require a protocol amendment and will include justification for continued 
accrual and for any treatment regimen modifications.   In addition, due to the absence of 
published data using N-AVD in the pediatric population, a toxicity review will be conducted 
after the first 10 patients who are 12-17 years of age are enrolled to Arm 1. A 
teleconference will be planned to discuss the AEs in this group of patients, the participants 
are expected to include SWOG and COG Study Chairs, Disease Committee Chair, SWOG 
executive officer, Study Statisticians and NCI CTEP representation.  
 
11.5 
Data and Safety Monitoring Committee  
 
A Data and Safety Monitoring Committee will oversee the conduct of the study.  The 
Committee consists of four members from outside of the SWOG, 3 SWOG members, 3 
non-voting representatives from the National Cancer Institute (NCI), and the Group 
Statistician (non-voting).  The members of this Committee will receive confidential reports 
every 6 months from the SWOG Statistics and Data Management Center and will meet at 
the Group's bi-annual meetings as necessary.  The Committee will be responsible for 
decisions regarding possible termination and/or early reporting of the study. PRO-CTCAE 
data should not be used in adverse event stopping rules. 
 
 
12.0 
DISCIPLINE REVIEW 
 
12.1 
Pathology Review 
 
All patients registered to this study will undergo retrospective pathology review. The 
purpose of this review is to verify histologic diagnosis.   
 
See Sections 14.4a and 14.4b for associated forms and pathology report submission 
instructions. See Section 15.1 for required tissue submission instructions. 
 
Pathology review will be coordinated by SWOG.  
 
In the event that a patient is deemed ineligible due to pathology review results, the patient 
will not be evaluated for the primary or secondary endpoints. 
 
 

 
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12.2 
Radiology Review  
 
All patients registered are planned to undergo retrospective PET-CT review.  The purpose 
of this planned review will be to retrospectively verify disease stage at study entry, 
response at Cycle 2 (in patients who undergo interim imaging per standard of care), end-
of-treatment response, and to retrospectively confirm patient eligibility for Radiation 
Therapy per criteria indicated in Section 7.5.   
 
See Section 15.4 for required image submission instructions. 
 
If participating sites would like assistance with interpretation of pediatric radiology 
results, pediatric courtesy reviews are available by contacting Sandy Kessel at IROC 
Rhode Island via E-mail at: SKessel@qarc.org.  
 
Radiology Courtesy Reviewers for Pediatric Patients: 
 
Drs. Lai and Mhlanga will be serving as Radiology Courtesy reviewers for pediatric patients 
enrolled to S1826. To request courtesy review, contact IROC at contact information 
listed above. 
 
Hollie A. Lai, MD 
Children’s Hospital of Orange County,  
Department of Radiology,  
1201 W. La Veta Ave,  
Orange, CA 92868 
Phone: 714/509-9160  
Email: hlai@choc.org    
 
Joyce Mhlanga, MD 
Mallinckrodt Institute of Radiology 
510 South Kingshighway Boulevard,  
St. Louis, MO 63110 
Phone: 314/362-2809 
Email: jmhlanga@wustl.edu   
 
12.3 
Radiation Therapy Review 
 
Radiotherapy (RT) for patients can only be delivered at approved RT facilities. Pre-
treatment Review of Radiation therapy plans will be conducted by IROC Rhode Island.  
 
Data detailed in Section 14.4h below must be submitted to IROC Ohio (via TRIAD 
preferred)  per instructions in Section 15.4 one week prior to the planned start of 
Radiation Therapy for review and approval.  
 
IROC Rhode Island will verify that the patient meets protocol-specified RT criteria 
indicated in Section 7.5b and will confirm eligibility for RT with the treating 
investigator or notify the investigator in the event that the patient does not meet 
protocol-specified criteria for RT. In the event that IROC Rhode Island RT 
interpretation differs from local participating site interpretation, the case will be 
forwarded to at least one of two expert reviewers for final confirmation. 
 
This RT QA review will also confirm sites of partial response which will require 
radiation.  
 
Any radiation therapy delivered not consistent with the RT QA review response 
categorization will be considered a major protocol deviation.   
 
 

 
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13.0 
REGISTRATION GUIDELINES 
 
13.1 
Registration Timing 
 
Initiation of treatment must be planned to start no more than 14 calendar days after 
registration.   
 
13.2 
Investigator/Site Registration 
 
Prior to the recruitment of a patient for this study, investigators must be registered members 
of a participating Cooperative Group.  Each investigator must have an NCI investigator 
number and must maintain an “active” investigator registration status through the annual 
submission of a complete investigator registration packet to CTEP. 
 
13.3 
CTEP Registration Procedures 
 
Food and Drug Administration (FDA) regulations and National Cancer Institute (NCI) policy 
require all individuals contributing to NCI-sponsored trials 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) must 
complete their annual registration using CTEP’s web-based Registration and Credential 
Repository (RCR) (https://ctepcore.nci.nih.gov/rcr).   
 
RCR utilizes five-person registration types. 
x 
IVR — MD, DO, or international equivalent; 
x 
NPIVR — advanced practice providers (e.g., NP or PA) or graduate level researchers 
(e.g., PhD); 
x 
AP — clinical site staff (e.g., RN or CRA) with data entry access to CTSU applications 
such as the Roster Update Management System (RUMS), OPEN, Rave, acting as a 
primary site contact, or with consenting privileges; 
x 
Associate (A) — other clinical site staff involved in the conduct of NCI-sponsored trials; 
and 
x 
Associate Basic (AB) — individuals (e.g., pharmaceutical company employees) with 
limited access to NCI-supported systems. 
 
RCR requires the following registration documents: 
Documentation Required 
IVR 
NPIVR 
AP 
A 
AB 
FDA Form 1572 
D 
D 
 
 
 
Financial Disclosure Form 
D 
D 
D 
 
 
NCI 
Biosketch 
(education, 
training, employment, license, 
and certification) 
D 
D 
D 
 
 
GCP training 
D 
D 
D 
 
 
Agent 
Shipment 
Form 
(if 
applicable) 
D 
 
 
 
 
CV (optional) 
D 
D 
D 
 
 
 
An active CTEP-IAM user account and appropriate RCR registration is required to access 
all CTEP and Cancer Trials Support Unit (CTSU) websites and applications.  In addition, 
IVRs and NPIVRs must list all clinical practice sites and Institutional Review Boards (IRBs) 
covering their practice sites on the FDA Form 1572 in RCR to allow the following: 
x 
Addition to a site roster 
x 
Assign the treating, credit, consenting, or drug shipment (IVR only) tasks in OPEN 
x 
Act as the site-protocol Principle Investigator (PI) on the IRB approval; and 
x 
Assign the Clinical Investigator (CI) role on the Delegation of Tasks Log (DTL).     

 
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In addition, all investigators acting as the Site-Protocol PI (investigator listed on the IRB 
approval), consenting/treating/drug shipment investigator in OPEN, or as the CI on the DTL 
must be rostered at the enrolling site with a participating organization.  
 
Additional 
information 
is 
located 
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. 
 
13.4 
CTSU Registration Procedures 
 
This study is supported by the NCI Cancer Trials Support Unit (CTSU). 
 
a. 
IRB Approval:   
 
For CTEP and Division of Cancer Prevention (DCP) studies open to the National 
Clinical Trials Network (NCTN) and NCI Community Oncology Research Program 
(NCORP) Research Bases after March 1, 2019, all U.S.-based sites must be 
members of the NCI Central Institutional Review Board (NCI CIRB). In addition, 
U.S.-based sites must accept the NCI CIRB review to activate new studies at the 
site after March 1, 2019. Local IRB review will continue to be accepted for studies 
that are not reviewed by the CIRB, or if the study was previously open at the site 
under the local IRB. International sites should continue to submit Research Ethics 
Board (REB) approval to the CTSU Regulatory Office following country-specific 
regulations.  
 
Sites participating with the NCI CIRB must submit the Study Specific Worksheet 
for Local Context (SSW) to the CIRB using IRBManager to indicate their intent to 
open the study locally. 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. The NCI CIRB’s 
approval of the SSW is automatically communicated to the CTSU Regulatory 
Office, but sites are required to contact the CTSU Regulatory Office at 
CTSURegPref@ctsu.coccg.org to establish site preferences for applying NCI 
CIRB approvals across their Signatory Network. Site preferences can be set at the 
network or protocol level. Questions about establishing site preferences can be 
addressed to the CTSU Regulatory Office by email or calling 1-888-651-CTSU 
(2878). 
 
In addition, the Site-Protocol Principal Investigator (PI) (i.e. the investigator on the 
IRB/REB approval) must meet the following criteria in order for the processing of 
the IRB/REB approval record to be completed: 
 
x 
Holds an active CTEP status; 
x 
Rostered at the site on the IRB/REB approval (applies to US and Canadian 
sites only) and on at least one participating roster; 
x 
If using NCI CIRB, rostered on the NCI CIRB Signatory record; 
x 
Includes the IRB number of the IRB providing approval in the Form FDA 1572 
in the RCR profile; and 
x 
Holds the appropriate CTEP registration type for the protocol.  
 
Additional Requirements 
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: 
x 
An active Federal Wide Assurance (FWA) number; 
x 
An active roster affiliation with the Lead Protocol Organization (LPO) or a 
Participating Organization (PO); and 
x 
Compliance with all protocol-specific requirements (PSRs). 
 

 
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b. 
Protocol-Specific Requirements For S1826 Site Registration 
 
This is a study with a radiation and/or imaging (RTI) component and the enrolling 
site must be aligned to an RTI provider. To manage provider associations or to 
add or remove associated providers, access the Provider Association page from 
the 
Regulatory 
section 
on 
the 
CTSU 
members’ 
website 
at 
https://www.ctsu.org/RSS/RTFProviderAssociation. Sites must be linked to at 
least one Imaging and Radiation Oncology Core (IROC) provider to participate on 
trials with an RTI component. Enrolling sites are responsible for ensuring that the 
appropriate agreements and IRB approvals are in place with their RTI provider. An 
individual with a primary role on any roster is required to update provider 
associations, though all individuals at a site may view provider associations. To 
find who holds primary roles at your site, view the Person Roster Browser under 
the RUMS section on the CTSU website. 
 
IROC Credentialing Status Inquiry (CSI) Form – this form is submitted to IROC 
Houston to verify credentialing status or to begin a new modality credentialing 
process.  See also  Section 18.6d. 
 
c. 
Downloading Site Registration Documents:   
 
Download the site registration forms from the S1826 protocol page located on the 
CTSU members’ website.  Permission to view and download this protocol and its 
supporting documents is restricted based on person and site roster assignment. 
To participate, the institution and its associated investigators and staff must be 
associated with the LPO or a Protocol Organization (PO) on the protocol. One way 
to search for a protocol is listed below. 
 
x 
Log in to the CTSU members’  website (https://www.ctsu.org) using your 
CTEP-IAM username and password 
x 
Click on Protocols in the upper left of your screen 
o 
Enter the protocol # in the search field at the top of the protocol tree; or 
o 
Click on the By Lead Organization folder to expand, then select SWOG 
protocol number S1826. 
x 
Click on Documents, select Site Registration, and download and complete 
the forms provided.  (Note: For sites under the CIRB, IRB data will load 
automatically to the CTSU.) 
 
d. 
Submitting Regulatory Documents:  
 
Submit required forms and documents to the CTSU Regulatory Office using the 
Regulatory Submission Portal on the CTSU website.  
 
To access the Regulatory Submission Portal, log in to the CTSU members’ website 
(www.ctsu.org), go to the Regulatory section and select Regulatory Submission 
 
Institutions with patients waiting that are unable to use the Regulatory Submission 
Portal should alert the CTSU Regulatory Office immediately at 866-651-2878 in 
order to receive further instruction and support. 
 

 
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e. 
Checking Your Site’s Registration Status: 
 
Site registration status may be verified on the CTSU members’ website.   
 
x 
Click on Regulatory at the top of the screen 
x 
Click on Site Registration; and  
x 
Enter the site’s 5-character CTEP Institution Code and click on Go 
o 
Additional filters are available to sort by Protocol, Registration Status, 
Protocol Status, and/or IRB Type. 
 
Note: The status shown only reflects institutional compliance with site registration 
requirements as outlined within the protocol. It does not reflect compliance with 
protocol requirements for individuals participating on the protocol or the enrolling 
investigator’s status with NCI or their affiliated networks. 
 
f. 
Delegation of Task Log (DTL) 
 
Each site must complete a protocol-specific Delegation of Tasks Log (DTL) using 
the DTL application in the Delegation Log section on the CTSU members’ website. 
The Clinical Investigator (CI) is required to review and electronically sign the DTL 
prior to the site receiving an approved site registration status and enrolling patients 
to the study. To maintain an approved site registration status the CI must re-sign 
the DTL at least annually and when a new version of the DTL is released; and 
activate new task assignments requiring CI sign-off. Any individual at the enrolling 
site on a participating roster may initiate the site DTL. Once the DTL is submitted 
for CI approval, only the designated DTL Administrators or the CI may update the 
DTL. Instructions on completing the DTL are available in the Help Topics button in 
the DTL application and include a Master Task List, which describes DTL task 
assignments, CI signature, and CTEP registration requirements. 
 
13.5 
OPEN Registration Requirements 
 
The Oncology Patient Enrollment Network (OPEN) is a web-based registration system 
available on a 24/7 basis. OPEN is integrated with CTSU regulatory and roster data and 
with the LPOs registration/randomization systems or the Theradex Interactive Web 
Response System (IWRS) for retrieval of patient registration/randomization assignment. 
OPEN will populate the patient enrollment data in NCI’s clinical data management system, 
Medidata Rave. 
 
Requirements for OPEN access:   
x 
A valid CTEP-IAM account; 
x 
To perform enrollments or request slot reservations: Must be on an LPO roster, 
ETCTN corresponding roster, or participating organization roster with the role 
of Registrar. Registrars must hold a minimum of an Associate Plus (AP) 
registration type; 
x 
If a Delegation of Tasks Log (DTL) is required for the study, the registrars must 
hold the OPEN Registrar task on the DTL for the site; and 
x 
Have an approved site registration for the protocol prior to patient enrollment. 
 
To assign an Investigator (IVR) or Non-Physician Investigator (NPIVR) as the treating, 
crediting, consenting, drug shipment (IVR only), or receiving investigator for a patient 
transfer in OPEN, the IVR or NPIVR must list the IRB number used on the site’s IRB 
approval on their Form FDA 1572 in RCR. If a DTL is required for the study, the IVR or 
NPIVR must be assigned the appropriate OPEN-related tasks on the DTL. 
 
 
 

 
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Prior to accessing OPEN, site staff should verify the following: 
x 
Patient has met all eligibility criteria within the protocol stated timeframes; and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
x 
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. You may print this confirmation for your records.  
 
Access OPEN at https://open.ctsu.org or from the OPEN tab on the CTSU members’ 
website.  Further instructional information is in the OPEN section of the CTSU website at 
https://www.ctsu.org or https://open.ctsu.org. For any additional questions, contact the 
CTSU Help Desk at 1-888-823-5923 or ctsucontact@westat.com. 
 
OPEN will also ask additional questions that are not present on the SWOG Registration 
Worksheet.  The individual registering the patient must be prepared to provide answers to 
the following questions: 
 
a. 
Institution CTEP ID 
b. 
Protocol Number 
c. 
Registration Step 
d. 
Treating Investigator 
e. 
Credit Investigator 
f. 
Patient Initials 
g. 
Patient’s Date of Birth 
h. 
Country of Residence 
i. 
ZIP Code 
j. 
Gender (select one): 
x 
Female Gender 
x 
Male Gender 
k. 
Ethnicity (select one): 
x 
Hispanic or Latino 
x 
Not Hispanic or Latino 
x 
Unknown 
l. 
Method of Payment (select one): 
x 
Private Insurance 
x 
Medicare 
x 
Medicare and Private Insurance 
x 
Medicaid 
x 
Medicaid and Medicare 
x 
Military or Veterans Sponsored NOS 
x 
Military Sponsored (Including Champus & Tricare) 
x 
Veterans Sponsored 
x 
Self Pay (No Insurance) 
x 
No Means of Payment (No Insurance) 
x 
Other 
x 
Unknown 
m. 
Race (select all that apply): 
x 
American Indian or Alaska Native 
x 
Asian 
x 
Black or African American 
x 
Native Hawaiian or other Pacific Islander 
x 
White 
x 
Unknown 
 
13.6 
Registration Procedures 

 
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a. 
All site staff will use OPEN to enroll patients to this study.  OPEN is integrated with 
the CTSU Enterprise System for regulatory and roster data and, upon enrollment, 
initializes the patient in the Rave database.  OPEN can be accessed at 
https://open.ctsu.org, from the OPEN tab on the CTSU members’ side of the 
website at https://www.ctsu.org, or from the OPEN Patient Registration link on the 
SWOG CRA Workbench. 
 
b. 
Prior to accessing OPEN site staff should verify the following: 
 
x 
All eligibility criteria have been met within the protocol stated timeframes and 
the affirmation of eligibility on the Registration Worksheet has been signed by 
the registering investigator or another investigator designate. Site staff should 
refer to Section 5.0 to verify eligibility. 
x 
All patients have signed an appropriate consent form and HIPAA 
authorization form (if applicable). 
 
c. 
The OPEN system will provide the site with a printable confirmation of registration 
and treatment information.   Please print this confirmation for your records. 
 
d. 
For COG Credited Enrollments ONLY: Prior to enrollment on this study, patients 
enrolling 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. 
 
e. 
Further instructional information is provided on the OPEN tab on the CTSU 
members’ side of the website at https://www.ctsu.org or at https://open.ctsu.org. 
For any additional questions contact the CTSU Help Desk at 888/823-5923 or 
ctsucontact@westat.com. 
 
13.7 
Exceptions to SWOG registration policies will not be permitted. 
 
a. 
Patients must meet all eligibility requirements. 
 
b. 
Institutions must be identified as approved for registration. 
 
c. 
Registrations may not be cancelled. 
 
d. 
Late registrations (after initiation of treatment) will not be accepted. 
 
 
14.0 
DATA SUBMISSION SCHEDULE 
 
14.1 
Data Submission Requirement 
 
Data must be submitted according to the protocol requirements for ALL patients registered, 
whether or not assigned treatment is administered, including patients deemed to be 
ineligible.  Patients for whom documentation is inadequate to determine eligibility will 
generally be deemed ineligible. 
 
 

 
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14.2 
Master Forms 
 
Master forms can be found on the protocol abstract page on the CTSU website 
(www.ctsu.org) and (with the exception of the sample consent form and the Registration 
Worksheet) must be submitted on-line via the Web; see below for details. 
 
14.3 
Data Submission Procedures 
 
a. 
Medidata Rave is a clinical data management system being used for data 
collection for this trial/study. Access to the trial in Rave is controlled through the 
CTEP-IAM system and role assignments.  
 
Requirements to access Rave via iMedidata: 
x 
A valid CTEP-IAM account; and  
x 
Assigned a Rave role on the LPO or PO roster at the enrolling site of: Rave 
CRA, Rave Read Only, Rave CRA (LabAdmin), Rave SLA, or Rave 
Investigator.  
 
Rave role requirements: 
o 
Rave CRA or Rave CRA (Lab Admin) role must have a minimum 
of an Associate Plus (AP) registration type; 
o 
Rave Investigator role must be registered as an Non-Physician 
Investigator (NPIVR) or Investigator (IVR); and 
o 
Rave Read Only role must have at a minimum an Associates (A) 
registration type. 
 
Refer to https://ctep.cancer.gov/investigatorResources/default.htm for registration 
types and documentation required. 
 
This study has a Delegation of Tasks Log (DTL). Therefore, those 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 Regulatory Support System 
(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 staff must log 
in to the Select Login (https://login.imedidata.com/selectlogin) using their CTEP-
IAM username and password and click on the accept link in the upper right-corner 
of the iMedidata page. Site staff 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. If an eLearning is 
required and has not yet been taken, the link to the eLearning will appear under 
the study name in iMedidata instead of the Rave EDC link; once the successful 
completion of the eLearning has been recorded, access to the study in Rave will 
be granted, and a Rave EDC link will display under the study name.  
 
Site staff that have not previously activated their iMedidata/Rave account at the 
time of initial site registration approval for the study in RSS will receive a separate 
invitation from iMedidata to activate their account. Account activation instructions 
are located on the CTSU website in the Data Management section under the Rave 
resource materials (Medidata Account Activation and Study Invitation 
Acceptance). Additional information on iMedidata/Rave is available on the CTSU 
members’ 
website 
in 
the 
Data 
Management 
> 
Rave 
section 
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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b. 
You may also access Rave® via the SWOG CRA Workbench via the SWOG 
website (www.swog.org).  
 
For difficulties with the CRA Workbench, please email  
technicalquestion@crab.org. 
 
c. 
Institutions participating through the Cancer Trials Support Unit (CTSU), please 
refer to the CTSU Participation Table. 
 
14.4 
Data Submission Overview and Timepoints  
 
a. 
WITHIN 15 DAYS AFTER REGISTRATION:    
 
Submit the following: 
x 
Vital Status Form 
x 
S1826 Onstudy Form 
x 
Baseline Tumor Assessment Form 
x 
Pathology Report 
(NOTE: Upload reports via the Source Documentation Baseline Form in 
Rave®.) 
x 
Submit radiology reports from all PET-CT, contrast-enhanced CT, MRI, or 
MR-PET scans performed to assess disease at baseline. (NOTE: Upload 
reports via the Source Documentation Baseline Form in Rave®.)  
x 
S1826 Imaging Adjunctive Data Sheet.  
This form is submitted electronically via the IROC website for PET scans; 
If PET scan is contraindicated and CT or MRI is submitted, the S1826 
Imaging 
Adjunctive 
Data 
Sheet 
is 
not 
required. 
Go 
to: 
https://wrightcenterofinnov.qualtrics.com/jfe/form/SV_cC0Pih8vSYcCnfU,    
then click on the arrow at the bottom of the screen to move to the screen 
with form questions, complete the form (clicking on arrows at bottom of 
screen to get to next page of questions), then click “submit”. Participating 
sites have the ability to save a copy of the submitted form responses by 
clicking “Download PDF” after submitting the form.     
x 
All PET-CT images (or if PET-CT contraindicated, then all contrast-
enhanced CT, MRI or MR-PET) from scans performed as standard of care 
to assess disease within 42 days prior to registration. Submit to IROC Ohio 
(via TRIAD strongly preferred) for retrospective central imaging review. 
 
b. 
WITHIN 28 DAYS AFTER REGISTRATION: 
 
Submit the following: 
x 
Specimens as outlined in Sections 15.1 and 15.2. 
x 
S1826 Pediatric PROMIS Global Health 7+2 (Pediatric) or S1826 
PROMIS-Global Health (Adults) 
x 
S1826 Pediatric PROMIS Fatigue 10a (Pediatrics) or S1826 PROMIS 
Fatigue 7a (Adults)  
x 
S1826 FACT/GOG-Ntx (Pediatric and Adult) 
x 
S1826 Cover Sheet for Patient-Completed Questionnaires or S1826 
Cover Sheet for Pediatric Patient-Completed Questionnaires 
 
c. 
WITHIN 15 DAYS AFTER CYCLE 1, DAY 1: 
 
Submit the Vital Status Form  
 
 

 
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d. 
WITHIN 15 DAYS AFTER EACH CYCLE OF TREATMENT 
 
Submit the following: 
x 
Vital Status Form 
x 
S1826 Treatment Form 
x 
S1826 Adverse Event Form 
x 
S1826 Concomitant Medication Form 
 
e. 
WITHIN 15 DAYS AFTER EACH PRO-CTCAE ASSESSMENT INCLUDING 
CYCLE 1 / DAY 1 (PRIOR TO BEGINNING OF TREATMENT), BEGINNING OF 
EACH SUBSEQUENT TREATMENT CYCLE (CYCLE 2 - 6), AFTER LAST DOSE 
OF STUDY DRUG, AFTER LAST DOSE OF RADIATION THERAPY (where 
applicable), 3-6 MONTHS AFTER DATE OF REGISTRATION (IF PATIENTS 
GOES OFF-TREATMENT EARLY), 9, 12, 18, 24, 30 AND 36 MONTHS AFTER 
DATE OF REGISTRATION. 
 
Submit the following: 
x 
S1826 PRO-CTCAE (Adults) or S1826 Pediatric PRO-CTCAE (Pediatrics) 
 
f. 
WITHIN 15 DAYS AFTER EACH DISEASE ASSESSMENT INCLUDING: CYCLE 
2 PET-CT (if done for clinical indication), CYCLE 6 (or at the End of Treatment if 
prior to Cycle 6), AT THE END OF RT (if patients received protocol-specified 
residual PET RT), and AT 1 YEAR AND 2 YEARS AFTER REGISTRATION 
 
For after Cycle 2, after Cycle 6 (or at the end of treatment if prior to Cycle 6), and 
at the end of RT PET-CT 
Submit the following: 
x 
Vital Status Form 
x 
Follow-up Tumor Assessment Form 
x 
Radiology reports from PET-CT, contrast-enhanced CT, MRI, or MR-
PET performed to assess disease at each time point. (NOTE: Upload 
reports via the Source Documentation: Disease Assessment form in 
Rave®.) 
x 
S1826 Imaging Adjunctive Data Sheet for PET scans; If PET scan is 
contraindicated and CT or MRI is submitted, the S1826 Imaging 
Adjunctive Data Sheet is not required.  
This form is submitted electronically via the IROC website at: 
https://wrightcenterofinnov.qualtrics.com/jfe/form/SV_cC0Pih8vSYcC
nfU.  See Section 14.4a for navigation instructions.  
x 
All PET-CT images (or if PET-CT contraindicated, then all contrast-
enhanced CT, MRI or MR-PET) from scans performed to assess 
disease as specified in Section 15.4.  Submit to IROC Ohio (via TRIAD 
strongly preferred) for retrospective central imaging review. 
 
For at 1-year and 2-year after registration contrast-enhanced CT 
Submit the following within 30 days of the above-specified timepoints: 
x 
Follow-up Tumor Assessment Form 
x 
Radiology reports from CT performed to assess disease at each time 
point. (NOTE: Upload reports via the Source Documentation: Disease 
Assessment form in Rave®). 
x 
All contrast-enhanced CT images of chest, abdomen and pelvis (+ 
neck or other involved areas, if involvement at baseline) (or if contra-
indicated, PET-CT, CT, MRI, or MR-PET) from scans performed to 
assess disease as specified in Section 15.4 Submit to IROC Ohio (via 
TRIAD strongly preferred) for retrospective central imaging review. 
o 
For patients who have had 1-year and 2-year after registration 
contrast-enhanced CT (or if contra-indicated, PET-CT, CT, 

 
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MRI, or MR-PET) scan performed prior to activation of S1826 
Protocol Revision 6, submit images to IROC Ohio within 60 
days after participating site activation of S1826 Protocol 
Revision 6 (Version Date 9/2/2023). 
 
o 
If CT scan is contraindicated and PET-CT scan is submitted, 
S1826 Imaging Adjunctive Data Sheet for PET scans is 
required. This form is submitted electronically via the IROC 
website 
at: 
https://wrightcenterofinnov.qualtrics.com/jfe/form/SV_cC0Pih
8vSYcCnfU. See Section 14.4a for navigation instructions. 
See Section 14.4a for navigation instructions.  
 
g. 
WITHIN 15 DAYS AFTER CYCLE 3, DAY 1: 
 
Submit the following: 
x 
Specimens as outlined in Section 15.2. 
x 
S1826 Pediatric PROMIS Global Health 7+2 (Pediatric) or S1826 
PROMIS-Global Health (Adults) 
x 
S1826 Pediatric PROMIS Fatigue 10a (Pediatrics) or S1826 PROMIS 
Fatigue 7a (Adults)  
x 
S1826 FACT/GOG-Ntx (Pediatrics and Adults) 
x 
S1826 Cover Sheet for Patient-Completed Questionnaires or S1826 
Cover sheet for Pediatric Patient-Completed Questionnaires. 
 
h. 
WITHIN 15 DAYS AFTER LAST DOSE OF PROTOCOL THERAPY (following last 
dose of study drug or radiation therapy, whichever is later): 
Submit the following: 
x 
Vital Status Form 
x 
Off Treatment Notice 
x 
S1826 Treatment Form 
x 
S1826 Adverse Event Form 
x 
S1826 Pediatric PROMIS Global Health 7+2 (Pediatric) or S1826 
PROMIS-Global Health (Adults)  
x 
S1826 Pediatric PROMIS Fatigue 10a (Pediatrics) or S1826 PROMIS 
Fatigue 7a (Adults)  
x 
S1826 FACT/GOG-Ntx (Pediatrics and Adults) 
x 
S1826 Cover Sheet for Patient-Completed Questionnaires or S1826 
Cover sheet for Pediatric Patient-Completed Questionnaires. 
i. 
WITHIN 15 DAYS AFTER THE END OF TREATMENT VISIT (4-8 weeks after last 
dose of study drug): 
 
Submit the following: 
x 
Vital Status Form 
x 
S1826 Adverse Event Form 
x 
S1826 Concomitant Medication Form 
x 
Follow-up Tumor Assessment Form 
x 
Radiology reports from PET-CT, contrast-enhanced CT, MRI, or MR-PET 
performed to assess disease at each time point. (NOTE: Upload reports 
via the Source Documentation: Disease Assessment form in Rave®.) 
x 
Specimens as outlined in Section 15.2. 
x 
S1826 Imaging Adjunctive Data Sheet for PET scans; If PET scan is 
contraindicated and CT or MRI is submitted, the S1826 Imaging Adjunctive 
Data Sheet is not required.  

 
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This form is submitted electronically via the IROC website at: 
https://wrightcenterofinnov.qualtrics.com/jfe/form/SV_cC0Pih8vSYcCnfU. 
See Section 14.4a for navigation instructions.  
x 
All PET-CT images (or if PET-CT contraindicated, then all contrast-
enhanced CT, MRI or MR-PET) from scans performed to assess disease 
as specified in Section 15.4.  Submit to IROC Ohio (via TRIAD strongly 
preferred) for retrospective central imaging review. 
 
 

 
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j. 
WITHIN 7 CALENDAR DAYS PRIOR TO THE START OF PLANNED RESIDUAL 
PET RT (per Section 7.5), as applicable: 
 
Submit the following: 
x 
Copies of reports (radiology, operative, pathology, cytology) and any 
other information used in defining the target volumes. Note: Reports and 
imaging previously submitted to IROC Ohio (via TRIAD strongly 
preferred) (per Section 15.4) need not be resubmitted. 
x 
Required data indicated in Section 18.6l to IROC Ohio (via TRIAD 
strongly preferred) for pre-treatment and approval. 
 
k. 
WITHIN 7 CALENDAR DAYS AFTER COMPLETION OF PLANNED RESIDUAL 
PET RT (per Section 7.5), as applicable: 
 
Submit the following: 
x 
S1826 Adverse Event Form 
x 
S1826 Protocol-specified Residual PET Radiation Therapy Form. 
x 
Submit the required data indicated in Section 18.6I.3 to IROC Ohio (via 
TRIAD strongly preferred). 
 
l. 
WITHIN 15 DAYS AFTER PROGRESSION/RELAPSE: 
 
Submit the following: 
x 
Vital Status Form 
x 
S1826 Treatment Form (if patient was still on treatment) 
x 
S1826 Adverse Event Form (if patient was still on treatment) 
x 
Follow-up Tumor Assessment Form 
x 
Radiology reports from PET-CT, contrast-enhanced CT, MRI, or MR-PET 
performed to assess disease at each time point. (NOTE: Upload reports 
via the Source Documentation: Disease Assessment form in Rave®.) 
x 
Specimens as outlined in Section 15.2. 
x 
S1826 Imaging Adjunctive Data Sheet for PET scans; If PET scan is 
contraindicated and CT or MRI is submitted, the S1826 Imaging Adjunctive 
Data Sheet is not required.  
This form is submitted electronically via the IROC website at: 
https://osu.az1.qualtrics.com/jfe/form/SV_8v1309A87eQOArb. 
See 
Section 14.4a for navigation instructions.  
x 
All PET-CT images (or if PET-CT contraindicated, then all contrast-
enhanced CT, MRI or MR-PET) from scans performed to assess disease 
as specified in Section 15.4.  Submit to IROC Ohio (via TRIAD strongly 
preferred) for retrospective central imaging review. 
x 
Follow-Up Form (if the patient was off protocol treatment) documenting 
date, site and method for determining progression/relapse. 
 
m. 
WITHIN 15 DAYS AFTER INITIATION OF NON-PROTOCOL THERAPY 
 
Submit the following: 
x 
Vital Status Form 
x 
S1826 Non-Protocol Therapy Form 
 
 

 
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n. 
AFTER OFF STUDY DRUG OR RADIATION THERAPY (WHERE APPLICABLE), 
EVERY 3 MONTHS FOR THE FIRST YEAR FROM REGISTRATION, THEN 
EVERY 6 MONTHS FOR THE SECOND AND THIRD YEAR FROM 
REGISTRATION, THEN ANNUALLY UNTIL 10 YEARS FROM THE DATE OF 
REGISTRATION.  
 
Submit the following within 30 days of the above-specified timepoints: 
x 
Vital Status Form 
x 
Follow Up Form  
x 
Late Adverse Events (if prior to treatment for progression or relapse or a 
second primary, and prior to non-protocol treatment, the patient 
experiences any severe [Grade ≥ 3] adverse event that is possibly, 
probably, or definitely related to protocol treatment, or a Serious Adverse 
Event [SAE] of any grade/attribution, that has not been previously 
reported). 
 
Note: After disease progression, above forms must be submitted annually 
(wherein, patients will be followed annually for survival and note of subsequent 
therapy which is typically performed by medical record review). 
 
o. 
AFTER OFF STUDY DRUG OR RADIATION THERAPY (WHERE APPLICABLE) 
TREATMENT, AT 1-YEAR AND 3-YEARS AFTER DATE OF REGISTRATION: 
 
Submit the following within 30 days of the above-specified timepoints: 
x 
Vital Status Form 
x 
S1826 Pediatric PROMIS Global Health 7+2 (Pediatric) or S1826 
PROMIS-Global Health (Adults) 
x 
S1826 Pediatric PROMIS Fatigue 10a (Pediatrics) or S1826 PROMIS 
Fatigue 7a (Adults)  
x 
S1826 FACT/GOG-Ntx (Pediatrics and Adults) 
x 
S1826 Cover Sheet for Patient-Completed Questionnaires or S1826 
Cover Sheet for Pediatric Patient-Completed Questionnaires 
 
p. 
WITHIN 4 WEEKS OF KNOWLEDGE OF DEATH: 
 
For all patients: 
Submit the following: 
x 
Vital Status Form 
x 
Notice of Death 
x 
S1826 End of Study Form 
 
If patient was on protocol treatment: 
Submit the following: 
x 
S1826 Treatment Form (final) 
x 
S1826 Adverse Event Form (final) 
 
If patient completed/ was off protocol treatment: 
Submit the following: 
x 
S1826 Follow Up Form 
x 
S1826 Non-protocol Therapy form (if non-protocol treatment was 
initiated and this form was not previously submitted). 
 
q. WITHIN 30 DAYS OF DECLARATION OF LOST TO FOLLOW-UP, REFUSAL OF 
ANY FOLLOW-UP, OR MAXIMUM FOLLOW-UP OF 10 YEARS: 
 
Submit the S1826 End of Study Form 
 

 
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15.0 
SPECIAL INSTRUCTIONS 
 
The following table provides an overview summary of the specimen submission timepoints. 
Please review the detailed specimen submission requirements outlined in Sections 15.1 -
15.3 below.  All specimen submissions will be shipped to the SWOG Biospecimen Bank 
(Lab #201). 
 
FFPE Tissue 
 
Timepoint 
Reason for 
Submission  
Specimen 
Kit 
Provided? 
Required? 
Baseline  
 
(submitted 
within 28 
days after 
registration) 
Pathology 
Review  
Diagnostic Biopsy 
FFPE block (preferred) * 
OR 
1 high-quality,  
4-5 micron, H&E slide 
No 
Required 
for 
Eligibility 
Banking for 
Planned 
future TM 
research 
Diagnostic Biopsy 
FFPE block (preferred) * 
OR  
1 high-quality,  
4-5 micron H&E slide ** 
and  
15 unstained,  
4-5 micron, positively-
charged slides ** 
No 
Required 
with 
patient 
consent 
No 
Required 
with 
patient 
consent 
*   Note: If the patient consents to specimen banking an FFPE block is 
strongly preferred. If the patient does not consent to specimen 
banking, then the H&E stained slide is preferred. 
**  For patients that consent to specimen banking: The baseline tissue 
submision should include either an FFPE tissue block (strongly 
preferred) or a total of 2 high-quality, 4-5 micron H&E slides plus 15 
unstained, 4-5 micron, positively-charged slides to meet both 
pathology reivew and banking requirements. (Note: If the patient 
consents to specimen banking and an FFPE tissue block is 
submitted, then the FFPE block will be utilized for both the required 
pathology specimen and the baseline tissue banking specimen for 
planned future research. Otherwise, a total of 17 tissue slides should 
be submitted as listed above.). 
Progression 
(submitted 
within 15 
days after 
progression) 
Banking for 
Planned 
future TM 
research 
Where a progression biopsy 
was performed via standard 
of care procedure and tissue 
is  available, submit:   
FFPE block (preferred)  
OR  
1 quality,  
4-5 micron, H&E slide  
and  
15 unstained,  
4-5 micron, positively-
charged slides. 
No 
Required 
with 
patient 
consent 

 
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Peripheral Blood 
 
Timepoint 
Allowable 
Window for 
Collection 
Specimen 
Kit 
Provided? 
Required? 
Cycle 1, Day 1 
Within 3 days 
prior to start 
of treatment 
Peripheral Blood in 
cfDNA Streck tubes 
Yes 
Required 
with patient 
consent 
Cycle 3, Day 1 
+/- 3 days 
Peripheral Blood in 
cfDNA Streck tubes 
Yes 
Required 
with patient 
consent 
After Cycle 6 / 
Day 15 * 
+/- 15 days 
Peripheral Blood in 
cfDNA Streck tubes 
Yes 
Required 
with patient 
consent 
Time of 
progression (if 
applicable) 
+/- 15 days 
Peripheral Blood in 
cfDNA Streck tubes 
Yes 
Required 
with patient 
consent 
* Note: The C6/D15 blood draw should be a fixed timepoint (even if patient comes off 
treatment early or goes on to receive RT). 
See also Section 7.1b for extended allowable collection windows in event of COVID-19 
extenuating circumstance. 
 
 
15.1 
Specimens for Pathology Review (REQUIRED): 
 
a. 
Specimens must be submitted at the time points listed below.  
 
1. 
Within 28 days after registration, submit:  
Formalin-fixed paraffin embedded (FFPE) diagnostic tumor tissue, 
including either: 1 block or 1 quality, 4-5 micron, H&E slide. 
 
NOTE: If the patient consents to specimen banking an FFPE tissue 
block is strongly preferred. If the patient does not consent to specimen 
banking, then the H&E stained slide is preferred. 
 
b. 
Specimen Collection and Submission Instructions 
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. Complete specimen collection and 
submission instructions can be accessed on the SWOG Specimen Submission 
webpage  
(https://www.swog.org/clinical-trials/biospecimen-resources/biospecimen-
processing-and-submission-procedures).  If collection/submission instructions 
differ from those in the protocol, the protocol instructions should be followed; 
otherwise, the website instructions should be followed. 
 
c. 
Specimen collection kits are not being provided for tissue submission; sites will 
use institutional supplies.  
 
 

 
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d. 
See Section 15.3 for Specimen Labelling and Shipping Instructions. 
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of diagnostic tissue samples for SWOG Biospecimen  
Submission and Pathology review is identified as follows: 
 
Lab #201:  
SWOG Biospecimen Bank – Solid Tissue, Myeloma and Lymphoma 
Division 
Phone: 614/722-2865 
E-mail:  bpcbank@nationwidechildrens.org  
  
15.2 
Banking for Planned future Translational Medicine  (REQUIRED with Patient Consent) 
 
Specimens for translational medicine and banking (submitted to the SWOG Biospecimen 
Bank – Solid Tissue, Myeloma and Lymphoma Division, Lab #201) (Optional for Patient): 
 
a. 
With patient consent, specimens must be submitted at the following times for 
planned future translational medicine objectives (see Section 9.0) 
 
1. 
20 ml Peripheral blood – collected in two 10ml cell-free DNA Streck 
tubes  (see Section 15.2c) – at the following timepoints: 
 
a. 
Cycle 1, Day 1 (within 3 days prior to start of treatment)   
 
b. 
Cycle 3, Day 1 (+/- 3 days) 
 
c. 
After Cycle 6 / Day 15 (+/- 15 days); Note: The C6/D15 blood draw 
should be a fixed timepoint (even if patient comes off treatment 
early or goes on to receive RT). 
 
d. 
Time of Progression, if applicable (+/- 15 days) 
 
See also Section 7.1b for extended allowable windows in event of COVID-
19 extenuating circumstance. 
 
2. 
Formalin-fixed paraffin embedded (FFPE) diagnostic tumor tissue for 
planned future translational medicine:  
 
At baseline:  If an FFPE tissue block was NOT submitted for pathology 
review (Section 15.1), then submit 1 high-quality, 4-5 micron H&E slide 
and 15 unstained, 4-5 micron, positively-charged slides for specimen 
banking within 28 days after registration.   If 1 FFPE tissue block was 
submitted for pathology review, then no additional tissue is required at 
baseline.  Include the corresponding pathology report, labeled with the 
SWOG patient number, in the shipment. 
 
At time of progression, where a biopsy was performed via standard 
of care procedure and tissue is available, submit:  1 FFPE tissue 
block or 1 high-quality, 4-5 micron, H&E slide and 15 unstained, 4-5 
micron, positively-charged slides within 28 days after biopsy was 
performed. Include the corresponding pathology report, labeled with the 
SWOG patient number, in the shipment. 
 
 
 

 
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Note: If the patient consents to optional specimen banking and limited 
tissue is available for the baseline submission, then at least 1 H&E slide 
must be submitted for eligiblity, as per Section 15.1. If the patient consents 
to optional specimen banking and limited or no tissue is available for 
submission at time of progression, then the site must document the reason 
for the incomplete specimen submission in the participant’s medical record 
and in the SWOG Specimen Tracking System, as follows:  
x 
If limited tissue is available, this must be documented in the 
Specimen Tracking System under “Comments” at the time of 
specimen submission.   
x 
If no tissue available, this must be documented in the Specimen 
Tracking System by choosing “Notify that Specimen Cannot be 
Submitted”. 
 
b. 
Specimen Collection and Submission Instructions 
 
Streck Cell-Free DNA Collection Tube Collection Guidelines 
x 
Fill tube completely (10 mL) 
x 
Immediately mix by gentle inversion 8 to 10 times. Inadequate or delayed 
mixing may result in an inadequate specimen.  
x 
After collection, blood in cfDNA Streck tubes should never be 
refrigerated, as this will compromise the specimen. Blood collected in 
cfDNA Streck tubes is stable at room temperature.  
 
If blood in Streck tube cannot be shipped the day of collection, then it must be kept 
at room temperature and shipped on the next working day to the SWOG 
Biospecimen Bank (Lab #201). Do not process.  
 
All specimen submissions for this study must be entered and tracked using the 
SWOG online Specimen Tracking system. Complete specimen collection and 
submission instructions can be accessed on the SWOG Specimen Submission 
webpage (https://www.swog.org/member-resources/biospecimen-resources).  If 
collection/submission instructions differ from those in the protocol, the protocol 
instructions should be followed; otherwise, the website instructions should be 
followed. 
 
c. 
Streck tubes for peripheral blood submisison may be ordered by using the SWOG 
Biospecimen Bank Management Application at  
https://ricapps.nationwidechildrens.org/KitManagement.   Sites must order 
collection kits in advance of each collection timepoint; A single collection kit will 
be provided for each collection timepoint. Allow at 5-7 days for shipment of 
collection kits. 
 
d. 
Specimen collection kits are not being provided for tissue submission; sites will 
use institutional supplies.   
 
e. 
See Section 15.3 for Specimen Labelling and Shipping Instructions  
 
In the online specimen tracking system, the appropriate SWOG laboratory for 
submission of diagnostic tissue samples for SWOG Biospecimen  
Submission and Pathology review is identified as follows: 
 
Lab #201:  
SWOG Biospecimen Bank – Solid Tissue, Myeloma and 
Lymphoma Division, Lab #201 
Phone: 614/722-2865 
E-mail:  bpcbank@nationwidechildrens.org  
 

 
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NOTE: Planned integrated biomarker testing of specimens banked for planned future 
research will not occur until an amendment to this protocol (or separate correlative science 
protocol) is reviewed and approved in accordance with National Clinical Trials Network 
(NCTN) policies. 
 
15.3 
SPECIMEN LABELING AND SHIPPING  
 
a. 
Label blood tubes with the following: 
 
x 
SWOG patient number 
x 
Patient initials 
x 
Collection date (date the specimen was collected from the patient) 
x 
Specimen type (i.e., whole blood) 
 
b. 
Include the following on FFPE tissue labels: 
 
x 
SWOG patient number 
x 
Patient initials 
x 
Collection date (date the specimen was collected from the patient) 
x 
Site of collection (e.g., Lymph node, left breast, liver, etc.) 
x 
Label the specimen type to be consistent with the specimen chosen in 
Specimen Tracking (e.g., FFPE tissue)  
x 
The Surgical Pathology ID # (Accession#) and block number (e.g., A2, 
3E, 2-1, B, etc.) must be on both the specimen label and the pathology 
report in order for the Bank to adequately match the specimen with any 
findings in the pathology report. 
x 
All slides derived from FFPE block(s) should be labeled with thickness 
(in μm).  
 
c. 
SHIPPING SAMPLES 
 
1. 
SWOG Specimen Tracking System (STS) 
All specimen submissions for this study must be entered and tracked using 
the SWOG online Specimen Tracking system. SWOG members may log 
on the online system via the CRA Workbench. To access the CRA 
Workbench, go to the SWOG Web site (http://swog.org) Non- SWOG 
users may log into SpecTrack using their CTSU UserID and password on 
the SpecTrack login page located at https://spectrack.crab.org (select the 
option “SWOG – SWOG – CTSU”).  SpecTrack start-up instructions (both 
written and demo) are available after signing in to SpecTrack.  
 
A copy of the Shipment Packing List produced by the online Specimen 
Tracking system should be printed and placed in the pocket of the 
specimen bag if it has one, or in a separate resealable bag. 
 
ALL SPECIMENS MUST BE LOGGED VIA THIS SYSTEM; THERE ARE 
NO EXCEPTIONS. 
 
To report technical problems with Specimen Tracking, such as database 
errors 
or 
connectivity 
issues, 
please 
send 
an 
email 
to 
technicalquestion@crab.org. For procedural help with logging and 
shipping specimens, there is an introduction to the system on the 
Specimen Tracking main page  
(https://spectrack.qacrab.org/Documents/SpecT%20Instructions-
Insts.pdf); or contact the SWOG Statistics and Data Management Center 
at 206/652-2267 to be routed to the Data Coordinator for further 
assistance. 
 

 
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In the online specimen tracking system, the appropriate SWOG laboratory 
for submission of diagnostic tissue samples for SWOG Biospecimen  
Submission and Pathology review is identified as follows: 
 
Lab #201:  
SWOG Biospecimen Bank – Solid Tissue, Myeloma and 
Lymphoma Division, Lab #201 
Phone: 614/722-2865 
E-mail:  bpcbank@nationwidechildrens.org  
 
NOTE: The SWOG Biospecimen Bank shipping address 
is accessible from the SWOG Specimen Tracking 
System, which must be utilized to log and track each 
specimen shipment. 
 
2. 
The cost of shipment of samples to the Biospecimen Bank is offset via the 
NCTN site payment at each collection timepoint. An overnight courier 
airbill is not provided. Participating sites are to use their instituional 
account number (or similar local method of payment) for the shipment. 
 
3. 
Complete instructions for packaging and shipping specimens are located 
on the SWOG Specimen submission webpage  
(https://www.swog.org/clinical-trials/biospecimen-
resources/biospecimen-processing-and-submission-procedures). 
 
15.4 
Imaging Submission Requirements (REQUIRED*) 
 
* If PET-CT is contraindicated for Patient, sites are to submit the contrast-enhanced 
CT, MRI or MR-PET from the same timepoint 
 
PET-CT images must be locally read and interpreted by the local site radiology service. 
PET-CT must then be submitted to the Imaging and Radiation Oncology Core (IROC) at 
Ohio (via TRIAD strongly preferred).  TRIAD will manage routing these studies to IROC 
Ohio for  Imaging Submission procedures for central data collection, and quality control 
(QC) check and retropective review as well as to IROC Rhode Island for the pre-treatment 
RT QA review as well as central review. 
 
a. 
Image Collection and Submission Time Points: 
 
Digital image collection is required at the following time points: 
 
1. 
PET-CT scans must be performed within 42 days prior to registration, as 
indicated in Section 5.1c and must be submitted to IROC within 15 days 
after registration, as indicated in Section 14.4a. 
 
2. 
Interim PET-CT scans that are performed for clinical purposes after Cycle 
2, Day 15 and prior to Cycle 3 must be submitted to IROC within 15 days 
after the assessment, as indicated in Section 14.4f.  
 
3. 
End of Treatment PET-CT scans must be performed 4-8 weeks after the 
last dose of study drug and must be submitted to IROC within 15 days 
after the assessment, as indicated in Sections 14.4f, 14.4i, and 14.4l. 
 
4. 
Progression/Relapse PET-CT scans must be performed and submitted to 
IROC within 15 days after progression/relapse, as indicated in Section 
14.4l. 
 

 
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5. 
1 year after registration contrast-enhanced CT scans of chest, abdomen 
and pelvis (+ neck or other involved areas, if involvement at baseline) (or 
if contra-indicated, PET-CT, CT, MRI, or MR-PET) must be performed and 
submitted to IROC within 30 days after the assessment, as indicated in 
Section 14.4f. 
 
6. 
2 years after registration contrast-enhanced CT scans of chest, abdomen 
and pelvis (+ neck or other involved areas, if involvement at baseline) (or 
if contra-indicated, PET-CT, CT, MRI, or MR-PET) must be performed and 
submitted to IROC within 30 days after the assessment, as indicated in 
Section 14.4f. 
 
 
See also Section 7.1b for extended allowable windows in event of COVID-19 
extenuating circumstance. 
 
b. 
Digital Image and Radiation Therapy Submission  
 
1. 
Image Submission Requirements 
 
Submission of treatment plans as DICOM RT is required. Digital data must 
include treatment planning CT, structures, plan, and dose files.  
TRIAD is the American College of Radiology’s (ACR) image exchange 
application.  TRIAD provides sites participating in clinical trials a secure 
method to transmit DICOM RT and other objects.  TRIAD anonymizes and 
validates the images as they are transferred. 
 
TRIAD is the preferred means of image transfer to the IROC. Due to the 
critical time constraints for submitting data for pre-treatment review, we 
encourage sites to submit data via TRIAD to ensure that the pre-treatment 
reviews are completed in a timely manner.  
In the event that a site has not completed all steps required for TRIAD data 
submission in time to meet the timeline for review, data submitted via 
SFTP will also be accepted.  See the instructions for submission of data 
via SFTP on the IROC Rhode Island website under Digital Data 
(www.irocri.qarc.org). 
 
2. 
TRIAD Access Requirements: 
 
TRIAD is the preferred means of image transfer to the IROC. TRIAD 
should be installed prior to study participant enrollment to ensure prompt 
secure, electronic submission of imaging and radiation therapy data. 
 
x 
Site staff who submit images through TRIAD will need to be registered 
with the Cancer Therapy Evaluation Program (CTEP) and have a valid 
and active CTEP-IAM account (see Section 13.2), and be registered 
as an AP, NPIVR or IVR.  Please refer to the CTEP Registration 
Procedures section for instructions on how to request a CTEP-IAM 
account and complete registration in RCR. 
x 
To submit images, the site user must be on the site’s affiliate rosters 
and be assigned the 'TRIAD site user' role on the CTSU roster.  Users 
should contact the site’s CTSU Administrator or Data Administrator to 
request assignment of the TRIAD site user role. RAs are able to 
submit standard of care imaging through the same method. 
 

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3.
TRIAD Installations:
After a user receives a CTEP-IAM account with the proper user role, 
he/she will need to have the TRIAD application installed on his/her 
workstation to be able to submit images. TRIAD installation documentation 
can be found by following this link https://triadinstall.acr.org/triadclient/ .
This process can be done in parallel to obtaining your CTEP-IAM 
account username and password.
If you have any questions regarding this information, please send an e-
mail to the TRIAD Support mailbox at TRIAD-Support@acr.org.
15.5
Patient-Reported Outcomes: Instructions for Administration (REQUIRED*)
*if patient speaks language in which the assessment tool is available (English, 
Spanish or French for most tools)
Patients are required to complete PRO forms at baseline and follow-up timepoints. 
Questionnaires should be completed at the time of the patient’s scheduled clinic visit but if 
this is not possible then the patient should complete them within ± 7 days of the follow-up 
contact. Please see Section 15.5c.4 for methods of administration in cases where patient 
visit is not conducted in the participating site’s clinic.
a.
QOL Instruments
The current CIRB-approved PRO (QOL) patient-facing forms are accessible on the 
CTSU website (www.ctsu.org) under “Documents” / “CIRB Documents” tab / 
“Amendment Reviews” subtab.
Patients who are <18 years of age at time of registration and turn age 18 while on 
protocol will continue to complete the Pediatric QOL assessments for the 
remainder of the protocol-specified timepoints. 
Pediatric PROMIS Global (Pediatric) or PROMIS-Global (Adults) 
(estimated time of completion:  1-2 minutes)
x
Available in English, Spanish, and French
Pediatric PROMIS Fatigue 10a (Pediatrics); 
PROMIS Fatigue 7a (Adults) 
(estimated time of completion:  2-3 minutes)
x
Fatigue 10a: Available in English, Spanish  
x
Fatigue 7a: Available in English, Spanish, and French.
FACT-GOG-NTX (both Pediatric and Adult, modified to remove platinum-
related items) 
(estimated time of completion:  < 5 minutes)
x
Available in English, Spanish, and French
b.
Administration Timepoints for all QOL instruments
Baseline (prior to registration)
Cycle 3 / Day 1 (prior to beginning treatment on Cycle 3)
4-8 weeks after the last dose of protocol therapy (following last dose of 
study drug or radiation therapy, whichever is later) 
1 year after date of registration

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3 years after date of registration
If a patient is removed from protocol therapy prior to an indicated 
administration timepoint, the indicated assessment tool must still be 
administered at that timepoint regardless of whether the patient has 
started a
subsequent anti-cancer therapy (after stopping protocol 
treatment).

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c.
Administration of Questionnaires
The first time the patient completes the questionnaires: Please read to the 
patient the instructions attached to each section. Explain the specific 
administration times for this protocol. Patients should be directed to report 
all symptoms and limitations whether or not they are related to the cancer 
or its treatment.
It is permissible to assist patients with completing the questionnaires, 
being careful not to influence the patient’s response. Note what assistance 
was required and indicate the reason in the Comments section (e.g., 
elderly, too sick, etc.). Discourage family members from: 1) being present 
while the patient completes the questionnaire and/or 2) influencing patient 
responses to the questions. 
If a patient refuses or cannot complete the questionnaire for some reason, 
then this must be documented in the S1826 Cover Sheet for Patient-
Reported Outcomes. 
If a patient misses an appointment or is too sick to complete the 
questionnaires on the scheduled date, a copy of the QOL questionnaires
must be provided to the patient (e.g. via e-mail, mail, or sent home with 
him/her). A telephone (or videoconference) interview must be scheduled 
and completed within one week of the originally scheduled timepoint. 
Patient responses to questionnaire items are to be obtained during the 
telephone (or videoconference) interview while the patient is looking at a 
copy of the questionnaire. The date of the telephone (or videoconference) 
interview is to be noted in the Cover Sheet for Patient-Reported
Outcomes. 
If a patient is deemed clinically ineligible after registration but protocol 
treatment was initiated, he/she should continue the PRO assessments as 
scheduled. PRO (QOL) assessments continue per scheduled timepoints 
even if the patient discontinues protocol treatment early and starts a 
subsequent anti-cancer therapy (after stopping protocol treatment). 
d.
Administration Quality Control Procedures
When a patient is registered to S1826, a calendar should be made with dates of 
upcoming patient-completed questionnaires noted. A copy of this calendar can be 
given to the patient with the notation that the questionnaires should be completed 
before receiving treatment. You may wish to photocopy the Study Calendar, 
Section 9.0, and include the patient’s name and specific dates. A copy of this (if 
created) should be kept in the patient file.
If a patient goes off protocol treatment, continue to administer the patient 
completed questionnaires according to the protocol-defined assessment 
schedule (time from registration date).
If a patient refuses or cannot complete the patient questionnaires at one 
time point, he/she should be asked to do so at the next scheduled 
administration time. 
The Quality of Life Coordinator will monitor compliance on a regular basis, 
having been provided with timely reports from the SWOG Statistical 
Center. The Expectation Report and the MediData RAVE system provides 
reminders of upcoming quality of life assessments for a patient.

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Anyone involved in the collection of quality of life data in SWOG trials 
should review the Patient-Reported Outcome Questionnaires training 
program available on the SWOG website (under the CRA workbench). The 
training program is a narrated set of slides designed to standardize the 
way quality of life data is collected from patients. Questions regarding the 
quality of life assessments can be addressed to the SWOG Statistics and 
Data Management Center (206/652-2267).
15.6
Patient-Reported Outcome Common Toxicity Criteria for Adverse Events (PRO-CTCAE) 
(REQUIRED for English- and Spanish- and French-speaking adult patients and English-
speaking pediatric patients)
PRO-CTCAE questions must be administered to English- and Spanish-, and French-
speaking patients weekly during the treatment period, as outlined below.
a.
Administration Timing
Patients will complete the PRO-CTCAE questions at the following time points:
1.
Cycle 1 / Day 1 (prior to beginning treatment)
2.
Day 1 of each subsequent treatment cycle (Cycle 2-6) (+/- 7 days)
3.
After last dose of study drug (+/- 7 days) and, where applicable, after last 
dose of radiation therapy, as applicable to the patient) (+/- 7 days)
4.
3-6 months after date of registration (if patient goes off-treatment early)
(+/- 7 days)
5.
9, 12, 18, 24, 30 and 36 months after date of registration (+/- 7 days)
The administration timing of the PRO-CTCAE questionnaire should coincide 
with the physician-directed toxicity assessment for the respective visit.
If a patient is removed from protocol therapy prior to an indicated 
administration timepoint, the scheduled PRO-CTCAE assessments must 
continue to be administered until such time that the patient starts a 
subsequent non-protocol systemic anti-cancer therapy.  
b.
Administration Instrument
The current CIRB-approved PRO (PRO-CTCAE) patient-facing forms are 
accessible on the CTSU website (www.ctsu.org) under “Documents” / “CIRB 
Documents” tab / “Amendment Reviews” subtab.
For adult patients (≥ 18 years of age), a total of 19 questions per timepoint will be 
answered using the Patient-Reported Outcomes Common Terminology Criteria for 
Adverse Events (PRO-CTCAE). The estimated time of completion for the Adult 
PRO questionnaire is 10 minutes.
For pediatric patients (12-17 years of age), a total of 33 questions per timepoint 
will be answered using the Pediatric Patient-Reported Outcomes Common 
Terminology Criteria for Adverse Events (Pediatric PRO-CTCAE).  The estimated 
time of completion for the Pediatric PRO questionnaire is 15 minutes. Patients who 
turn age 18 while on protocol will continue to complete the Pediatric PRO-CTCAE 
assessment for the remainder of the protocol-specified timepoints.

 
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The study-specific PRO-CTCAE items for this protocol can be found in Section 
18.10. 
 
c. 
Questionnaire Administration Instructions 
 
1. 
The first time the patient completes the questionnaire: Please read the 
instructions attached to the patient questionnaire to the patient. Explain 
the specific administration times for this protocol. Patients should be 
directed to report all symptoms and limitations, whether or not they are 
related to the cancer or its treatment. 
 
2. 
It is permissible to assist patients with completing the questionnaires being 
careful not to influence the patient's response. Discourage family 
members from: 1) being present while the patient completes the 
questionnaire and/or 2) influencing patient responses to the questions. 
 
3. 
It is very important to review the PRO-CTCAE questionnaire after the 
patient has completed it to be sure all questions have been answered and 
that only one answer is marked per question. If the patient has marked 
more than one answer per question, ask the patient which answer reflects 
how he/she is feeling. If the patient has skipped a question, tell the patient 
that a question was not answered and ask if she would like to answer the 
question. Always give the patient the option to refuse. If the patient 
declines to answer any question, indicate on the form by the question that 
the patient did not want to answer this question. 
 
4. 
If a patient misses an appointment and the physician-directed toxicity 
assessment is not conducted, then the PRO-CTCAE assessment for that 
timepoint should be documented as missed on the respective S1826 PRO-
CTCAE form.   
 
5. 
If the patient appointment is conducted via a telehealth visit within one 
week of the originally scheduled timepoint, and the toxicity assessment is 
also conducted via the telehealth visit, then, the PRO-CTCAE 
questionnaire 
may 
also 
be 
administered 
via 
telephone 
(or 
videoconference) at the same timepoint.  A copy of the PRO-CTCAE 
questionnaire must be provided to the patient (e.g. via e-mail or mail), and 
a telephone (or videoconference) interview may completed at the same 
telehealth visit as the toxicity assessment or may be scheduled separately 
as close to possible (and within the 7-day window of the original 
assessment timepoint) to the physician-directed toxicity assessment. 
Patient responses to questionnaire items are to be obtained during the 
telephone (videoconference) interview while the patient is looking at a 
copy of the questionnaire.  
 
6. 
If a patient is deemed clinically ineligible after registration but protocol 
treatment was initiated, he/she should continue the PRO assessments as 
scheduled. If the patient discontinues protocol treatment early, the PRO-
CTCAE assessments continue at the scheduled timepoints until such time 
that the patient begins new/different systemic anti-cancer therapy off-
protocol. 
 

 
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d. 
Additional Quality Control Procedures: 
 
When an English-, Spanish-, or French-speaking patient is registered on S1826, a 
calendar should be made with dates of upcoming patient-completed 
questionnaires noted. A copy of this calendar can be given to the patient with the 
notation that the questionnaires should be completed.  
 
If a patient refuses or cannot complete the PRO questionnaire at any time point, 
he or she should be asked complete the next set of patient questionnaires at 
the next scheduled assessment time.  
 
Anyone involved in the collection of quality of life data in SWOG trials should review 
the Patient-Reported Outcome Questionnaires training program available on the 
SWOG website (under the CRA workbench). The training program is a narrated 
set of slides designed to standardize the way quality of life data is collected from 
patients. Questions regarding the quality of life assessments can be addressed to 
the SWOG Statistics and Data Management Center (206/652-2267). 
 
16.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
The following must be observed to comply with Food and Drug Administration regulations for the 
conduct and monitoring of clinical investigations; they also represent sound research practice: 
 
Informed Consent and Assent 
The principles of informed consent are described by Federal Regulatory Guidelines (Federal 
Register Vol. 46, No. 17, January 27, 1981, part 50) and the Office for Protection from Research 
Risks Reports:  Protection of Human Subjects (Code of Federal Regulations 45 CFR 46).  They 
must be followed to comply with FDA regulations for the conduct and monitoring of clinical 
investigations. 
 
Institutional Review 
This study must be approved by an appropriate institutional review committee as defined by Federal 
Regulatory Guidelines (Ref. Federal Register Vol. 46, No. 17, January 27, 1981, part 56) and the 
Office for Protection from Research Risks Reports:  Protection of Human Subjects (Code of Federal 
Regulations 45 CFR 46). 
 
Drug Accountability 
An investigator is required to maintain adequate records of the disposition of investigational drugs 
according to procedures and requirements governing the use of investigational new drugs as 
described in the Code of Federal Regulations 21 CFR 312.  
 
Publication and Industry Contact 
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 in this study: 
 
1. 
Agent(s) may not be used 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 investigational 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 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 which 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 
investigational 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 exclusively 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 the Collaborator(s) for Phase III 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 the 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 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: E-mail:  ncicteppubs@mail.nih.gov. 
 
The Regulatory Affairs Branch will then distribute them to the Collaborator(s).  No 
publication, manuscript or other form of public disclosure shall contain any of the 
Collaborator's confidential/proprietary information. 
 
 
 

 
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Monitoring 
This study will be monitored by the Clinical Data Update System (CDUS) Version 3.0.  Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means.  Reports are due January 31, 
April 30, July 31 and October 31. 
 
Confidentiality 
Please note that the information contained in this protocol is considered confidential and should 
not be used or shared beyond the purposes of completing protocol requirements until or unless 
additional permission is obtained. 
 
 

 
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17.0 
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Press OW, et al. US Intergroup Trial of Response-Adapted Therapy for Stage III to IV 
Hodgkin Lymphoma Using Early Interim Fluorodeoxyglucose-Positron Emission 
Tomography Imaging: Southwest Oncology Group S0816. Journal of Clinical Oncology: 
Jun 10;34(17):2020-7. doi: 10.1200/JCO.2015.63.1119. Epub 2016 Apr 11. 2016. PMID: 
27069074. 
 
77.  
Johnson P, et al. Adapted Treatment Guided by Interim PET-CT Scan in Advanced 
Hodgkin's Lymphoma. New England Journal of Medicine: Jun 23;374(25):2419-29. doi: 
10.1056/NEJMoa1510093. 2016, PMID: 27332902. 
 
78.  
Connors JM, et al. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin's 
Lymphoma. New England Journal of Medicine: Jan 25;378(4):331-344. doi: 
10.1056/NEJMoa1708984. Epub 2017 Dec 10. 2018. PMID: 29224502 
 
79.  
Kelly KM et al. American Society Hematology 2015, Abstract #3927. 
 
80.  
Green MR, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-
1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin 
lymphoma and primary mediastinal large B-cell lymphoma. Blood: Oct 28;116(17):3268-
77. doi: 10.1182/blood-2010-05-282780. Epub 2010 Jul 13. 2010. PMID: 20628145. 
 
81.  
Younes A, et al. Nivolumab for classical Hodgkin's lymphoma after failure of both 
autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, 
single-arm phase 2 trial. Lancet Oncology: Sep;17(9):1283-94. doi: 10.1016/S1470-
2045(16)30167-X. Epub 2016 Jul 20. 2016. PMID: 27451390. 
 
82.  
Chen R, et al. Phase II Study of the Efficacy and Safety of Pembrolizumab for 
Relapsed/Refractory Classic Hodgkin Lymphoma. Journal of Clinical Oncology: Jul 
1;35(19):2125-2132. doi: 10.1200/JCO.2016.72.1316. Epub 2017 Apr 25. 2017. PMID: 
28441111. 
 
 

 
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Ramchandren R, et al. Nivolumab for newly diagnosed advanced-stage classical Hodgkin 
lymphoma: results from the phase 2 CheckMate 205 study [ASH abstract 651]. Blood. 
2017;130(suppl 1). 
 
84.  
Aleman BM, et al; European Organization for Research and Treatment of Cancer 
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J Med. 2003 Jun 12;348(24):2396-406. PubMed PMID: 12802025. 
 
85.  
Gallamini A, et al. Early Chemotherapy Intensification With Escalated BEACOPP in 
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Emission Tomography/ Computed Tomography Scan After Two ABVD Cycles: Long-Term 
Results of the GITIL/FIL HD 0607 Trial. J Clin Oncol. 2018 Feb 10;36(5):454-462. doi: 
10.1200/JCO.2017.75.2543. Epub 2018 Jan 23. PMID: 29360414. 
 
86.  
Borchmann P, et al. Eight cycles of escalated-dose BEACOPP compared with four cycles 
of escalated-dose BEACOPP followed by four cycles of baseline-dose BEACOPP with or 
without radiotherapy in patients with advanced-stage hodgkin's lymphoma: final analysis 
of the HD12 trial of the German Hodgkin Study Group. J Clin Oncol. 2011 Nov 
10;29(32):4234-42. doi: 10.1200/JCO.2010.33.9549. Epub 2011 Oct 11. PubMed PMID: 
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Johnson PW, et al. Consolidation radiotherapy in patients with advanced Hodgkin's 
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Borchmann P, et al. PET-guided treatment in patients with advanced-stage Hodgkin's 
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the German Hodgkin Study Group. Lancet. 2018 Dec 23;390(10114):2790-2802. doi: 
10.1016/S0140-6736(17)32134-7. Epub 2017 Oct 20. PubMed PMID: 29061295. 
 
89.  
Milgrom SA, Pinnix CC, Chuang H, et al. Early-stage Hodgkin lymphoma outcomes after 
combined modality therapy according to the post-chemotherapy 5-point score: can residual 
pet-positive disease be cured with radiotherapy alone? Br J Haematol. 2017 
Nov;179(3):488-496. 
 
90.  
Sher DJ, Mauch PM, Van Den Abbeele A, LaCasce AS, Czerminski J, Ng AK. Prognostic 
significance of mid- and post-ABVD PET imaging in Hodgkin's lymphoma: the importance 
of involved-field radiotherapy. Ann Oncol. 2009 Nov;20(11):1848-53. 
 
91.  
Borchmann P, Goergen H, Kobe C, et al. PET-guided treatment in patients with advanced-
stage Hodgkin's lymphoma  (HD18): final results of an open-label, international, 
randomised phase 3 trial by the German Hodgkin Study Group. Lancet. 2018 Dec 
23;390(10114):2790-2802. 
 
92.  
Diefenbach CS et al. Evaluation of the International Prognostic Score (IPS-7) and a Simpler 
Prognostic Score (IPS-3) for advanced Hodgkin lymphoma in the modern era. British 
Journal of Haematology: 2015 Nov;171(4):530-8. doi: 10.1111/bjh.13634. Epub 2015 Sep 
7. 2015. PMID: 26343802. 
 
93.  
Mottok A, et al. PREDICTION OF PRIMARY TREATMENT RESPONSE AND OUTCOME 
IN PEDIATRIC HODGKIN LYMPHOMA USING DIGITAL GENE EXPRESSION 
PROFILING  Abstract P069. haematologica Journal of the European Hematology 
Association Published by the Ferrata Storti Foundation 0th International Symposium on 
Hodgkin Lymphoma, Cologne, October 22-25, 2016 Abstract BooK| 2016; 101(s5). 
 
 

 
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Roemer MGM, et al. Major Histocompatibility Complex Class II and Programmed Death 
Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic 
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10.1200/JCO.2017.77.3994. Epub 2018 Feb 2.  2018, PMID: 29394125. 
 
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Hasenclever D and Diehl V. A prognostic score for advanced Hodgkin's disease. 
International Prognostic Factors Project on Advanced Hodgkin's Disease. N Engl J Med 
339:1506-14, 1998. 
 
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Schwartz GJ, B G: A simple estimate of glomerula filtration rate in adolescent boys. J. 
Pediatr. 106:522-6, 1985. 
 
97.  
Boleti E and Mead GM. ABVD for Hodgkin's lymphoma: full-dose chemotherapy without 
dose reductions or growth factors. Ann Oncol 18:376-80, 2007. 
 
98.  
Evens A, Cilley J, Ortiz T, et al. G-CSF is not necessary to maintain over 99% dose-
intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent 
outcomes in a 10-year analysis. Br J Haematol 137:545-52, 2007. 
 
99.  
Boleti E and Mead GM. ABVD for Hodgkin's lymphoma: full-dose chemotherapy without 
dose reductions or growth factors. Ann Oncol 18:376-80, 2007. 
 
100.  
Evens A, Cilley J, Ortiz T, et al. G-CSF is not necessary to maintain over 99% dose-
intensity with ABVD in the treatment of Hodgkin lymphoma: low toxicity and excellent 
outcomes in a 10-year analysis. Br J Haematol 137:545-52, 2007. 
 
101.  
PG Kluetz, DT Chingos, EM Basch, et al.  Patient-Reported Outcomes in Cancer Clinical 
Trials:  Measuring Symptomatic Adverse Events with the National Cancer Institute’s 
Patient-Reported Outcomes Version of the Common Terminology Criteria for Adverse 
Events (PRO-CTCAE).  Am Soc Clin Oncol Educ Book 35:67-73, 2016. 
 
 

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18.0 
APPENDIX 
 
18.1  
LYRIC Criteria 
 
18.2 
Quality of Life  
 
18.3 
Management 
Algorithms 
Immuno-Oncology 
(I-O) 
Therapy 
for 
Endocrinopathy, 
Gastrointestinal, Hepatic, Neurological, Pulmonary, Renal and Skin Adverse Events for 
Nivolumab (Arm 1) Adverse Event Management 
 
18.4 
Performance Status Scales 
 
18.5 
FDG-PET-CT Imaging Procedures and Image Acquisition 
 
18.6 
Radiation Therapy Guidelines 
 
18.7 
Measurement-Based Response Assessment According to the Lugano Classification 
 
18.8  
Instructions for the SWOG Biospecimen Bank – Lab #201: Solid Tissue, Myeloma and 
Lymphoma Division 
 
18.9 
CYP1A2 and CYP3A Inhibitors and Inducers 
 
18.10  PRO-CTCAE Common Terminology Criteria for Adverse Events (PRO-CTCAE) Instrument 
 
18.11 
Patient Clinical Trial Wallet Card 
 
18.12 
AYA Educational Resource Information, COG Participating Site Frequently Asked 
Questions, NCTN Adult Group Participating Site Frequently Asked Questions 
 
 
 
 
 
 
 
 
 

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18.1 
LYRIC Criteria 
 
Lugano Classification was developed based on treatment with cytotoxic agents. 
Immunotherapeutic drugs may produce antitumor effects by potentiating endogenous 
cancer-specific immune responses. The response patterns seen with such an approach 
may extend beyond the typical time course of responses seen with cytotoxic agents and 
can manifest as clinical responses after initial increases in tumor burden or even the 
appearance of new lesions.  
Thus, the 2014 Lugano Classification may not provide an accurate assessment of 
response to immunotherapeutic agents. Provisional modification of the Lugano criteria 
(LYRIC Criteria) may be used to assess participants who meet progressive disease per 
Lugano Classification. (132F1,13F2)  
The LYmphoma Response to Immunomodulatory therapy Criteria (LYRIC) has recently 
been proposed for tumor response assessment after immunomodulatory therapies such 
as immune checkpoint inhibitors. (134F3) These criteria address possible flare phenomenon or 
pseudoprogression that may be misclassified as progressive disease (PD) particularly 
during the first two or three weeks of treatment thus leading to underestimation of the 
clinical benefit of the treatment.  
LYRIC criteria introduced a term “Indeterminate Response (IR)” to be able to distinguish 
between flare/pseudo-progression and true PD. A mandatory subsequent evaluation within 
12 weeks is required to confirm or refute true progressive disease.  
 
 

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Complete 
Response 
Partial 
Response 
Progressive Disease 
Same as 
Lugano  
Same as 
Lugano  
As with Lugano with the following exceptions: 
Indeterminate response (IR) 
IR1: ≥50% increase in SPD of up to 6 measurable lesions 
in first 12 weeks of therapy without clinical deterioration 
IR2: <50% increase in the overall SPD with 
a. Appearance of a new lesion(s), or 
b. ≥50% increase in PPD of a lesion or set of 
lesions at any time during treatment 
IR(3): Increase in FDG uptake without a concomitant 
increase in lesion size or number  
Patients with IR should continue on therapy and have 
repeat imaging after an additional 12 weeks (or sooner if 
clinically indicated). 
Progressive disease criteria in these patients will be met if:  
IR1: An additional increase in the target SPD of ≥ 10% 
between the first IR1 timepoint and the SPD being 
assessed; or an increase in ≥ 5mm in either dimension of 
at least one lesion for lesions ≤ 2cm and 10mm for lesions 
> 2cm. 
IR2: the new or growing lesion(s) should be added to the 
target lesions (total of no more than 6) and there is PD if 
the SPD if the newly defined set of target lesions has 
increased ≥50% from their nadir value (which may 
precede the IR time point). 
IR3: There is evidence of PD by an increase in lesion size 
or the development of new lesions. 
Abbreviations: SPD, sum of the product of the diameters; PPD, product of the 
perpendicular diameters. 
 
 
 

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References
 
1  
Cheson BD, Fisher RI, Barrington SF, et al. Recommendations for initial 
evaluation, staging, and response assessment of Hodgkin and non-Hodgkin 
lymphoma: the Lugano classification. J Clin Oncol 32:3059-68, 2014. 
 
2  
Barrington SF, Mikhaeel NG, Kostakoglu L, et al. Role of imaging in the staging 
and response assessment of lymphoma: consensus of the International 
Conference on Malignant Lymphomas Imaging Working Group. J Clin Oncol. 
32:3048-58, 2014. 
 
3  
Cheson BD, Ansell S, Schwartz L et al. Refinement of the Lugano Classification 
lymphoma response criteria in the era of immunomodulatory therapy. Blood 
128:2489-2496, 2016. 
 
 
 
 
 

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18.2 
Quality of Life  
 
a. 
Quality of Life Objectives 
 
To compare between arms patient-reported fatigue, neuropathy and health-related 
quality of life over time (baseline prior to registration, at Day 56 (corresponding to 
the beginning of Cycle 3), 4-8 weeks after the last dose of protocol therapy 
(following last dose of study drug or radiation therapy, whichever is later), and 1 
and 3 years after randomization) using the PROMIS-Fatigue (or Ped PROMIS 
Fatigue), the FACT/GOG-Ntx, and the PROMIS Global (or Ped PROMIS-Global), 
respectively 
 
1. 
Hypothesis: 1: Patients randomly assigned to the N-AVD arm will have 
worse fatigue scores during initial treatment with resolution by one-year 
post treatment than patients randomly assigned to the BV arm. Patients 
receiving both nivolumab and radiation therapy will have worse fatigue 
than recipients of nivolumab without radiation. Self-reported fatigue and 
HRQL will be measured by the PROMIS Fatigue scale(s) (adult or 
pediatric versions) and PROMIS-Global or Pediatric PROMIS-Global, 
respectively. 
 
2. 
Hypothesis 2: Patients randomly assigned to the BV-AVD will have worse 
FACT/GOG-Ntx scores on treatment and by 1 year after the completion of 
treatment, as compared to patients randomly assigned to the N-AVD arm. 
Scores will be worse for patients 40 years or older.  
 
b. 
Background 
 
Patients with newly diagnosed, advanced stage HL are at risk for poor HQRL as a 
result of their underlying disease and its treatment -- whether dose-dense 
chemotherapy alone or in combination with planned radiotherapy. Several studies 
in adults with HL have also demonstrated that a subset of patients report severe 
fatigue at the time of diagnosis (est. 10%) and that for some fatigue persists long 
after completion of therapy.  The introduction of novel therapies into the upfront 
treatment of HL, including the antibody-drug conjugate Brentuximab vedotin (BV) 
and PD-1 inhibitors, such as Nivolumab offer the promise of improved disease-free 
and overall survival, the potential reduction of radiotherapy, and the associated 
decrease in late effects. These agents, however, are associated with their own 
symptoms burden, such as peripheral neuropathy (BV) or rashes, colitis, 
pneumonitis, and endocrinopathies (Nivo). Recent studies suggest a rate of 
peripheral sensory neuropathy of 20% or higher with BV, and toxicity that was 
associated with premature abandonment of the experimental arm on the 
ECHELON1 trial. The long term impact of Nivo on HRQL after successful 
immunomodulation of the tumor is not known, although recent studies have 
demonstrated the relationship between adverse events and poorer HRQL. Hence, 
we propose the first study to capture longitudinal HRQL, anchored to symptom 
burden in pediatric and adult patients with advanced stage HL.  
 
Recently validated measures within the constructs of overall HRQL, fatigue, and 
patient-reported symptoms afford us with an instrument battery that is targeted and 
brief, spans the full age span of the trial population, and generally available in the 
needed target languages (i.e., English, Spanish, and French).   
 
 
 

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In the current Children’s Oncology Group (COG) Phase III trial in HL (AHOD 1331; 
NCT02166463) in which we are evaluating the inclusion of BV into the existing 
chemotherapy backbone, we have serially measured HRQL, patient-reported 
CIPN, health care utilization and health utilities from more than 300 children and 
where appropriate, from their parent proxies. (Proxy report was used in children 
under 11 years, who could not provide unassisted self-report). We have collected 
provider grading of targeted toxicities, most notably peripheral neuropathy, at each 
cycle. More than 97% of eligible patients participated in the study, completing 
baseline measures prior to the start of planned therapy. At scheduled follow up 
time points (Cycle 2, D8; Cycle 5, D8; 6-8 weeks off therapy; 12- and 36- months 
off-therapy), we have collected measures from 95% of participants. Similar to the 
proposed study, we have begun the analysis with aggregate results (preserving 
the blinding by study arm) with the plan of ultimately comparing by study arm, 
following completion of full trial accrual.  
 
c. 
Quality of Life Instruments 
 
In this study we rely on validated measures (PROMIS Global, PROMIS fatigue, 
and FACT/GOG-Ntx) to be completed by patients in a 15-minute period at key 
clinical time points during the trial.  All of these instruments are available and have 
been validated for both youth and adult self-report in English, French, and Spanish, 
allowing for broad participation across the age span of the trial population. 
Moreover, the youth and adult versions of the same instruments have been 
determined to measure the same constructs, enabling us to combine the age 
groups into unified analyses, stratified by age.  
 
1. 
PROMIS Fatigue 
 
The PROMIS Fatigue measure is the standard for evaluating cancer-
related fatigue in clinical trials. (1)  The seven item PROMIS-Fatigue short 
form for adults and the 10 item short form for children < 18 years have 
been created from validated item banks (adult, 95 total items; pediatric 23 
total items). The PROMIS Fatigue instruments evaluate self-reported 
symptoms ranging from mild subjective feelings of tiredness to a 
sustained, overwhelming sense of exhaustion that affects one’s ability to 
perform daily activities and function normally [PROMS-Fatigue manual].  
PROMIS Fatigue instruments provide a unidimensional assessment of 
fatigue that captures both the experience of fatigue (frequency, duration, 
and intensity) and its impact on physical, mental, and social activities. (2)  
A raw summary score of survey results is rescaled into a standardized 
score (T-score) with a mean of 50 and standard deviation of 10 (i.e., scores 
above 50 indicate worse than average fatigue) [PROMS-Fatigue manual].        
 
2. 
FACT/GOG-Ntx 
 
Neurotoxicity will be assessed using the 11-item Neurotoxicity component 
of the Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group—Neurotoxicity (FACT/GOG-Ntx) questionnaire. The FACT/GOG-
Ntx is the FACT-G plus an eleven-item subscale that evaluates symptoms 
and concerns associated specifically with chemotherapy-induced 
neuropathy. The scale contains two items related to platinum-based 
chemotherapy, which will be deleted for the scale score (thus, a maximum 
score of 36 vs. 44). Additionally, the scale contains a 4-item peripheral 
sensory neuropathy subscale, which has been shown by Huang et al. to 
be sensitive to change over time. A one-point difference in the sensory 
subscale is clinically important. (Cella, personal communication, October 
2018).   

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The FACT/GOG-Ntx and its peripheral sensory subscale measures the 
severity on a continuous scale. The FACTGOG-Ntx is a reliable and valid 
instrument for assessing the impact of neuropathy on health-related 
quality of life in adults, having demonstrated strong psychometric 
properties, including sensitivity to meaningful clinical distinctions and 
responsiveness to change over time patterns were reported by the 
National Surgical Adjuvant Breast and Bowel Project. (141F3,142F4,143F5,14F6) 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%. (145F7) 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. (146F8)  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, a finding echoed in 
the qualitative research of Textor et al. (147F9,148F10)  
 
The FACT/GOG-Ntx also has been used successfully in the ongoing 
Children’s Oncology Group study AHOD 1331 for both youth self-report 
(patients ages 11 years and older) and parent proxies. Internal 
consistency reliability exceeded 0.80 for both raters on the 9-item total 
neuropathy scale score and on the 4-item sensory neuropathy subscale. 
(Parsons, personal communication). Additionally, mean scale scores for 
the FACT-Ntx differed significantly by clinical grading (stratified as any 
neuropathy vs. no neuropathy) for both raters. Compared to patients 
without neuropathy, those with neuropathy reported significantly lower 
HRQL scores, as has been documented in adults with neuropathy.   
 
3. 
PROMIS Global 
 
The PROMIS-Global is a 10-item measure of general health and 
functioning, detailing the respondent’s perceptions of physical function, 
pain, fatigue, emotional distress, social health, and overall health. In 
addition to specific item scores, the measure yields two summary scores 
for global physical health and global mental health. These summary 
scores can be compared to general population norms when converted to 
a T-score metric (mean, 50; SD, 10). Using an established algorithm, this 
measure can also be used to calculate EQ-5D index scores. (11)  
 
d. 
Timepoints 
 
The quality of life assessments are scheduled to occur at baseline prior to 
registration, at Day 56 (corresponding to Day 1 of Cycle 3 [assessment window +/- 
7 days]), 4-8 weeks after the last dose of protocol therapy (following last dose of 
study drug or radiation therapy, whichever is later) [assessment window 4 weeks]), 
at 1 year after registration (assessment window +/- 7 days), and at 3 years after 
registration (assessment window +/- 7 days). 
 

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e. 
Experimental Research Techniques/tests Employed and Expertise of PI  
 
Research staff members will be trained to administer quality of life forms by viewing 
a training module available on the SWOG website (www.swog.org); the program 
can be found at the CRA WorkBench/Training. For example, this training program 
indicates that research staff should not influence the patient’s responses to the 
questionnaires. Research staff will need to enter the reported data into the online 
Medidata RAVE system. Efforts to minimize missing data are critical to obtaining 
interpretable results. The training module addresses methods for reducing missing 
data.   
 
Susan Parsons, M.D., M.R.P., Tufts Medical Center, is the Principal Investigator 
on two ongoing embedded studies within AHOD 1331 (study Chair: Sharon 
Castellino, M.D., MSc., Emory, Children’s Hospital of Atlanta) to evaluate 
chemotherapy-induced peripheral neuropathy, using the FACT/GOG-Ntx and 
global HRQL.  
 
Statistical analyses will be performed by Joseph Unger, Ph.D., who leads the PRO 
Core within the SWOG Statistical Center. 
 
f. 
Recall Period for the measures is as follows: 
 
1. 
FACT/GOG-Ntx: 7 days 
2. 
PROMIS-Global (adults): 7 questions “in general,” 3 questions past 7 
days; Pediatric Global: 7 “in general”, 2 questions past 7 days 
3. 
Fatigue 7a (adults) OR Fatigue 10a (kids): 7 days 
 
g. 
QOL Statistical Considerations 
 
Quality of life assessments will occur in conjunction with the clinical follow-up 
schedule in order to minimize missing data and to link the clinical assessments 
with patients’ self-reported symptom burden. This design should also minimize 
patient and staff burden. The assessment times are fixed and are scheduled to 
occur as noted in Section 18.2d. The time points are designed to capture acute 
toxicity and HRQL impact prior to treatment initiation, during planned therapy (e.g., 
Cycle 3, Day 1) and at the end of planned therapy (including radiation), as well as 
the persistence of toxicity and HRQL impact after date of registration (at 12 and 36 
months). The assessment at Cycle 3, Day 1 was selected to align with a post 2 
cycle disease response that will be done on the trial in the same time frame. The 
end-of-treatment visit after completion of planned therapy also coincides to the 
anticipate dose peak level of the tubulin toxins and thus, the potentially greatest 
risk of CIPN, as has been seen in our ongoing COG study. The 12-month after 
date of registration time points are important to understanding the potential 
resolution of acute toxicities and their impact on HRQL for these novel agents.  The 
36-month after date of registration time point is deliberately chosen both to assess 
persistence of toxicity (i.e., fatigue and neuropathy), as well as to capture HRQL 
in cases where salvage therapy may have been necessary in cases of failure of 
primary treatment on either study arm. In addition, given the unknown temporal 
course of immune modulation in de novo disease both with regard to control of HL 
and to the risk of immune-mediated toxicity, a 36-month assessment time point is 
thought to be important. The specification of fixed assessment times helps limit the 
potential to induce a dependence between the clinical and QOL outcomes, which 
could bias the QOL results. Study windows have been created around each of the 
planned assessments to avoid dependency of the treatment course (e.g., due to 
treatment delays).   

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Multiple primary endpoints will be examined, two for fatigue, and two for 
neuropathy. To examine the four independent endpoints with full power that 
includes adjustment for multiple comparisons, all 940 eligible patients will be 
included in the QOL analyses. To adjust for multiple comparisons, we will set 
alpha=.0125 based on Bonferonni.  
Two primary endpoints are specified for fatigue, one 4-8 weeks after the last dose 
of protocol therapy (following last dose of study drug or radiation therapy, 
whichever is later) and one at 1 year after randomization. We hypothesize that 
patients randomly assigned to the N-AVD arm will have worse fatigue scores 
during initial treatment, although there is uncertainty about the direction of the 
effect, suggesting that a two-sided design is appropriate. Fatigue is further 
hypothesized to be mitigated by year 1, although again there is uncertainty 
regarding the impact of the therapies on the magnitude and direction of the affects 
at this timepoint. Fatigue will be examined by arm using the PROMIS Fatigue. 
(12,13,14,15) Both a pediatric and adult version of the PROMIS Fatigue have been 
validated as noted above and have been determined to assess the same 
constructs in the different patient age groups (pediatric vs. adults). This allows the 
combining of scores across age, although stratification by age will be conducted 
given potentially different levels of fatigue. The PROMIS-Fatigue scale has a 
standardized mean of 50 with a SD of 10 points. (16,17,18,19) Representative 
literature about the trajectory of fatigue over time in a broad range of cancer 
patients indicates that follow-up scores after treatment initiation have a standard 
deviation of about 12 points. (20)  Our goal is to identify an effect size of 0.3, a 
small to medium effect, with good power. (21) This corresponds to a difference of 
3.6 points or larger in the PROMIS-Fatigue between arms, which has been shown 
to be approximately in the middle of the range (3-5 points) of clinically meaningful 
differences identified for this instrument. (22) We assume, conservatively, dropout 
or non-response of 20% at the first assessment (time of  completion of treatment) 
and 25% at the second assessment (1 year after randomization). Based on these 
parameters and using a two-sided two-arm normal design, there will be 95% power 
to detect a difference of 3 points in the PROMIS-Fatigue at last day of protocol 
therapy and 93% power at 1 year after randomization.  
 
Neuropathy will be analyzed by arm at 1 year and at 3 years after randomization. 
This instrument is validated for both pediatric and adult patients. We hypothesize 
that patients assigned to the BV-AVD arm will have worse neuropathy over time 
compared to patients on the N-AVD arm, although as for fatigue, we allow 
uncertainty about the direction of the effect and will rely on a two-sided design. 
Neuropathy will be measured using the FACT/GOG-Ntx. The modified 9-item scale 
FACT/GOG-Ntx measures the severity of neurotoxicity on a continuous scale. A 
change of 3 points has been proposed as the minimally significant (i.e., clinically 
important) difference for this subscale. (161F23) Standard deviations at ≥ 3 months after 
initiation of treatment are generally about 9 points; for design purposes, we 
assume a more conservative standard deviation of 10 points, corresponding to an 
effect of 0.3 points, a small to medium effect. (162F24,163F25) Greater dropout and non-
response of 25% is assumed at 1 year, and 35% at 3 years. Based on these 
parameters and using a two-sided two-arm normal design with alpha=.0125, there 
will be 93% power to detect a difference of 3 points in the FACT/GOG-Ntx at 1 
year after randomization and 89% at 3 years.  
 
Consistent with the design, the analyses of the PROMIS-Fatigue and FACT/GOG-
Ntx endpoints will be conducted using multiple linear regression analysis, adjusting 
for stratification factors and the baseline score as covariates. See Section 6.0 for 
stratification factors. We will also conduct longitudinal modeling of the outcome 
measures over time. Power for the longitudinal analysis will be greater since the 
addition of all available scores over time will provide more information. For 
longitudinal modeling, linear mixed models will be used. The potential for 

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differential dropout by arm will be mitigated by reminder notifications to site 
investigators to encourage proper assessment and submission of forms at every 
required time point for all patients. Dropout patterns will be monitored on an 
ongoing basis. Nonetheless the potential for non-random dropout exists. Cohort 
plots will be prepared to examine the extent to which missing data are informative 
(i.e., scores are higher (worse) for patients just before their data are missing for 
the subsequent assessment).  If there is evidence of non-random dropout, pattern-
mixture models will be utilized as a sensitivity analysis.  Covariates for longitudinal 
modeling will include intervention assignment, assessment time, their interaction, 
the baseline score, and the stratification factors as covariates. We will also explore 
differences in trajectories by categorical age (12-17 years, 18-39 years, ≥ 40 
years). 
 
Secondary objectives include examinations by arm of fatigue and neuropathy at 
the other specified discrete timepoints (fatigue: beginning of Cycle 3, and 3 years 
after randomization; neuropathy: beginning of Cycle 3 and time of completion of 
treatment). Analyses by arm at these individual assessment times will be 
conducted using multiple linear regression, adjusting for stratification factors and 
the baseline score as covariates.  For all secondary analyses, no adjustment for 
multiple comparisons will be made, as these are considered hypothesis-
generating, requiring confirmation in independent analysis.  
 
We will also examine patient-reported health-related quality of life by arm using the 
PROMIS Global for pediatric and adult patients.  (26,27,28)   Further, we will 
compare the quality-adjusted survival between the study arms, using the Q-TWiST 
method from diagnosis to the end of follow up. Utility weights for this analysis will 
be obtained from the PROMIS-Global, via established crosswalk algorithms. (167F29) 
 
We will describe scores on all patient-reported measures at each time period using 
means, standard deviations, medians, 25th-75th percentiles, minimums and 
maximums, histograms, frequencies, and percentages. Missing data will be 
explored for all variables. 
 
h. 
References
 
1  
Barsevick, A. M., Irwin, M. R., Hinds, P., Miller, A., Berger, A., Jacobsen, 
P., et al. National Cancer Institute Clinical Trials Planning, M. (2013). 
Recommendations for high-priority research on cancer-related fatigue in 
children and adults. Journal of the National Cancer Institute, 105(19), 
1432-1440. Retrieved from http://www.ncbi.nlm.nih.gov/pubmed/2404 
7960 doi:10.1093/jnci/djt242. 
 
2  
Lai JS, Stucky B, Thissen D, et al: Development and Psychometric 
Properties of the PROMIS Pediatric Fatigue Item Banks. Qual Life Res. 
22(9): 2417–2427, 2013. 
 
3  
Cella D, Peterman A, Hudgens S, et al. Measuring the side effects of 
taxane therapy in oncology: the functional assessment of cancer therapy-
taxane (FACT-taxane). Cancer 98:822-31, 2003. 
 
4  
Postma TJ, Hoekman K, van Riel JM, et al: Peripheral neuropathy due to 
biweekly paclitaxel, epirubicin and cisplatin in patients with advanced 
ovarian cancer. J Neurooncol 45:241-6, 1999. 
 
5  
Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of 
the Functional Assessment of Cancer Therapy/Gynecologic Oncology 
 

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Group-Neurotoxicity (Fact/GOGNtx) questionnaire for patients receiving 
systemic chemotherapy. Int J Gynecol Cancer. 13(6):741-748, 2003. 
 
6  
Kopec JA, Land SR, Cecchini RS, et al: Validation of a Self-Reported 
Neurotoxicity Scale in Patients with Operable Colon Cancer Receiving 
Oxaliplatin. J Support Oncol. 4(8):W1-W7, 2006. 
 
7  
Huang HQ, Brady MF, Cella D, et al: Validation and reduction of 
FACT/GOG-Ntx subscale for platinum/paclitaxel-induced neurologic 
symptoms: a gynecologic oncology group study. Int J Gynecol Cancer 
17:387-93, 2007. 
 
8  
Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of 
the Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity (Fact/GOGNtx) questionnaire for patients receiving 
systemic chemotherapy. Int J Gynecol Cancer 13(6):741-748, 2003. 
 
9  
Mols F, Beijers T, Lemmens V, et al: Chemotherapy-induced neuropathy 
and its association with quality of life among 2- to 11-year colorectal 
cancer survivors: results from the population-based PROFILES registry. J 
Clin Oncol 31:2699-707, 2013. 
 
10  
Textor LH, Hedrick J: The lived experience of peripheral neuropathy after 
solid organ transplant. Prog Transplant 22:271-9, 2012 
 
11  
Revicki DA, Kawata AK, Harnam N, et al: Predicting EuroQol (EQ-5D) 
scores from the patient-reported outcomes measurement information 
system (PROMIS) global items and domain item banks in a United States 
sample. Qual Life Res. 18(6):783-91, 2009. 
 
12  
Lai JS, Stucky B, Thissen D, et al: Development and Psychometric 
Properties of the PROMIS Pediatric Fatigue Item Banks. Qual Life Res. 
22(9): 2417–2427, 2013. 
 
13  
Cella D, Lai JS, Jensen SE, et al: PROMIS Fatique Item Bank had Clinical 
Validity across Diverse Chronic Conditions. J Clinical Epidemiol. 73:128-
134, 2016. 
 
14  
Ameringer S, Elswick RK, Menzies V, et al: Psychometric Evaluation of 
the PROMIS Fatigue-Short Form Across Diverse Populations. Nurs Res. 
65(4):279-289, 2016. 
 
15  
Reeve BB, Pinheiro LC, Jensen RE, et al: Psychometric evaluation of the 
PROMIS Fatigue measure in an ethnically and racially diverse population-
based sample of cancer patients. Psychol Test Assess Model. 58(1):119-
139, 2016. 
 
16  
Lai JS, Stucky B, Thissen D, et al: Development and Psychometric 
Properties of the PROMIS Pediatric Fatigue Item Banks. Qual Life Res. 
22(9): 2417–2427, 2013. 
 
17  
Cella D, Lai JS, Jensen SE, et al: PROMIS Fatique Item Bank had Clinical 
Validity across Diverse Chronic Conditions. J Clinical Epidemiol. 73:128-
134, 2016. 
 
 

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18  
Ameringer S, Elswick RK, Menzies V, et al: Psychometric Evaluation of 
the PROMIS Fatigue-Short Form Across Diverse Populations. Nurs Res. 
65(4):279-289, 2016. 
 
19  
Reeve BB, Pinheiro LC, Jensen RE, et al: Psychometric evaluation of the 
PROMIS Fatigue measure in an ethnically and racially diverse population-
based sample of cancer patients. Psychol Test Assess Model. 58(1):119-
139, 2016. 
 
20  
Jensen, RE, et al. United States Population-Based Estimates of Patient-
Reported Outcomes Measurement Information System Symptom and 
Functional Status Reference Values for Individuals With Cancer. Journal 
of 
Clinical 
Oncology. 
2017 
Jun 
10;35(17):1913-1920. 
doi: 
10.1200/JCO.2016.71.4410. Epub 2017 Apr 20. PMID: 28426375. 
 
21  
Cohen J. Statistical Power Analysis. Association for Psychological 
Science: 
Sage 
Journal. 
1992 
Jun 
1;1(3):98-101. 
https://doi.org/10.1111/1467-8721.ep10768783. 
 
22  
Yost, KJ, et al. Minimally important differences were estimated for six 
Patient-Reported Outcomes Measurement Information System-Cancer 
scales in advanced-stage cancer patients. Journal of Clinical 
Epidemiology. 
2011 
May;64(5):507-16. 
doi: 
10.1016/j.jclinepi.2010.11.018. PMID: 21447427. 
 
23  
Cella D, Peterman A, Hudgens S, et al. Measuring the side effects of 
taxane therapy in oncology: the functional assessment of cancer therapy-
taxane (FACT-taxane). Cancer 98:822-31, 2003. 
 
24  
Cella D, Peterman A, Hudgens S, et al. Measuring the side effects of 
taxane therapy in oncology: the functional assessment of cancer therapy-
taxane (FACT-taxane). Cancer 98:822-31, 2003. 
 
25  
Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of 
the Functional Assessment of Cancer Therapy/Gynecologic Oncology 
Group-Neurotoxicity (Fact/GOGNtx) questionnaire for patients receiving 
systemic chemotherapy. Int J Gynecol Cancer. 2003;13(6):741-748. 
 
26  
Hays RD, Bjorner JB, Revicki DA, et al: Development of physical and 
mental health summary scores from the patient-reported outcome 
measurement information system (PROMIS) global items. Qual Life Res. 
18(7): 873-80, 2009. 
 
27  
Forrest CB, Bevans KB, Pratiwadi R, et al: Development of the PROMIS 
pediatric blobal health (PGH-7) measure. Qual Life Res. 23(4): 1221-31, 
2014. 
 
28  
Forrest CB, Tucker CA, Ravens-Sieberer U, et al: Concurrent validity of 
the PROMIS pediatric global health measure. Qual Life Res. 25(3): 739-
51, 2016. 
 
29  
Revicki DA, Kawata AK, Harnam N, et al: Predicting EuroQol (EQ-5D) 
scores from the patient-reported outcomes measurement information 
system (PROMIS) global items and domain item banks in a United States 
sample. Qual Life Res. 18(6):783-91, 2009. 
 
 
 

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18.3 
Management Algorithms for Immuno-Oncology (I-O) Therapy for Endocrinopathy, 
Gastrointestinal, Hepatic, Neurological, Pulmonary, Renal and Skin Adverse Events for 
Nivolumab (Arm 1) Adverse Event Management 
 
Note:  For the following algorithms, prednisone PO may be utilized in place of 
methylprednisone IV. 
 
Please see below. 
 
 
a. 
Endocrinopathy Management Algorithm 
 
 
 
 

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b. 
GI Adverse Event Management Algorithm 
 
 

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c. 
Hepatic Adverse Event Management Algorithm 
 
 
 
 
 

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d. 
Neurological Adverse Event Management Algorithm 
 
 
 
 
 

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e. 
Pulmonary Adverse Event Management Algorithm 
 
 
 

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f. 
Renal Adverse Event Management Algorithm 
 
 
 
 
 
 
 
 

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g. 
Skin Adverse Event Management Algorithm 
 
 
 
 

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18.4 
Performance Status Scales 
 
Performance Status Criteria 
Lansky performance scores are intended to be multiples of 10 
Zubrod 
Lansky* 
Score 
Description 
Score 
Description 
0 
Fully active, able to carry on all 
pre-disease performance without 
restriction. 
100 
Fully active, normal. 
90 
Minor restrictions in physically 
strenuous activity. 
1 
Restricted in physically strenuous 
activity but ambulatory and able to 
carry out work of a light or 
sedentary 
nature, 
e.g., 
light 
housework, office work. 
80 
Active, but tires more quickly 
70 
Both greater restriction of and 
less time spent in play activity. 
2 
Ambulatory and capable of all 
self-care but unable to carry out 
any work activities. Up and about 
more than 50% of waking hours 
60 
Up and around, but minimal 
active play; keeps busy with 
quieter activities. 
50 
Gets dressed, but lies around 
much of the day; no active play, 
able to participate in all quiet 
play and activities. 
3 
Capable of only limited self- care, 
confined to bed or chair more 
than 50% of waking hours. 
40 
Mostly in bed; participates in 
quiet activities. 
30 
In bed; needs assistance even 
for quiet play. 
4 
Completely 
disabled. 
Cannot 
carry on any self-care. Totally 
confined to bed or chair. 
20 
Often sleeping; play entirely 
limited to very passive activities. 
10 
No play; does not get out of bed. 
*The conversion of Lansky to Zubrod scales is intended for NCI reporting purposes only. 
 
 

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18.5
FDG PET-CT Imaging Procedures and Image Acquisition
a.
FDG-PET-CT Requirements for Participation 
Access:
The participating center must have, or have access to, a facility with an 
integrated positron-emission tomography and computed tomography 
(PET-CT) scanner. 
Electronic Submission
The participating center must have the ability to submit PET and CT 
studies electronically to the ACRIN Imaging Core Laboratory in digital 
DICOM format (other formats: BITMAP, JPG). Hardcopy or scanned files 
are not acceptable. 
b.
FDG-PET-CT Imaging Procedures 
Patient Preparation 
Patients must fast for at least four hours before the PET-CT scan. Oral hydration 
is strongly encouraged prior to and during injection of 18F-FDG (250-500 mL water 
can be given PO during the uptake period). Intravenous fluids containing dextrose 
or parenteral feeding should be withheld for at least 6 hours prior to the injection 
of 18F-FDG. No steroid administration is allowed for at least 7 days prior to FDG-
PET imaging. Active exercise should be discouraged for at least 24 hours prior to 
the study. Muscle stress, tension, chewing, and movement during the uptake 
period should be minimized to decrease muscle uptake. Patients should not speak 
during the injection and uptake period. Interviews with the patient should be 
withheld until after completion of the imaging study. 
The blood glucose level should be checked before 18F-FDG injection. Blood sugar 
(measured by glucometer) must be less than 200 mg/dL at the time of the FDG-
PET-CT study. If the blood glucose level is greater than 200 mg/dL, the FDG-PET-
CT imaging should be rescheduled. If the blood glucose level still exceeds 200 
mg/dL on the following scheduled day for PET scanning, the patient will not be 
included in the analysis. Insulin administration immediately before the PET-CT
study to reduce the glucose levels is not allowed. Patients with diabetes should 
continue to adhere to their oral agents or insulin routines. These medications 
should not be administered near the 18F-FDG injection time. In insulin-dependent 
patients, insulin should be administered at least 5 hours prior to the 18F-FDG 
injection. Patients with diabetes who are on diabetic medication should take their 
medication 4-5 hours prior to the test. 
Metallic objects should be removed from the patients whenever possible. Patients 
should be kept in a warm waiting room prior to 18F-FDG injection to avoid brown 
adipose tissue uptake. In anxious and claustrophobic patients, administration of 
oral diazepam (0.06-0.10 mg/kg) is recommended 30-40 minutes prior to the 
initiation of the imaging study. 
Weight (kg), height (cm), blood glucose (mg/dL), and the date and time of 
chemotherapy, glucose levels and colony stimulating factor administration (e.g., 
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The dose of 
18F-FDG should be based on the scanner manufacturer’s 
recommendation (per institutional procedure). A 10-20 mL saline flush is 
recommended in reducing the venous retention of 18F-FDG. The patient must wait 
at least 60 minutes (+/-10 minutes) prior to the initiation of the PET-CT acquisition 
for all PET-CT scans (both pre-and post-therapy scans). The imaging wait from 
injection period should be kept with a minimal variation of 10 minutes among 
patients. The wait period should not be shorter than 50 min and longer than 75 
minutes at baseline. The time difference between baseline and other time points 
(i.e. interim and end of therapy) should not exceed 10 minutes.  
 
The imaging will start after voiding the bladder. 150-200 mL of water should be 
given to the patient immediately prior to the study acquisition before they are 
positioned on the table to distend stomach and avoid physiologic stomach uptake.  
 
c. 
FDG-PET-CT Image Acquisition  
Patients should be positioned on the table in a headfirst, supine position with arms 
elevated above the abdomen to reduce beam-hardening artifacts at the level of the 
liver. The use of IV and oral contrast is at the discretion of each institution. 
However, IV-contrast CT acquisition is recommended to follow PET imaging 
acquired with non-contrast CT to avoid variations in FDG uptake in the blood pool 
and the tumor. 
 
If IV contrast is not used, CT should be acquired using a current of not less than 
120 mA/second to allow for sufficient resolution for definition of anatomic 
structures. Immediately after CT scanning, a PET emission scan will be obtained.  
 
The PET-CT scan should cover at least from the mid skull to the 1/3 proximal 
femurs. The time/bed position should be in accordance with the manufacturer’s 
recommendations for optimal imaging.  
 
It is critical that follow-up PET-CT scans be performed in an identical way to the 
baseline scan, with the same scanner, same scan direction (skull to thighs or 
thighs to skull), and consistent arm positioning (arms up or arms down).  
 
 

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18.6
Radiation Therapy Guidelines
End of treatment Residual PET RT may be administered at the discretion of the treating 
physician, provided that the intent to deliver RT was declared at study enrollment and the 
criteria in Section 7.5 are met.
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 can only be delivered at approved RT facilities. 
Pre-treatment Review of Radiation therapy plans will be conducted by IROC Rhode 
Island. Data detailed in Section 14.4 must be submitted one week prior to the start 
of Radiation Therapy for review and approval. This RT QA review will also confirm 
sites of partial response which will require radiation. Any radiation therapy delivered 
not consistent with the RT QA review response categorization will be considered a 
major protocol deviation.
a.
Indications for Radiotherapy 
The indication for RT will be based on imaging evaluation performed upon 
completion of 6 cycles of systemic therapy. In general terms, RT will be delivered 
when patients have 1-2 sites initially involved with HL that achieve only a partial 
response. Specifically, RT will be indicated when the patient has persistent sites 
upon completion of 6 cycles of systemic therapy that meet all of the following 
criteria: 
Residual nodal mass ≥ 2.5cm in axial diameter, or residual extranodal 
lesion >1cm in axial diameter (e.g. lung nodule or splenic nodule), and 
Has Deauville score = 4 or 5, and  
Has ≥ 30% reduction in maximal transverse diameter compared to pre-
treatment imaging.
RT may be given to one or two nodal sites.  
The following circumstances are contraindications for RT:
Deauville score 5 due to development of new PET avid sites during 
systemic therapy.
Three or more persistent PET-avid (Deauville score 4-5) sites at 
completion of systemic therapy.
A PET-avid site contained within a CT abnormality that has not achieved 
at least 30% reduction in transverse diameter.
Patients with these features are unlikely to be cured with RT, and biopsy with 
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b. 
Radiotherapy Dose and Schedule  
PET Positive After 6 Cycles of Systemic Therapy (PET score 4-5) 
Radiotherapy will consist of 3000-3600 cGy in fractions of 150-200 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 4 weeks.  
 
c. 
Timing of Radiotherapy and Starting Criteria 
Treatment should begin 5-12 weeks from Cycle 6, Day 15 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. 
 
d. 
Credentialing Requirements 
Patients may receive RT with photons or proton therapy. Intensity Modulated 
Radiation Therapy (IMRT), VMAT (or its equivalents) 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 must irradiate the Proton Lung 
Phantom available from IROC Houston. 
 
 
 

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The credentialing requirements by treatment modality are summarized in the 
following table. 
 
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 
thoracic 
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. 
 
 
 

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e.
Equipment
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. 
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. 
Use of IMRT in conjunction with gating or tracking techniques requires 
credentialing by the IROC Houston. The Motion Management Reporting 
Form shall be submitted with the Quality Assurance Documentation 
materials whenever motion management techniques are used.
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. Questions 
regarding proton therapy on trial should be sent to Bradford Hoppe MD 
(hoppe.bradford@mayo.edu) 
and/or 
Stella 
Flampouri 
PhD 
(stella.flampouri@emory.edu). 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.
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 or spleen is being treated, the entire 
thoracic volume should be scanned to create accurate estimates of lung 
and heart dose.
There are mandatory requirements for submission of the dose to selected 
normal tissues (see Section 18.6l). A Dose Volume Histogram (DVH) is 
necessary to determine target coverage and evaluate dose to normal 
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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.
f.
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). 
It is not necessary to treat initially involved sites that have achieved an anatomic 
and metabolic Complete Response. The indications for RT are outlined in Section 
18.6a and should be the principal determinants in defining the gross tumor volume 
(GTV), the clinical target volume (CTV) and the planning target volume (PTV). 
Note: The following definitions apply only to sites of disease that meet the criteria 
for receiving RT.
Post-Chemotherapy GTVtotal
Following completion of 6 cycles of systemic therapy, the post-
chemotherapy GTVtotal includes persisting imaging abnormalities seen 
on CT that encompass a PET-avid site (Deauville 4-5). Note that for RT 
planning purposes, this includes the parts of that mass that are PET-
negative. The GTV (and CTV) are not just the PET-avid volume within the 
persistent CT abnormality. Residual nodal masses must be ≥2.5 cm in 
greatest axial diameter and residual extranodal lesions (lung nodules, 
splenic nodules) must be ≥1cm to be eligible for RT. The CTV and PTV 
encompassing the GTVtotal are to be prescribed 30Gy. 
GTVPET+: This is defined as the volume of imaging abnormality that 
remains PET avid (Deauville score 4-5) following completion of 6 cycles of 
systemic therapy. This volume is contained within, and is typically smaller 
than, the post-chemotherapy GTVtotal defined above. This volume, and 
its surrounding PTV, should be boosted with an additional 6Gy (total 36Gy) 
provided the boost does not cause the normal tissue dose limits described 
below to be exceeded. The boost is not required if it causes the normal 
tissue constraints to be exceeded. When a boost is to be employed, a CTV 
expansion is not required around the GTVPET+ volume, although an 
ITV/PTV expansion is required. 
Post-Chemotherapy Clinical Target Volume (CTV) 
For this study, the CTV should encompass the GTVtotal volume described 
above, plus any additional volume that may be required to account for 
uncertainty in disease localization due to variation in imaging, patient 
positioning, etc. Since the at-risk CT abnormality encompasses the PET-
avid volume, this volume will almost always be larger than the GTVPET+ 
volume. 

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Delineation of the CTV requires consideration of the expected routes of 
disease spread, and the quality of the 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 CT/PET 
abnormality within an exact location in an axial image of the involved nodal 
space. Consideration of other clinical and imaging factors 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 
uncertainties inherent with GTV delineation due to inaccuracies in 
matching patient positioning and the variable internal anatomy shifts that 
change with patient position between diagnostic and treatment positions.
As a guideline, a margin of 1.0 cm above and below the GTVtotal is 
recommended. When boosting the PET-avid volume, it is not necessary 
to add a CTV expansion around the GTVPET+ volume (i.e. the CTVPET+ 
and the GTVPET+ are the same).
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.
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. 
For proton treatments, target motion assessment should be performed 
4DCT and dose distributions should be calculated and reviewed on the 
two extreme breathing phases. When motion reduction techniques are 
used such as breath-hold or abdominal compression, multiple scans 
should be acquired during simulation to evaluate the reproducibility of the 
method. ITV should encompass the CTV from all available scans.
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, for a CTV that includes inferior mediastinal structures, an 
isometric 5 mm expansion around will rarely provide adequate coverage. 
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.
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.

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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 consistent with the motion control and 
setup accuracy for the particular type of treatment (scattered versus 
scanning) at the treating proton center. Robustness evaluation based on 
dose calculations of error scenarios as described in Section 18.6g.4a. is 
an alternative to PTV dose reporting.
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 18.6g.
Special Circumstances
Sites of initially involved nodal disease adjacent to PET-avid target site 
It is not required to include within the CTV sites of initial involvement that 
are adjacent to a PET-avid mass and that have achieved anatomic and 
metabolic Complete Response.  However, in some circumstances,
inclusion of immediately adjacent sites in the CTV may be viewed as 
clinically appropriate and may be achieved without significantly increasing 
normal tissue dose (for example, adjacent extranodal involvement where 
recurrence could cause nerve root compression). In these circumstances, 
treating clinicians can include adjacent sites of involvement without 
incurring a protocol violation.
Circumstances in which PET-negative adjacent sites should be excluded 
from the CTV include: axillae in females, the high cervical nodes (salivary 
structures), and cardiophrenic/diaphragmatic nodes (heart).
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.

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Joining separate sites of disease receiving RT
When two 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.
Specific Anatomic Sites
a.
Spleen
The spleen will be treated if it is a site containing PET-avid 
lesion(s) meeting the criteria listed above. In such cases, the 
entire spleen should be targeted as the CTVtotal, not just the 
incompletely responding nodule. 
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 6 may be 
affected by muted immune response at that time.
b.
Lung, pericardium, liver, bone or other parenchymal nodules
These sites are treated only if they contain localized sites of 
incomplete response meeting the RT-eligibility criteria listed 
above. Irradiation of the whole lung, whole liver or entire bones is 
to be avoided. 
c.
Mediastinum (including hila)
In cases where the residual mediastinal disease is enmeshed 
within the major vessels, it is acceptable to contour the entire 
mediastinum as the CTVtotal at levels above the heart. However, 
at the level of the heart, effort should be made to localize 
GTV/CTV volumes as precisely as possible using the definitions 
above without including the heart in the CTV (unless there is direct 
pericardial/cardiac involvement). 
In circumstances when the mediastinum is being treated for 
protocol-directed indications and when the adjacent nodal or 
extranodal sites (e.g. chest wall, internal mammary nodes, hilar 
nodes) were involved but achieved a complete anatomic response 
on CT and PET, it is not necessary to encompass the adjacent 
sites. However, the volume may be extended at the discretion of 
the treating oncologist to include these immediately adjacent sites 
if they are viewed to be at substantial risk and can be 
encompassed without significantly increasing normal tissue dose 
to the lung, female breast, or heart. This is not mandatory, 
however, and will not be counted as a protocol deviation. 

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d. 
Spleen only 
 
In those patients scheduled to receive RT to the spleen because 
of incomplete response, the entire spleen should be treated as the 
CTVtotal. A 6Gy boost to the PET avid volume is allowable, but 
not necessary. Target delineation with 4D-CT imaging is 
preferred, but in the absence of 4D-CT, a 1.0 -1.5 cm field margin 
to account for respiratory movement is acceptable. The post-
chemotherapy spleen volume should be used, as defined by CT 
scan. If the paraaortic lymph nodes were not initially involved, or 
achieved a metabolic complete response, they do not need to be 
included.  
 
e. 
Paraaortic lymph nodes only 
 
Intravenous contrast is recommended for RT planning CT scans. 
In cases where the involvement of lymph nodes meeting the 
criteria for RT is 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. 
 
f. 
Pelvic lymph nodes 
 
Intravenous contrast is recommended for RT planning CT scans. 
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.  
 
For female patients, 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. 
 
g. 
Pericardium 
 
Whole pericardial irradiation is contra-indicated. If the pericardium 
was extensively involved by lymphoma and is part of the CTV 
definition, the mean dose to the heart should be limited to < 15 Gy.  
In circumstances where this cannot be achieved, the treating 
oncologist should review the case with a study investigator. 
 
h. 
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 criteria listed above. Whole organ irradiation is 
contraindicated. For PET avid lung nodules, the involved portion 
of lung (or lungs) should be treated with at least a 1.5 cm margin. 
Patients presenting with a pleural effusion should not receive 
treatment to the whole hemithorax. Similarly, isolated liver or bone 
lesions meeting criteria for RT may be treated with GTV, CTV, and 
PTV definitions as described above. Whole liver or bone RT is not 
required. 

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i.
Solitary Bone or Bone Marrow Lesion
A skeletal lesion seen on FDG-PET should only be considered true 
bone lesion if there is an associated bone abnormality seen on CT 
at the time of diagnosis. Abnormal sites involving the skeleton 
without an associated CT abnormality should be considered as 
bone marrow involvement. 
RT is only indicated for true bone involvement that remains PET 
avid (Deauville 4-5) at completion of systemic therapy. Bone sites 
meeting the criteria for RT should be treated with at least a 1 cm 
margin around the radiological abnormality. No more than 2 sites 
should be considered for radiation. 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.
g.
Target Dose
The dose to the GTVtotal, CTVtotal, and PTVtotal, should be 3000-3600 cGy in 
150-200 cGy fractions, with a sequential or concurrent boost of 600 cGy to the 
PET avid volume (GTVPET+/PTVPET+).   
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. 
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 indicated below should 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.
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 
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Dose Uniformity
For all treatments, 95% of the prescription dose must cover ≥ 99% of the CTV
and ≥ 95% of the PTV. 
For patients not receiving a 6Gy boost, no more than 10% of the CTV or PTV 
should receive more than 110% of the protocol dose (i.e. 3300cGy). 
Concurrent boost will produce allowable dose inhomogeneity within the 
GTVtotal, CTVtotal and PTVtotal. For patients receiving a 600cGy boost, 95% 
of the total 3600cGy dose (i.e. 3420cGy) must cover >95% of the PTVPET+ 
volume, and no more than 10% of the PTVPET+ volume should receive more 
than 110% of the protocol dose (i.e. 3960cGy). 
In addition, 95% of the prescription dose should cover ≥ 95% of the PTV and 
≥ 99% of the CTV. The maximum dose in the patient should not exceed 110% 
of the prescription dose.
No more than 0.03 cc of the PTV should receive less than 85% of the 
prescription dose.
x
If > 0.03 cc of the PTV receives 75-85% of the prescription dose, this 
will be a minor deviation.
x
If > 0.03 cc of the PTV receives <75% of the prescription dose, this 
will be a major deviation.
a.
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. For PBS, robust optimization should be used. If robust 
optimization is not available, treatment plan robustness should be 
evaluated. Dose distribution of each beam should be reviewed 
individually to ensure that CTV plus the lateral, distal and proximal 
margins are covered. In cases that CTV is affected by breathing 

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motion, coverage must also be reviewed in both inhale and exhale 
breathing phases. 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. 
In this case, robustness evaluation based on dose distribution 
calculations of error scenarios is recommended. CTV coverage must 
be maintained, and normal tissue constraints should not be violated 
in the presence of set-up errors, range calculation uncertainties and 
breathing motions. Target coverage should be maintained on inhale, 
exhale and under the worst-case scenarios that combine setup and 
range uncertainties. Questions related to proton therapy on trial can 
be made to Bradford Hoppe (hoppe.bradford@mayo.edu) and Stella 
Flampouri PhD (sstella.flampouri@emory.edu)
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.
h.
Treatment Technique
There is no limitation to the use of IMRT, Volumetric Arc Therapy (VMAT, or similar 
approaches) or protons, provided immobilization, motion management, 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.
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. 

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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:
x
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.
x
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.
x
It is strongly advised that when IMRT/VMAT or protons are used for 
targets within the thorax, the degree of tumor motion should be
assessed and 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.
x
In cases where 4D-CT is not used to assess target motion in the chest 
because a breath-hold technique is being employed, the superior and 
inferior PTV margin around the CTV should be ≥8mm. For protons is 
recommended that multiple CT scans on breath-hold are acquired 
during simulation to assess the reproducibility of the breath-hold and 
the robustness of the plan to variations.
x
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 18.6l.
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.
i.
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. 
j.
Organs at Risk
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.

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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.
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.
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.
Heart
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. A 
mean heart dose exceeding 2000 cGy will be considered a protocol 
deviation unless reviewed with IROC and a study radiation oncologist and 
deemed unavoidable prior to treatment.
Breast and Thyroid
Doses to the breast and thyroid should be kept as low as reasonably 
achievable. 
Dosimetric data should 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 when any of these tissues are 
in the entrance or exit path of any beam. (See below).
k.
Dose Calculations and Reporting
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. 

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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. 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.
Normal Tissue Dosimetry
Dose volume histograms (DVH) and tabular dose reports including mean 
and maximum dose 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. 
Standard Naming Convention for Structures
Please use the following standard naming convention for delineated 
structures.
Standard Name
Description
GTVtotal
Total GTV
CTVtotal
Total CTV
PTVtotal
Total PTV
Lung_L
Left lung
Lung_R
Right lung
Lungs
Combined left and right lungs
Kidney_L
Left kidney
Kidney_R
Right kidney
Liver
Liver
SpinalCord
Spinal cord
Heart
Heart
Breast_L
Left breast for female patients
Breast_R
Right breast for female patients
Breasts
Combined left and right breasts
Thyroid
Thyroid

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l.
Quality Assurance Documentation
Digital Submission
Submission of treatment plans as DICOM RT is required. Digital data must 
include treatment planning CT, structures, plan, and dose files. 
Submission of required data below via TRIAD is strongly preferred. See
Section 15.4 for TRIAD instructions. Due to the critical time constraints for 
submitting data for pre-treatment review, we encourage sites to submit 
data via TRIAD to ensure that the pre-treatment reviews are completed in 
a timely manner. In the event that a site has not completed all steps 
required for TRIAD data submission in time to meet the timeline for review, 
data submitted via SFTP will also be accepted. See the instructions for 
submission of data via SFTP on the IROC Rhode Island website under 
Digital Data (www.irocri.qarc.org). 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. 
At least 1 week prior to the start of radiotherapy, submit the following for 
pre-treatment review:
a.
Treatment Planning System Output
x
RT treatment plans including CT, structures, dose, and plan 
files. These items are included in the digital plan. 
x
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.
x
Digitally reconstructed radiographs (DRR) for each treatment 
field with outlines of target volumes only. Submission of 
DRR’s is not required for IMRT.
x
Treatment planning system summary report that includes the 
monitor unit calculations, beam parameters, calculation 
algorithm, and volume of interest dose statistics.
b.
Supportive Data
x
All diagnostic imaging used to plan the target volume. 
x
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.
x
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.
x
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).

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c.
Forms
x
RT-1 Dosimetry Summary Form
x
Proton Reporting Form (if applicable)
x
Motion Management Reporting Form (if motion management 
techniques are used)
Within 1 week following the completion of radiotherapy, submit the 
following:
x
Radiotherapy record (treatment chart) including prescription and daily 
and cumulative doses to all required areas and organs at risk.
x
RT-2 Radiotherapy Total Dose Record Form.
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
m.
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 18.6j.
Will be assessed at the time 
of final review

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18.7 
Measurement-Based Response Assessment According to the Lugano Classification 
 
Complete 
Response 
 
Complete radiologic response 
(all of the following) 
Complete 
metabolic 
response 
(even with a persistent mass) 
Lymph nodes 
and 
extralymphatic 
sites 
x Target nodes/nodal masses 
must regress to ≤1.5 cm in 
longest diameter.  
x No extralymphatic sites of 
disease. 
x Score ≤ 3* with or without a residual 
mass on 5-point scale†. 
x It is recognized that in Waldeyer’s 
ring or extranodal sites with high 
physiologic 
uptake 
or 
with 
activation within spleen or marrow 
(e.g., with chemotherapy or myeloid 
colony-stimulating factors), uptake 
may 
be 
greater 
than 
normal 
mediastinum and/or liver. In this 
circumstance, complete metabolic 
response may be inferred if uptake 
at sites of initial involvement is no 
greater than surrounding normal 
tissue even if the tissue has high 
physiologic uptake. 
Nonmeasured 
lesion 
Absent 
Not applicable 
Organ 
enlargement 
Regress to normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Normal 
by 
morphology; 
if 
determinate, IHC negative 
No evidence of FDG-avid disease in 
marrow 
Partial 
Response 
 
Partial remission (all of the 
following) 
Partial metabolic response 
Lymph nodes 
and 
extralymphatic 
sites 
x ≥ 50% decrease in SPD of up 
to 6 target measurable nodes 
and extranodal sites 
x When a lesion is too small to 
measure on CT, assign 5 mm 
X 5 mm as the default value 
x When no longer visible, 0 X 0 
mm 
x For a node > 5 mm X 5 mm, 
but smaller than normal, use 
actual 
measurement 
for 
calculation 
x Score 4 or 5† with reduced uptake 
compared 
with 
baseline 
and 
residual mass(es) of any size 
x At interim, these findings suggest 
responding disease 
x At end of treatment, these findings 
indicate residual disease 
Nonmeasured 
lesion 
Absent/normal, regressed, but 
no increase 
Not applicable 
Organ 
enlargement 
Spleen must have regressed by 
> 50% in length beyond normal 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
Residual uptake higher than uptake in 
normal marrow but reduced compared 
with 
baseline 
(diffuse 
uptake 
compatible with reactive changes from 
chemotherapy allowed). If there are 
persistent focal changes in the marrow 
in the context of a nodal response, 
consideration should be given to 
further evaluation with MRI or biopsy 
or an interval scan 
 
 

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No 
response or 
stable 
disease 
 
Stable disease 
No metabolic response 
Target nodes/ 
nodal masses, 
extranodal 
lesions 
< 50% decrease from baseline 
in SPD of up to 6 dominant, 
measurable 
nodes 
and 
extranodal sites; no criteria for 
progressive disease are met 
Score 4 or 5† with no significant 
change in FDG uptake from baseline 
at interim or end of treatment 
Nonmeasured 
lesion 
No increase consistent with 
progression 
Not applicable 
Organ 
enlargement 
No increase consistent with 
progression 
Not applicable 
New lesions 
None 
None 
Bone marrow 
Not applicable 
No change from baseline 
Progressive 
disease 
 
Progressive disease requires 
at least 1 of the following 
Progressive metabolic disease 
Individual 
target nodes/ 
nodal masses 
PPD progression: 
Score 4 or 5 with an increase in 
intensity of uptake from baseline 
and/or 
Extranodal 
lesions 
An individual node/lesion must 
be abnormal with: 
x Longest diameter (LDi) > 1.5 
cm and 
x Increase by ≥ 50% from PPD 
nadir and 
x An increase in LDi or smallest 
diameter (SDi) from nadir 
x 0.5 cm for lesions ≤ 2 cm 
x 1.0 cm for lesions > 2 cm 
x In 
the 
setting 
of 
splenomegaly, the splenic 
length must increase by > 
50% of the extent of its prior 
increase 
beyond 
baseline 
(e.g., a 15-cm spleen must 
increase to 16 cm). If no prior 
splenomegaly, must increase 
by at least 2 cm from baseline 
x New 
or 
recurrent 
splenomegaly 
x New FDG-avid foci consistent with 
lymphoma at interim OR 
x end-of-treatment assessment 
Nonmeasured 
lesion 
New or clear progression of 
preexisting 
nonmeasured 
lesions 
None 
New lesions 
x Regrowth 
of 
previously 
resolved lesions 
x A new node > 1.5 cm in any 
axis 
x A new extranodal site < 1.0 
cm in any axis; if > 1.0 cm in 
any axis, its presence must 
be unequivocal and must be 
attributable to lymphoma 
x Assessable disease of any 
size 
unequivocally 
attributable to lymphoma 
x New FDG-avid foci consistent with 
lymphoma rather than another 
etiology 
(e.g., 
infection, 
inflammation).  
x If uncertain regarding etiology of 
new lesions, biopsy or interval scan 
may be considered. 
Bone marrow 
New or recurrent involvement 
New or recurrent FDG-avid foci 
 
 
 

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18.8
Instructions for the SWOG Biospecimen Bank – Lab #201, Solid Tissue, Myeloma and 
Lymphoma Division
a.
Formalin-Fixed Paraffin-Embedded (FFPE) Tissue: The SWOG Biospecimen
Bank will receive FFPE specimens as either blocks or slides/sections at baseline.
If tissue block is received, then upon receipt, Bank will cut 1 H&E slide for 
Pathology Review. Any remaining tissue (in block) will be stored at room 
temperature. (Priority of slides for planned future TM objectives will be 
specified in a forthcoming revision.)
If slides are received, then 1 H&E slide will be scanned for Pathology 
Review and then all unstained slides will be stored refrigerated (2-8°C) 
and under desiccant, until distribution for planned future TM objectives. 
a.
Pathology review:
For each case, the Bank will scan 1 H&E slide to digital images
at 40x magnification. The digital images and corresponding 
redacted pathology reports will be sent to study pathologists for 
QC pathology review. Case review will be split amongst the 
following pathologists and will be sent in batches throughout 
the duration of accrual.
b.
The following pathologists will conduct Pathology review:
Joo Y. Song, M.D. 
City of Hope Medical Center
1500 E Duarte Rd, # 2202A
Duarte, CA 91010
Phone: 626/256-4673 ext:62037
Fax: 626/218-8463
Email: josong@coh.org
William R. Macon, M.D.
Department of Laboratory Medicine and Pathology
Mayo Clinic
200 First Street SW
Rochester, MN 55905
Phone: 507-284-1198
Fax: 507-284-5115
Email: Macon.William@mayo.edu
Anamarija Perry, M.D.
Department of Pathology
University of Michigan
2800 Plymouth Road, Bldg 35
Ann Arbor, MI 48109
Phone: 734-232-5376
Fax: 734-232-5360
Email: anaperry@med.umich.edu
Alexandra Kovach, M.D.
Department of Pathology and Laboratory Medicine
Children’s Hospital Los Angeles
4650 Sunset Blvd, Mailstop #32
Los Angeles, CA 90027

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Phone: 323-361-5405 
Fax: 323-361-8039 
Email: akovach@chla.usc.edu 
 
 
b. 
Peripheral Blood in cfDNA Streck Tubes: The SWOG Biospecimen Bank will 
receive ambient peripheral blood in cfDNA Streck tubes at up to 4 timepoints. Upon 
receipt, the Bank will accession and process for plasma and buffy coat. Plasma is 
processed using the following double-centrifugation protocol: 1,500xg for 10 minutes 
at room temperature with brake (buffy coat is removed at this point); plasma is 
removed and centrifuged again at 3,000xg for 10 minutes at room temperature with 
brake. Plasma will be stored in 1-mL aliquots, and buffy coat will be stored as 1 
aliquot; both plasma and buffy coat will be banked in a -80°C freezer until distribution. 
Planned future correlatives (ctDNA analysis) are planned for incorporation with a 
forthcoming revision. 
 
 
 

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18.9 
CYP1A2 and CYP3A Inhibitors and Inducers  
 
 
Strong inhibitors 
Moderate inhibitors Weak inhibitors 
CYP1A2 
ciprofloxacin,  
enoxacin,  
fluvoxamine(a),  
zafirlukast 
methoxsalen, 
mexiletine, 
oral contraceptives 
acyclovir, 
allopurinol,  
cimetidine,  
peginterferon 
alpha-
2a,  
piperine,  
zileuton 
CYP3A 
boceprevir,  
cobicistat(c),  
conivaptan(c),  
danoprevir and ritonavir(d),  
elvitegravir and ritonavir(d),  
grapefruit juice(e),  
indinavir and ritonavir(d),  
itraconazole(c),  
ketoconazole,  
lopinavir and ritonavir(c,j),  
paritaprevir and ritonavir and 
(ombitasvir 
and/or 
dasabuvir)(d), 
posaconazole,  
ritonavir(c,d),  
saquinavir and ritonavir(c,d), 
telaprevir(c),  
tipranavir and ritonavir(c,d),  
troleandomycin,  
voriconazole 
aprepitant,  
cimetidine,  
ciprofloxacin,  
clotrimazole,  
crizotinib,  
cyclosporine,  
dronedarone(c),  
erythromycin,  
fluconazole(b),  
fluvoxamine(a),  
imatinib,  
tofisopam,  
verapamil(c) 
chlorzoxazone,  
cilostazol,  
fosaprepitant,  
istradefylline,  
ivacaftor(c),  
lomitapide,  
ranitidine,  
ranolazine(c),  
tacrolimus,  
ticagrelor(c) 
clarithromycin(c),  
diltiazem(c),  
idelalisib,  
nefazodone,  
nelfinavir(c) 
  
  
1. Note: Strong, moderate, and weak inhibitors are drugs that increase the AUC of 
sensitive index substrates of a given metabolic pathway ≥5-fold, ≥2 to <5-fold, and 
≥1.25 to <2-fold, respectively. Strong inhibitors of CYP3A causing ≥10-fold increase in 
AUC of sensitive index substrate(s) are shown above the dashed line. 
2. This table is prepared to provide examples of clinical inhibitors and is not intended to 
be an exhaustive list. DDI data were collected based on a search of the University of 
Washington Metabolism and Transport Drug Interaction Database [Hachad et al. 
(2010), Hum Genomics, 5(1):61]. 
3. 
(a) Strong inhibitor of CYP1A2 and CYP2C19, and moderate inhibitor of CYP2D6 and 
CYP3A. 
(b) Strong inhibitor of CYP2C19 and moderate inhibitor of CYP2C9 and CYP3A.   
(c) Inhibitor of P-gp (defined as those increasing AUC of digoxin to ≥1.25-fold). 
(d) Ritonavir is usually given in combination with other anti-HIV or anti-HCV drugs in 
clinical practice. Caution should be used when extrapolating the observed effect of 
ritonavir alone to the effect of combination regimens on CYP3A activities. 
(e) The effect of grapefruit juice varies widely among brands and is concentration-, 
dose-, and preparation-dependent. Studies have shown that it can be classified as a 
“strong CYP3A inhibitor” when a certain preparation was used (e.g., high dose, double 
strength) or as a “moderate CYP3A inhibitor” when another preparation was used (e.g., 
low dose, single strength). 

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4. Abbreviations: AUC: area under the concentration-time curve; CYP: cytochrome P450; 
DDI: drug-drug interaction; OATP1B1: organic anion transporting polypeptide 1B1; 
OAT3: organic anion transporter 3; P-gp: P-glycoprotein. 
 
 
 
Strong inducers 
Moderate inducers 
Weak inducers 
CYP1A2 
  
phenytoin(a)  
rifampin(b),  
ritonavir(c),  
smoking,  
teriflunomide 
- 
CYP3A 
carbamazepine(d), 
enzalutamide(e), 
mitotane, 
phenytoin(b), 
rifampin(a),  
St. John’s wort(f) 
bosentan,  
efavirenz,  
etravirine,  
modafinil 
armodafinil, 
rufinamide 
1. Note: Strong, moderate, and weak inducers are drugs that decreases the AUC of 
sensitive index substrates of a given metabolic pathway by ≥80%, ≥50% to <80%, and 
≥20% to <50%, respectively. 
2. This table is prepared to provide examples of clinical index inducers and not intended 
to be an exhaustive list. DDI data were collected based on a search of the University 
of Washington Metabolism and Transport Drug Interaction Database [Hachad et al. 
(2010), Hum Genomics, 5(1):61]. 
(a) Strong inducer of CYP3A and moderate inducer of CYP1A2, CYP2C19. 
(b) Strong inducer of CYP2C19, CYP3A, and moderate inducer of CYP1A2, CYP2B6, 
CYP2C8, 
CYP2C9. 
(c) Strong inducer of CYP2C19 and moderate inducer of CYP1A2, CYP2B6, CYP2C9. 
(d) Strong inducer of CYP2B6, CYP3A, and moderate inducer of CYP2C9. 
(e) Strong inducer of CYP3A and moderate inducer of CYP2C9, CYP2C19, CYP3A.  
(f) The effect of St. John’s wort varies widely and is preparation-dependent. 
3. Abbreviations: AUC: area under the concentration-time curve; CYP: cytochrome P450; 
DDI: drug-drug interaction. 
 
 

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18.10 
PRO-CTCAE Common Terminology Criteria for Adverse Events (PRO-CTCAE) Instrument 
 
a. 
General Information: 
 
The PRO-CTCAE instruments will be used to assess Patient-Reported toxicity 
outcomes.  
 
Clinician graded CTCAE is the adverse event safety standard. PRO-CTCAE is 
intended to enhance the quality of adverse event data reporting in clinical trials, 
provide data that complements and extends the information provided by clinician 
reporting using CTCAE, represent the patient perspective of the experience of 
symptomatic adverse events, and improve detection of potentially serious adverse 
events.   
 
The selection of PRO-CTCAE should be complementary to the clinician identified 
AEs for ongoing monitoring.   
 
Adverse Event Characteristics:  PRO-CTCAE is not intended for expedited reporting, 
real time review, or safety reporting. 
 
Routine Adverse Event Reporting:  Symptomatic Adverse Events reported by 
patients through PRO-CTCASE are not safety reporting and may be presented with 
other routine AE data. 
 
PRO-CTCAE (adult and pediatric) assessment tools are available in the following 
languages. Estimated time of completion:  10 minutes. 
x 
PRO-CTCAE: Available in English, Spanish, and French 
x 
Ped PRO-CTCAE: Available in English  
 
PRO-CTCAE is not currently available on the Medidata Patient Cloud ePRO.  
Forms are accessible from the S1826 protocol abstract page on the CTSU website 
at www.ctsu.org. Administration instructions are included in Section 15.6. 
 
Please refer to the PRO-CTCAE Terms of Use for more information. 
 
b. 
Recall Period for the PRO-CTCAE measures is: 7 days 
 
c. 
PRO-CTCAE Analyses  
 
The examination of PRO-CTCAE is exploratory, given there are currently no 
standardized scoring rules for how to combine attributes into a single score or how 
best to analyze PRO-CTCAE data longitudinally. PRO-CTCAE responses are scored 
from 0 to 4. For each of the PRO-CTCAE adverse events examined, the scores for 
each attribute (frequency, severity and/or interference) will be presented 
descriptively using summary statistics at each assessment time. Additionally, the 
worst severity and/or interference over the entire course will be summarized. 
 
d. 
Study-Specific PRO-CTCAE Questions for Adults (≥ 18 years of age):  
 
Solicited Adverse Events: The following adverse events are considered expected 
and their presence/ absence should be solicited and severity graded at timepoints 
indicated in Section 9.0. 
 
 

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CTCAE Item - Adult 
PRO-CTCAE Item (Attributes) 
Mucositis oral 
Mucositis oral (SI) 
Nausea 
Nausea (FS) 
Vomiting 
Vomiting (F) 
Diarrhea 
Diarrhea (F) 
Abdominal pain 
Abdominal pain (FSI) 
Dyspnea 
Shortness of breath (SI) 
Cough  
Cough (SI) 
Rash 
Rash (P) 
Pruitis 
Itchy Skin (S) 
Peripheral Sensory Neuropathy 
Numbness or tingling in hands or feet (SI) 
Pain 
Pain (FSI) 
Myalgia 
Aching muscles (FSI) 
Arthralgia 
Aching joints (FSI)  
Decrease sexual interest 
Decreased sexual interest (S) 
Any other symptoms that you 
wish to report? 
Other symptoms (PS) 
 
Attribute Acronyms:  
 
F: Frequency, S: Severity, I: Interference, P: Presence/Absence/Amount 
 
Symptom 
AE 
Attributes 
PRO-CTCAE Items 
Response options 
Mucositis 
oral 
Frequency 
-- 
-- 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your 
MOUTH 
OR 
THROAT SORES at 
their WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
In the last 7 days, how 
much did MOUTH OR 
THROAT 
SORES 
INTERFERE with your 
usual 
or 
daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 
Nausea 
Frequency 
In the last 7 days, how 
OFTEN did you have 
NAUSEA? 
Never, 
Rarely, 
Occasionally, 
Frequently, 
Almost 
constantly 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your NAUSEA at its 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 

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Symptom 
AE 
Attributes 
PRO-CTCAE Items 
Response options 
Interference 
-- 
-- 
Diarrhea 
Frequency 
In the last 7 days, how 
OFTEN did you have 
LOOSE OR WATERY 
STOOLS (DIARRHEA/ 
DIARRHOEA)? 
Never, 
Rarely, 
Occasionally, 
Frequently, 
Almost 
constantly 
Severity 
-- 
-- 
Interference 
-- 
-- 
Abdominal 
pain 
Frequency 
In the last 7 days, how 
OFTEN did you have 
PAIN 
IN 
THE 
ABDOMEN 
(BELLY 
AREA)? 
Never, 
Rarely, 
Occasionally, 
Frequently, 
Almost 
constantly 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your 
PAIN 
IN 
THE 
ABDOMEN 
(BELLY 
AREA) at its WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
In the last 7 days, how 
much did PAIN IN THE 
ABDOMEN 
(BELLY 
AREA) 
INTERFERE 
with your usual or daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 
Dyspnea 
Frequency 
-- 
-- 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your SHORTNESS OF 
BREATH 
at 
its 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
In the last 7 days, how 
much 
did 
your 
SHORTNESS 
OF 
BREATH INTERFERE 
with your usual or daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 
Cough 
Frequency 
In the last 7 days, what 
was the SEVERITY of 
Never, 
Rarely, 
Occasionally, 

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Symptom 
AE 
Attributes 
PRO-CTCAE Items 
Response options 
your COUGH at its 
WORST? 
Frequently, 
Almost 
constantly 
Severity 
In the last 7 days, how 
much 
did 
COUGH 
INTERFERE with your 
usual 
or 
daily 
activities? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
-- 
-- 
Rash 
Frequency 
In the last 7 days, did 
you have any RASH? 
Yes, No 
Severity 
-- 
-- 
Interference 
-- 
-- 
Pruritis 
Frequency 
-- 
-- 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your ITCHY SKIN at its 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
-- 
-- 
Peripheral 
Sensory 
Neuropathy 
Frequency 
-- 
-- 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your NUMBNESS OR 
TINGLING IN YOUR 
HANDS OR FEET at its 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
In the last 7 days, how 
much did NUMBNESS 
OR 
TINGLING 
IN 
YOUR 
HANDS 
OR 
FEET INTERFERE with 
your 
usual 
or 
daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 

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Symptom 
AE 
Attributes 
PRO-CTCAE Items 
Response options 
Pain 
Frequency 
In the last 7 days, how 
OFTEN did you have 
PAIN? 
Never, 
Rarely, 
Occasionally, 
Frequently, 
Almost 
constantly 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your 
PAIN 
at 
its 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
In the last 7 days, how 
much 
did 
PAIN 
INTERFERE with your 
usual 
or 
daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 
Myalgia 
Frequency 
In the last 7 days, how 
OFTEN did you have 
ACHING MUSCLES? 
Never, 
Rarely, 
Occasionally, 
Frequently, 
Almost 
constantly 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your 
ACHING 
MUSCLES 
at 
their 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
In the last 7 days, how 
much 
did 
ACHING 
MUSCLES 
INTERFERE with your 
usual 
or 
daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 
Arthralgia  
Frequency 
In the last 7 days, how 
OFTEN did you have 
ACHING 
JOINTS 
(SUCH AS ELBOWS, 
KNEES, 
SHOULDERS)? 
Never, 
Rarely, 
Occasionally, 
Frequently, 
Almost 
constantly 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your ACHING JOINTS 
(SUCH AS ELBOWS, 
KNEES, SHOULDERS) 
at their WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 

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Symptom 
AE 
Attributes 
PRO-CTCAE Items 
Response options 
Interference 
In the last 7 days, how 
much 
did 
ACHING 
JOINTS 
(SUCH 
AS 
ELBOWS, 
KNEES, 
SHOULDERS) 
INTERFERE with your 
usual 
or 
daily 
activities? 
Not at all, A little bit, 
Somewhat, Quite a 
bit, Very much 
Decreased 
Sexual 
Interest 
Frequency 
-- 
-- 
Severity 
In the last 7 days, what 
was the SEVERITY of 
your 
DECREASED 
SEXUAL INTEREST at 
its WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
-- 
-- 
Do you have 
any other 
symptoms 
that you 
wish to 
report? 
 
Do you have any other 
symptoms 
that 
you 
wish to report? 
Yes, No 
Please list 
any other 
symptoms: 
(5 slots to 
list) 
Frequency 
-- 
-- 
Severity 
In the last 7 days, what 
was the SEVERITY of 
this symptom at its 
WORST? 
None, 
Mild, 
Moderate, 
Severe, 
Very Severe 
Interference 
-- 
-- 
 
 
e. 
Pediatric PRO-CTCAE Questions:  
 
CTCAE Item - Pediatric 
PRO-CTCAE Item (Attributes) 
Mucositis oral 
Mucositis oral (FSI) 
Nausea 
Nausea (FSI) 
Vomiting 
Vomiting (FI) 
Diarrhea 
Diarrhea (FI) 
Abdominal pain 
Abdominal pain (FSI) 
Dyspnea 
Shortness of breath (FSI) 

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Cough  
Cough (FSI) 
Rash acneiform 
Pimples (bumps on face or chest) (S) 
Pruitis 
Itchy Skin (SI) 
Peripheral Sensory Neuropathy 
Numbness or tingling in hands or feet (SI) 
Pain 
Pain (FSI) 
Myalgia 
Aching muscles (FSI) 
Arthralgia 
Aching joints (FSI)  
 
Attribute Acronyms:  
 
f. 
Frequency, S: Severity, I: Interference, P: Presence/Absence/Amount 
 
 
Symptom 
AE 
Attributes 
Pediatric PRO-CTCAE 
Items 
Response options 
Mucositis 
oral 
Frequency 
In the past 7 days, how 
often did you have pain in 
your mouth or throat? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad was the pain in your 
mouth or throat? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did pain in your 
mouth or throat keep you 
from doing things you 
usually do? 
Not at all, Some, A 
lot, A whole lot 
Nausea 
Frequency 
In the past 7 days, how 
often did you feel sick to 
your stomach (nausea)? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad was your feeling sick 
to 
your 
stomach 
(nausea)? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did feeling sick to 
your stomach (nausea) 
keep 
you 
from 
doing 
things you usually do? 
Not at all, Some, A 
lot, A whole lot 
Vomiting 
Frequency 
In the past 7 days, how 
often did you throw up? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Interference 
In the past 7 days, how 
much did throwing up 
keep 
you 
from 
doing 
things you usually do? 
Not at all, Some, A 
lot, A whole lot 

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Symptom 
AE 
Attributes 
Pediatric PRO-CTCAE 
Items 
Response options 
Diarrhea 
Frequency  
In the past 7 days, how 
often did you have runny 
or watery poop? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Interference 
In the past 7 days, how 
much did having runny or 
watery poop keep you 
from doing things you 
usually do? 
Not at all, Some, A 
lot, A whole lot 
Abdominal 
Pain 
Frequency  
In the past 7 days, how 
often 
did 
you 
have 
stomach pain? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad was your stomach 
pain? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did stomach pain 
keep 
you 
from 
doing 
things you usually do? 
Not at all, Some, A 
lot, A whole lot 
Dyspnea 
Frequency 
In the past 7 days, how 
often 
did 
you 
have 
problems 
breathing 
(shortness of breath)? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad were your problems 
breathing (shortness of 
breath)? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did your problems 
breathing (shortness of 
breath) keep you from 
doing things you usually 
do? 
Not at all, Some, A 
lot, A whole lot 
Cough 
Frequency 
In the past 7 days, how 
often did you cough? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad was your coughing? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did coughing keep 
Not at all, Some, A 
lot, A whole lot 

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Symptom 
AE 
Attributes 
Pediatric PRO-CTCAE 
Items 
Response options 
you from doing things you 
usually do? 
Rash 
 
No Pediatric PRO-CTCAE 
item for Rash. Pediatric 
PRO-CTCAE does have 
Rash Acneiform or Hives 
 
Rash 
acneiform 
Severity 
In the past 7 days, how 
bad were your pimples 
(bumps on face or chest)? 
Did not have any, A 
little bad, Bad, Very 
bad 
Pruritus 
Severity 
In the past 7 days, how 
bad was your itchy skin? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference  
In the past 7 days, how 
much did your itchy skin 
keep 
you 
from 
doing 
things you usually do? 
Not at all, Some, A 
lot, A whole lot 
Peripheral 
Sensory 
Neuropathy 
Severity 
In the past 7 days, how 
bad was the numbness or 
tingly feeling in your hands 
or feet? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did the numbness or 
tingly feeling in your hands 
or feet keep you from 
doing things you usually 
do? 
Not at all, Some, A 
lot, A whole lot 
Pain 
Frequency 
In the past 7 days, how 
often did you have pain? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad was your pain? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did pain keep you 
from doing things you 
usually do? 
Not at all, Some, A 
lot, A whole lot 

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Symptom 
AE 
Attributes 
Pediatric PRO-CTCAE 
Items 
Response options 
Myalgia 
Frequency 
In the past 7 days, how 
often did your muscles 
hurt? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
In the past 7 days, how 
bad did your muscles 
hurt? 
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
In the past 7 days, how 
much did your muscles 
hurting keep you from 
doing things you usually 
do? 
Not at all, Some, A 
lot, A whole lot 
Arthralgia  
Frequency 
How often did you have 
pain in any bendable part 
of 
your 
body 
(knees, 
ankles, 
shoulders, 
or 
fingers)? 
Never, Sometimes, 
Most of the time, 
Almost all the time 
Severity 
How bad was the pain in 
any bendable part of your 
body 
(knees, 
ankles, 
shoulder, or fingers)?   
Did not have any, A 
little bad, Bad, Very 
bad 
Interference 
How much did pain in any 
bendable part of your 
body 
(knees, 
ankles, 
shoulders, 
or 
fingers) 
keep 
you 
from 
doing 
things you usually do? 
Not at all, Some, A 
lot, A whole lot 
Decreased 
Sexual 
Interest 
 
No Pediatric PRO-CTCAE 
item for decreased sexual 
interest 
 
Do you have 
any other 
symptoms 
that you 
wish to 
report? 
 
Currently, our Pediatric 
PRO-CTCAE 
system 
does not provide options 
for children to report any 
additional symptoms they 
may be experiencing. 
 
 
g. 
References 

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x 
PRO-CTCAE Website:  https://healthcaredelivery.cancer.gov/pro-ctcae/ 
x 
PRO-CTCAE Items Library 
x 
PRO-CTCAE NCI Scientific Leadership Team 
x 
PRO-CTCAE Development Team 
x 
Publications 
 
 
 

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18.11
Patient Clinical Trial Wallet Card
CLINICAL TRIAL WALLET CARD
Show this card to all of your 
healthcare providers and keep 
it with you in case you go to 
the emergency room.
Patient Name:  
Diagnosis:  
Study Doctor: 
Study Doctor Phone #: 
NCI Trial #:  
Study Drug(S):  
For more information: 1-800-4-CANCER
cancer.gov | clinicaltrials.gov

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18.12
AYA Educational Resource Information, COG Participating Site Frequently Asked 
Questions, NCTN Adult Group Participating Site Frequently Asked Questions
a.
AYA Educational Resource Information
The “Enrolling Adolescent and Young Adults (AYAs) onto NCTN and NCORP Trials 
Frequently Asked Questions (FAQs)” document is accessible from the S1826 
protocol abstract page on www.ctsu.org under the “Education and Promotion” tab.
Additional pertinent AYA study conduct, regulatory, funding, CTSU navigational, 
RAVE access and other instructional information is accessible from the following 
NCTN training presentations for AYA studies. For access to the presentation links 
below, login to the CTSU website at www.ctsu.org prior to clicking on the links below.
How to Enroll onto Adolescent and Young Adult (AYA) Studies – A Step-by-Step 
Guide is accessible from: https://www.ctsu.org/readfile.aspx?sectionid=166924.The 
corresponding 
audio 
recording 
is 
accessible 
from:
https://www.ctsu.org/readfile.aspx?sectionid=166925. 
Webinar: Access to NCTN AYA Trials is accessible from:
https://www.ctsu.org/readfile.aspx?sectionid=156366. The corresponding audio 
recording 
is 
accessible 
from:  
https://ctwestat.webex.com/ctwestat/lsr.php?RCID=23cf391fc69844928d537d8ec8
0167b5   
Highlights of the “How to Enroll onto Adolescent and Young Adult (AYA) Studies – A 
Step-by-Step Guide,” as relevant to S1826 are excerpted below for ease of 
reference.
Regulatory Considerations – Activating When Adult and Pediatric 
Groups at the same institution are BOTH Participating:
x
When Adults and Pediatric groups share the same IRB of Record (local 
or CIRB)
o
CTSU only accepts a single IRB approval for the institution

Identify who will do the regulatory submission
o
Only a single PI can be listed for the study
o
IRB paperwork needs to indicate both adults and pediatrics are 
listed in the accrual goals
o
Adult and Pediatric engaged research team members need to be 
listed on IRB paperwork
o
Adult and Pediatric consenters need to be listed in IRB paperwork
o
All locations (site codes) of research activity need to be listed
Crediting Rules
For NCTN AYA trials that are led by an Adult NCTN Group (e.g. SWOG), 
participating sites/investigators can credit any NCTN Group which they are a 
member of at the time of enrollment of each patient into OPEN.

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For COG-credited Patient Registration:
For participating COG sites and sites crediting patient registration to COG:
x
Prior to registration to S1826, a COG patient ID number must be 
assigned to all COG-credited patients. The COG patient ID is then used 
to complete the registration process.
o
The COG patient ID number is obtained via the Patient Registry 
module in OPEN once authorization for the release of protected 
health information (PHI) has been obtained.
o
The COG patient ID number is used to identify the patient in all 
future interactions with COG.
x
If you have problems with the COG registration, please refer to the 
online help.
o
For additional help or information, please contact the CTSU Help 
Desk at 1-888-823-5923 or ctsucontact@westat.com.
x
Once the registration process is completed in OPEN, a SWOG Patient 
ID will be generated.
o
The SWOG Patient ID must be utilized for all data entry, specimen 
shipment, and TRIAD entry.
Funding for AYA Trials:
Whether COG or an adult NCTN Group is leading an AYA trial, funding for 
enrollments is determined as follows:
x
AYA Enrollments credited to COG:
o
COG will provide funding to their member sites.
x
AYA enrollments credited to an adult NCTN group:
o
Funding will be provided by the NCTN credited Group for Rostered 
sites (non-LAPS and non-
o
NCORP);
o
LAPS Grants provide funding for AYA trial enrollments;
o
NCORP Site Grants provide funding for AYA trial enrollments.
x
Please review the funding information posted on the S1826 protocol 
abstract page at www.ctsu.org. 
b.
COG Participating Site Frequently Asked Questions:
1.
Does SWOG conduct a site initiation visit (SIV)?
x
No. As with all cooperative group trials, participating sites are responsible 
for conduct of the protocol, including ensuring site staff are trained on the 
procedures/assessments outlined in the protocol. To assist sites  in 
managing initiation activities, there are three informational overview 
documents posted on the protocol abstract page at: www.ctsu.org under 
the Education and Promotion tab: 1) S1826 Training Presentation;  2) 
S1826 Investigator Training Reference for PET-CT, and 3) Financial 
Assistance Navigation Information. 
2.
How do I order nivolumab?
x
See protocol Section 3.1g for ordering instructions. 
x
Note: A patient must be randomized to the N-AVD arm before the site can 
order drug.
x
Drug ordering, shipment, stability, and accountability questions should be 
directed to CTEP/PMB. Contact information is included in Section 3.1g.4.
3.
How do I order Streck tube kits?
x
See Section 15.2c for a link to the online ordering system.
x
Allow 5-7 days after placing the order for receipt of the shipment.

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4. 
How do I get air bills or an account number to ship the specimens to the bank? 
x 
Neither air bills nor a courier account number are supplied. 
x 
Sites are to use their institutional account number (or similar institutional 
method of payment) for the shipment. 
x 
The shipping cost is offset via the NCTN site payment to the site for each 
sample submission timepoint. 
 
5. 
For dosing based upon the patients’ weight, should dose be re-calculated for 
each administration? 
x 
Dose should only be re-calculated if the patient has a change in weight 
that is >/= 10% from baseline. 
 
6. 
If the patient turns 18 while on protocol, should the dose switch to the adult 
dose administration guidelines? 
x 
No. The patient should continue on the dose administered at previous 
administration unless there is a change in weight that is >/= 10% from the 
previous weight used to calculate BSA (applicable to nivolumab, 
brentuximab vedotin, and G-CSF). 
 
7. 
Is there an iMedidata RAVE guidance document? 
x 
No. The Master Forms Set, posted at: www.ctsu.org under the Case 
Report Forms tab (see snapshot below) includes paper versions of the 
case report forms (CRFs). The paper CRFs in the Master Forms Set 
contain the same entry fields as are included in RAVE, however, in some 
cases the paper versions include more detail/instruction than can be 
included in the RAVE system. Please direct questions regarding data entry 
(including cycle/scheduling questions as pertain to data entry), form 
instructions, query resolution to: LymphomaQuestion@crab.org.   

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8. 
Are Patient-Reported Outcomes (QOL and PRO-CTCAE) forms required? 
x 
Yes.  If the patient is able to complete the forms in English, Spanish or 
French, then the forms are required at the timepoints indicated in Sections 
15.5 and 15.6 of the protocol. Note: The Pediatric PROMIS Fatigue 10a is 
validated in English and Spanish only (not French).  Baseline QOL forms 
must be completed by the patient prior to registration, or else the patient 
will be considered ineligible per Section 5.6. 
x 
If the patient is not able to complete the forms in English, Spanish or 
French, patient does not speak, read, or write in at least one of these 
languages), then the forms are not required to be completed. The 
participating site will document that the patient does not speak one of the 
languages in which the PRO forms are validated.  
                                            
9. 
If a patient turns 18 while on protocol, does the patient complete the adult or 
the pediatric PRO forms? 
x 
Pediatric. (Patients are to complete the version of the forms that was 
appropriate for the patient at time of completion of the initial 
questionnaires. 
 
10. 
Where do I access the Patient-Reported Outcomes (QOL and PRO-CTCAE) 
forms? 
x 
The current PRO (QOL and PRO-CTCAE) Forms are posted individually 
on the CTSU protocol abstract page at www.ctsu.org under “Documents” 
/ “CIRB Documents” tab / “Amendment Reviews” subtab / “Participant 
Materials” section / “Recruitment Material” subsection. 
 
 
11. 
Where do I find the address for the SWOG Biospecimen Bank?  
x 
Prior to shipment, all specimen must be entered into the SWOG online 
Specimen Tracking System. 
x 
Log on to the SWOG Specimen Tracking System using your CTEP IAM 
username and password.  
x 
If it is your first time logging in to the Specimen Tracking System 
(SpecTrack), please note that you can access start-up instructions (both 
written and demo) after signing into the online system. 
x 
You will be able to print labels via the online SpecTrack system. 

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12.
What Grade AEs do I need to report?
x
ALL adverse events are reported for both arms (for the duration of the 
reporting requirement).
13.
For adverse event reporting, when Medidata Rave requests an answer to 
“attribution to study intervention,” how is that defined?
x
The attribution code indicates the likelihood that the condition/event 
observed is related to protocol treatment.
14.
How do I clear the “sticky note” for the AE?
x
Sticky notes remain for AEs that may require reporting via CTEP-AERS. If 
you are certain that an AE does not require reporting, then you can 
override the request for submission of a CTEP-AERs report then you can 
override the request for submission of a CTEP-AERs report, but the sticky 
note will remain visible in RAVE as a record of the reporting 
recommendation. 
15.
My patient was deemed ineligible after registration. Can they continue with 
protocol treatment? 
x
Yes. Once registered, all participants are to be treated per protocol as long 
as there is not a medical contra-indication for doing so.
c.
NCTN Adult Group Participating Site Frequently Asked Questions:
Does our institution need an assent document?
x
For non-COG institutions enrolling pediatric patients, institutions are to 
document assent per the local policy. CIRB has approved the Youth 
Information Sheets for utilization in the Assent process.
x
If your institution/PI will not be enrolling patients under age 18, then an 
assent document is not needed.
Can we remove the Parent/Guardian and Physician/PNP signature lines from 
the consent document?
x
No, per CIRB guidelines, participating sites may not remove, replace, or 
revise any of the language in the CIRB-approved consent. Sites may 
request additions to boilerplate language, as indicated in the CIRB Quick 
guide titled, “Guidelines  for Permitted Boilerplate Language Additions” 
which can be found on the NCI CIRB website under the “For Institutions” 
section: https://www.ncicirb.org/content/guidelines-permitted-boilerplate-
language-additions. 
18.13
Translational Medicine: Circulating Tumor DNA
a.
Translational Medicine Objectives
1.
Assess prognostic significance of genetic alterations in advanced stage 
cHL treated with N-AVD or BV-AVD.
2.
Assess the prognostic significance of baseline and interim (i.e. 2-log 
reduction after 2 cycles), and end-of-treatment molecular tumor burden 
(MTB) in patients with advanced stage cHL treated with N-AVD or BV-
AVD.

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b. 
Background 
The paucity of malignant Reed Sternberg cells (1-2%) in primary cHLs precludes 
conventional genetic analyses of bulk tumor specimens. As a consequence, 
emerging insights regarding disease-defining and potentially therapeutically 
actionable molecular alterations in cHL have not been translated into scalable 
robust genetic assays for use in clinical investigation or routine practice. Despite 
the paucity of RS cells in cHL tumors, next generation sequencing (NGS)-based 
detection of cell-free ctDNA is feasible in cHL. (1,2,3,4) Using a panel-directed 
NGS-based approach to ctDNA analysis, noninvasive genotyping of cHL is 
validated in cHL and enables monitoring of clonal evolution in patients with 
treatment failure. The presence and rate of ctDNA decline with standard treatment 
as well as with nivolumab treatment is highly associated with the presence of active 
lymphoma and with PFS. (5) Another study using a similar targeted ctDNA assay 
defined associations between dynamic ctDNA results and PFS. (6) The validation 
of ctDNA in cHL, as a sensitive and specific marker of the malignant clone, has the 
potential to supplant PET/CT scans as a dynamic disease assessment tool. 
Dynamic response to therapy and the detection of residual cHL are suboptimal 
with the current gold-standard PET scans. There remain a high number of disease 
progression events in patients who have negative interim and EOT PET scans 
(e.g. 2/3 of the total PFS events in SWOG S0618 were in PET-negative 
patients).(7) Nevertheless, PET assessment of cHL remains the primary method 
of assessing response and guiding therapeutic interventions in cHL. Furthermore, 
interpreting PET scans is particularly challenging in the setting of PD-1 blockade, 
even requiring a modification to the standard lymphoma response assessment 
criteria (i.e. LYRIC criteria(8)). 
 
In the current proposal, we will assess the prognostic impact of specific genetic 
alterations (i.e. 9p24.1) and MTB in patients with advanced stage cHL treated on 
S1826. To accomplish this, we will deploy our comprehensive targeted sequencing 
ctDNA assay to capture the cHL molecular signature, including genetic alterations 
associated with sensitivity to PD-1 blockade(9,10,11,12,13). CtDNA assessment 
provides real-time information about tumor burden and dynamic response to 
therapy, non-invasive genomic profiling, and monitoring of clonal dynamics – 
opening the door to numerous applications that could significantly impact the care 
of patients with cHL. We anticipate that the use of ctDNA as a non-real time 
integrated biomarker in S1826 will establish the clinical utility of ctDNA in cHL as: 
(1) “Liquid biopsy” – given the paucity of genetic data in primary cHL, our non-
invasive genomic profiling via ctDNA of adult and pediatric patients with newly 
diagnosed advanced stage disease will be a major contribution to the field, 
enabling precision medicine approaches in cHL (e.g. prioritization of anti-PD1 
therapy for patients with high burden 9p24.1 alteration); (2) Prognostic biomarker 
– current clinical prognostic indices (e.g. IPS score) inadequately risk-stratify 
advanced stage cHL patients for risk-adapted therapeutic approaches; however, 
MTB determined by ctDNA can provide a highly sensitive measurement of tumor 
burden prior to therapy as a tool for refining pre-treatment risk stratification and 
designing clinical trials studying intensification or de-escalation of therapy; (3) 
Dynamic measure of response – rather than relying on imperfect PET scans, 
ctDNA provides real-time, highly sensitive information about molecular depth of 
response (i.e. MTB) that will inform ctDNA-response driven clinical trials; (4) 
Disease monitoring – Imaging surveillance and the detection of clinically occult 
relapse is not associated with improved outcomes in cHL,(14) but detection of 
molecular relapse using ctDNA may provide the opportunity to study pre-emptive 
intervention with well-tolerated novel agents to prevent clinical relapse.  
 
As a randomized evaluation of the incorporation of PD-1 blockade into frontline 
therapy, our proposed S1826 ctDNA analysis can identify the patients most likely 
to benefit from a particular frontline immuno-chemotherapy intervention (i.e. N-

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AVD or BV-AVD) regardless of the result of the primary analysis and can inform 
the design of the next cHL clinical trial in the cooperative groups (e.g. response 
adapted therapy using ctDNA and/or PET). 
We hypothesize that ctDNA will identify characteristic alterations of chromosome 
9p24.1 (i.e. amplification) and genes (i.e. JAK/STAT pathway genes - SOCS1, 
STAT6) that result in overexpression of PD-1 ligands in cHL and that these genetic 
features will be selectively associated with favorable response and PFS in patients 
treated with N-AVD,(24, 29) but not after BV-AVD. Therefore, we are testing if 
treatment effect of N-AVD versus BV-AVD on PFS depends on 9p24.1 and specific 
gene alterations. Additionally, we hypothesize that MTB will be prognostic for PFS 
in patients treated with either N-AVD or BV-AVD (i.e. irrespective of regimen): (1) 
baseline MTB will be prognostic for PFS, (2) interim on-treatment kinetic changes 
in MTB (i.e. achievement of 2-log drop in MTB after 2 cycles) will be prognostic for 
PFS, and (3) MTB at EOT will have superior PPV and NPV to 5-point PET-CT at 
interim and EOT. 
 
c. 
Experimental Approach and Assays 
1. 
Sample Collection  
 
Patients have 20mL of whole blood collected at baseline, on C3D1, at 
EOT, and at the time of relapse or progression (if applicable) in BCT cell-
free DNA Streck tubes. Samples are shipped to the SWOG central 
biorepository where the whole blood is separated into plasma and buffy 
coat, yielding 10-12mL of plasma per time point, separated into 1mL 
aliquots. Samples are stored at -80C. Frozen samples will be shipped on 
dry ice from the SWOG biorepository to DFCI/Broad. 
 
2. 
Collection Kits / Order of Sample Collection / Sample Collection and 
Submission Instructions 
 
3. 
Description of Assay or Methods 
 
We will utilize a custom targeted sequencing panel that includes 34 
recurrently mutated genes (candidate cancer genes; CCGs), 6 somatic 
copy number alterations (SCNAs) and 3 structural variants (SVs) in 
cHL(15,16). The ~300kb panel also contains probes to identify 
microsatellite instability and determine EBV status, which are of particular 
importance in cHL(17). The coding portions of the CCGs from cHL are tiled 
in their entirety. Focal CNA regions identified in cHL by GISTIC2.0 are tiled 
with 120 bp SNP probes at a density of ~1 probe every 200 kb (but no less 
than 12 probes per CNA). To optimize assay performance, we prioritized 
SNPs residing in exonic regions with the alignment scores (ENCODE 
Mapability) of 1, meaning that the probe sequences align to the genome 
only once. Additionally, preference was given to SNPs with higher minor 
allele population frequency as reported in gnomAD database. All included 
SNPs were required to have a population frequency > 10% and an 
alignment score > 0.5. Finally, we prioritized high-quality SNPs that were 
included in the Affymetrix Human SNP Array 6.0. Structural variant regions 
were selected that contained recurrent breakpoints identified in cHL or 
PMBL and rearrangements of the immunoglobulin loci. Regions with a 
high density of breakpoints were tiled at 2x. Bait design was optimized 
using TWIST DNA chemistry which produces high-fidelity double-stranded 
DNA probes with increased specificity and uniform target enrichment. 
TWIST-designed probes are associated with increased sequencing depth 
due to the low frequency of dropout regions. CtDNA libraries also contain 
double-stranded unique molecular indices (UMI) with separate dual 

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barcoding which eliminates false positives, enables duplex consensus 
calling and results in dramatically improved error correction. 
 
The computational pipeline combines evidence from two data types: Low 
pass (~0.2x) WGS (LP WGS) and targeted sequencing. LP WGS allows 
an estimate of the genome-wide CNA profile as well as an estimate of 
tumor fraction (TF). In patients with sufficient DNA input, we may perform 
deeper WGS as necessary to allow for optimal characterization of the 
tumor mutational profile and molecular tumor burden. From the targeted 
panel sequencing, at high coverage with duplex reads, the pipeline 
provides high precision detection of driver gene mutations, SCNAs, SVs, 
as well as other targeted sites that help estimate mutational signatures.  
The pipeline was built using both existing tools, many of which were 
developed by the Getz lab, along with new tools that were specifically 
designed for these data types. Some existing tools (such as Mutect1) were 
optimized for the deep coverage in the targeted panel and higher base 
qualities of duplex reads. 
 
For the LP WGS data, we will use iChorCNA(30) to estimate the TF and 
generate genome-wide CNA profiles.  More recently, the Getz lab has 
developed TuFEst (github.com/getzlab/TuFEst) which uses somatic 
differences in the ctDNA fragment length distribution as well as the tumor-
specific CNA profile to estimate MTB. Using the deep coverage targeted 
panel data, we detect mutations, CNAs, and SVs. For each category of 
genetic alterations, we apply multiple algorithms in a consensus approach 
to optimize detection sensitivity.  Of particular note, we developed a CNA 
algorithm (github.com/getzlab/Chute) which combines information from 
the LP WGS with Targeted Panel coverage and observed germline het-
site allele fraction shifts to identify arm-level CNAs and focal CNAs. The 
pipeline is run in Terra, the Broad Institute’s established workflow 
manager, allowing for secure, scalable, and reproducible analysis and 
collaboration.  
 
Molecular tumor burden (MTB) estimate. For the estimate of Molecular 
Tumor Burden (MTB), we combine independent estimates of TF, weighted 
by their confidence. We derived TF estimates from mutation variant allele 
frequencies (VAFs), CNA profile (using Chute), and LP data (iChor and 
TuFEst) (Table 18.13). 
 
 
Table 18.13 Protocol for sensitive and precise Molecular Tumor Burden 
(MTB) estimation. 
 
 
Step 
Methodological details 
1 
For each cfDNA sample, obtain independent estimates of tumor 
purity:  
a) using LP WGS CNAs and fragment length,  
b) CNVs from the targeted panel data,  
c) mutation variant allele fractions (VAFs).  
 
Since we have several independent estimates of tumor purity, each with 
its own confidence interval, we combine them with a weight that is 
inversely proportional to their variance. 

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2 
Convert the sample tumor purity to DNA tumor fraction:  
 
TF = (purity*ploidy) / (purity*ploidy + 2[1-purity]) 
 
This step requires an estimate of tumor ploidy, which can be challenging 
for samples with low tumor purity.  In cases in which the ploidy is not 
known, we can use a representative ploidy value for ploidy value tumor 
cells (e.g., cHL median 3.1)(26). 
3 
Convert DNA tumor fraction (TF) to units of Human Genome 
Equivalents (hGE):  
 
#hGE / ml ~ (TF*mDNA)/(mHG * vTube) 
 
Where mDNA is the mass of DNA from sequencing library preparation, 
mHG is the mass of a human genome (~6.5e-3 ng), and vTube is the 
volume of blood collected (3ml for the preliminary data shown here). 
 
 
4. 
Case Selection (if applicable) 
 
As a first step, we will analyze the first half of patients enrolled to the study, 
who will have sufficient follow-up and a full set of specimens - baseline, 
C3D1, EOT, relapse (if applicable). We anticipate that about 80% of 
patients will have the full set of serial specimens. As of May 15, 2022, there 
were currently 400 patients with paired baseline, C3D1, EOT, and paired 
normal buffy coat samples banked at the SWOG biorepository. We will 
also analyze patients who progress on therapy but have baseline and at 
least one on-treatment sample (and paired baseline buffy coat specimen). 
We will reserve the samples from patients enrolled to the second half of 
the study for validation purposes and/or to further interrogate preliminary 
findings from the initial analysis. 
 
5. 
Methods 
 
d. 
Statistical Design and Underlying Assumptions 
Endpoints and Definitions 
 
The primary clinical endpoint is progression-free survival (PFS). 
Secondary clinical endpoints include complete response (CR), event-free 
survival (EFS), and overall survival (OS). 
 
Progression-free survival (PFS) is defined as time from date of registration 
to date of first observation of progressive disease according to the 2014 
Lugano classification, or death due to any cause.  Patients last known to 
be alive and without report of progression are censored at date of last 
contact. Complete response (CR) at the end of therapy is defined 
according to the 2014 Lugano classification (e.g. Deauville score 1-3). 
Overall survival (OS) is time from date of registration to date of death due 
to any cause. Patients last known to be alive are censored at date of last 
contact. Event-free survival (EFS) is defined as time from date of 
registration to date of first occurrence of EFS event. Patients last known 
to be alive and without EFS event are censored at date of last contact.  
EFS Events are defined as:  

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•   
Disease progression/relapse  
•   
Administration of non-protocol specified systemic anti-lymphoma 
therapy (i.e. salvage therapy) at any time after initiation of protocol 
therapy. o Administration of non-protocol specified systemic anti-
lymphoma therapy for residual or relapsed Hodgkin lymphoma 
(whether or not confirmed by biopsy) in the absence of formal 
progression of disease according to the Lugano classification  
•   
Administration of any non-protocol specified radiation therapy at 
any time after initiation of protocol therapy: o Administration of 
radiation therapy in a patient who was not declared eligible for 
radiation therapy at registration 
•   
Administration of radiation in a patient who was declared eligible 
for radiation therapy but does not meet protocol-specified criteria 
for use of radiation  
 
The biomarker analysis team at DFCI/Broad will be blinded to treatment 
arm and patient outcomes. Data standardization and coding will be 
completed by DFCI/Broad and prior to analysis of the outcome data. The 
SWOG biostatistical team (M. LeBlanc, H. Li) will assess the relationship 
between genetic alterations or MTB and patient outcomes. 
 
The S1826 study will accrue 470 eligible patients per arm. Based on 
previous data, the 2-year PFS after BV-AVD is estimated to be 
approximately 82%. An exponential cure rate model is assumed for both 
arms. In addition, among the fraction of patients with disease progression, 
a hazard ratio of 1.67 is assumed between the arms. Under the above 
assumptions, for the proposed initial sampling size of 400 patients 
(accrued during the first half of study accrual) with samples and designed 
follow-up, we assume that there will be a total of 94 PFS events across 
both arms under the alternative hypothesis.  Hence, we believe most 
power calculations are conservative.   
 
Objective 1: To test if the treatment effect of N-AVD versus BV-AVD on 
PFS depends on specific genetic alterations, we will power this analysis 
using 9p24.1 amplification, which are characteristic in cHL. We assume 
400 patients with evaluable samples and similar follow-up by study design. 
Based on our prior work, 9p24.1 amplification will be present in 50% of 
advanced stage cHL patients.(18) Based on its established prognostic 
impact in standard frontline chemotherapy-based treatment of cHL, it is 
assumed that 9p24.1 alteration will be positively associated with PFS after 
N-AVD but not after BV-AVD.  A two-sample, two-sided level .05 of a Cox 
Regression score test of the interaction for patients with and without 
9p24.1 amplification has power of approximately 80% to detect an 
interaction ratio of hazard ratios of 3.3. In addition, we will test the 
prognostic association in each of the treatment groups. Testing the 
prognostic association within the BV-AVD group, a two-sample log-rank 
test for patients as defined by 9p24.1 amplification among BV-AVD 
patients has power of approximately 90% to detect a hazard ratio of 2.5.  
In both analyses, the magnitude effect sizes are critical for interpretation 
and 95% confidence intervals will be presented. In addition, we will use 
descriptive statistics to characterize the frequency of each type of genetic 
alteration at baseline in the S1826 cohort, and evaluate associations with 
outcome.  

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We will use descriptive statistics to characterize the frequency of each type 
of genetic alteration at baseline in the S1826 cohort. We will investigate 
the impact of each identified recurrent genetic alteration on PFS in a 
univariable model. Specific alterations of interest that will be formally 
assessed are JAK/STAT pathway mutations (i.e. SOCS1, STAT6), EBV-
associated alterations, and MSI-associated alterations. We will also 
evaluate the interaction between 9p24.1 alterations and JAK/STAT 
mutations and impact on PFS. Additionally, we will use Elastic Net(19) to 
select, out of all the genetic alterations, and clinical and demographic 
features, the ones important for the model, by using both linear and 
quadratic penalty components.   
 
We will also assess differences in PFS for all of the above-mentioned 
prognostic factors (including 9p24.1 alteration and JAK/STAT mutations), 
now incorporating the randomized treatment assignment (N-AVD vs BV-
AVD).  Our prior studies(20, 21) suggest that high-level 9p24 CNAs may 
be associated with a more favorable outcome in the N-AVD, but not the 
BV-AVD, treatment arm of S1826.  We will first examine treatment by the 
individual alterations or dysregulated pathways, and then apply the Elastic 
Net model with the treatment arm as an additional available covariate.  
Next, we will allow the Elastic Net to also use clinical and demographic 
features. Thus, the final models will be able to combine features detected 
in the ctDNA, the randomized treatment arms, and the patient’s clinical 
and demographic information.  We will also assess whether specific 
molecular features are selectively predictive in one of the treatment arms.   
 
We appreciate the sample size is limited to detect complex associations 
hence results will primarily hypothesis generating.  However, to yield the 
most interpretable results we plan to pre specify potential alterations and 
clinical factors (age,  IPS,  Stage, extranodal involvement) and key tuning 
parameters for the elastic net algorithm. Model complexity will be selected 
by generalized cross-validation.  By fully specifying the statistical algorithm 
we can then assess the statistical strength of the individual molecular 
components by utilizing the appropriate resampled permutation tests.      
 
 
Objective 2: Assess the prognostic significance of MTB in patients treated 
with either N-AVD or BV-AVD.  The primary MTB analysis will consider the 
change in MTB between baseline and C3D1, the cut-point will be the 2-
log change.  We anticipate 70% of patients will achieve the 2-log change 
(including those patients who transition to unmeasurable).  Testing the 
prognostic association combining but stratified by treatment group, a two-
sample log-rank test for patients landmarked at C3D1 has a power of 
approximately 93% to detect a hazard ratio of 2.1.  The expected width of 
the 95% confidence interval for this effect is (1.4,3.2). Secondary analyses 
will consider MTB at baseline on the continuous log scale. In addition, if 
for the continuous scale there is a significant association with outcome, 
adaptive split point optimization will be considered.  The algorithm to select 
cut point will be fully specified including the minimum fraction of patients 
above will be set at 20% of sample size prior to analysis of any outcome 
data.  Permutation re-sampling will be used to assess significance in the 
context of this correlated multiple comparison problem (22eg. LeBlanc and 
Crowley, 1995)  
 

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We will characterize the MTB at baseline in units of HGE/ml and assess 
its prognostic value as a single variable and after adjusting for clinical 
prognostic features/stratification factors age (<18, 18-60, >60 yrs.) and 
International Prognostic Score (0-3 vs 4-7)(2333).  We will also consider 
baseline MTB categorized by a median cut-point. 
 
At subsequent time points, we will evaluate changes in MTB at both C3D1 
and EOT compared to baseline. In cHL and other lymphoid malignancies, 
a 2-log (100-fold) decrease in MTB after 2 cycles of therapy (C3D1) 
predicts outcome(2434). We will use this parameter in S1826 trial patients 
as a binary covariate. Outcomes of interest will include both PFS (the 
primary endpoint of S1826) and achievement of CR at EOT as determined 
by PET/CT.  We will characterize the magnitude of change descriptively 
for those who exhibit progressive disease within the 6 cycles of therapy 
and those who do not, and also by categories of response for those who 
do not progress. These measures look at per patient MTB changes, and 
do not rely on the baseline threshold(s) defined above.  
 
We will initially investigate change in MTB in a univariable setting but will 
also use multivariable models incorporating other demographic and 
clinical features from diagnosis to understand how these additional 
features may modify the interpretation of changes in MTB. To more clearly 
consider the relationship between changes in MTB and PFS outcomes, 
we will also perform a landmark analysis of PFS including only those 
patients who remain alive without progression at EOT. All assessments of 
MTB and PFS will rely on log rank tests in the setting of a single threshold 
for all patients or stratified log rank tests in the setting of customized 
thresholds for the age and IPS risk score strata defined in the protocol, 
and Cox proportional hazards models for the multivariable setting, using 
either stepwise selection or a lasso approach. Again, to assess overall 
multivariable performance, variables and cut points will be specified prior 
to using the Lasso.  In addition, it is recognized that cross-validated partial 
likelihood is unstable; therefore, model selection (complexity) will use 
generalized cross-validation.   
 
We will specifically assess the PPV/NPV of detectable ctDNA at EOT and 
compare this to the gold standard EOT PET-CT scan response according 
to the 2014 Lugano Classification. We assume that approximately 20% of 
patients will be ctDNA positive at EOT, and 10% will be PET-CT positive 
(Deauville Score 4-5) at EOT.  With approximately 200 patient samples 
per arm, then the PPV for either of those measures can be estimated to 
within +/- 11% (95% confidence interval) for the case with 20% ctDNA 
positive.  Analogous results hold for PET-CT and NPV. 
 
e. 
Materials Handling 
Frozen samples will be shipped on dry ice from the SWOG biorepository 
at Nationwide Children’s Hospital to DFCI/Broad for analysis. 
 
f. 
Funding  
BIQSFP funding has been secured from NCI CTEP for the Translational 
Medicine analysis. Additional funding support will be provided by BMS 
and/or the TM investigators internal institutional funding. 
 
 
 

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