Conditions: AIDS-Related Hodgkin Lymphoma Ann Arbor Stage II Hodgkin Lymphoma Ann Arbor Stage IIA Hodgkin Lymphoma Ann Arbor Stage IIB Hodgkin Lymphoma Ann Arbor Stage III Hodgkin Lymphoma Ann Arbor Stage IIIA Hodgkin Lymphoma Ann Arbor Stage IIIB Hodgkin Lymphoma Ann Arbor Stage IV Hodgkin Lymphoma Ann Arbor Stage IVA Hodgkin Lymphoma Ann Arbor Stage IVB Hodgkin Lymphoma Classic Hodgkin Lymphoma HIV Infection
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 41
Healthy volunteers: no

Brief summary:
This pilot phase I/II trial studies the side effects and the best dose of brentuximab vedotin when given together with combination chemotherapy and to see how well they work in treating patients with stage II-IV human immunodeficiency virus (HIV)-associated Hodgkin lymphoma. Brentuximab vedotin is a monoclonal antibody, called brentuximab, linked to a chemotherapy drug called vedotin. Brentuximab attaches to CD30-positive cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving brentuximab vedotin together with combination chemotherapy may kill more cancer cells.

Detailed description:
PRIMARY OBJECTIVES I. To identify the maximum tolerated dose (MTD) of brentuximab vedotin when combined with the doxorubicin hydrochloride, vinblastine sulfate, and dacarbazine (AVD) chemotherapy regimen in the treatment of HIV-associated stage II-IV Hodgkin lymphoma. (Phase I) II. Establish an estimate of the two-year progression-free survival (PFS) for participants with HIV-associated stage II-IV Hodgkin lymphoma when treated using brentuximab vedotin plus the AVD chemotherapy regimen. (Phase II)

SECONDARY OBJECTIVES:

I. To evaluate the toxicity of AVD and brentuximab vedotin with highly active antiretroviral therapy (HAART).

II. To estimate the partial response (PR) rate, complete response (CR) rate, overall survival (OS), and event free survival (EFS) at 2 and 5 years.

III. To evaluate the effect of AVD and brentuximab vedotin on cluster of differentiation (CD)4 and CD8 counts after cycle 1, 4, at the end of therapy, and every 3 months after treatment completion for one year.

IV. To investigate the prognostic value of fludeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) scans at baseline, after cycle 2, and at treatment completion, with respect to 2-year progression free survival.

V. To evaluate HAART status at baseline and to correlate this with tumor response to therapy and OS and PFS.

VI. To characterize the histologic subtypes in HIV-Hodgkin lymphoma (HL) in the highly active antiretroviral therapy (HAART) era.

VII. To assess the neurotoxicity of HAART in combination with AVD and brentuximab vedotin.

VIII. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, at the completion of therapy, and every 3 months after treatment completion for one year.

IX. To perform pharmacokinetic and immunogenicity studies to determine drug levels during therapy.

X. To perform micro ribonucleic acid (miRNA) profile analysis on the HIV-HL tumor specimens and to correlate miRNA expression with OS, PFS, tumor response to therapy, histologic subtype of HIV-HL, and HIV disease characteristics.

XI. To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate the markers studied with OS, PFS, and tumor response to therapy.

XII. To identify Epstein-Barr virus (EBV)-associated tumor derived deoxyribonucleic acid (DNA) in the plasma of study participants and to correlate these levels during therapy with disease response and OS. (Phase II) XIII. To identify cytokines in the plasma of participants during therapy that can be used as tumor and prognostic markers. (Phase II) XIV. To assess latent and expressed HIV reservoirs before, during, and post chemotherapy. To understand how cytotoxic chemotherapeutic agents affect HIV expression.

OUTLINE: This is a phase I, dose-escalation study of brentuximab vedotin followed by a phase II study.

Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.

Arms:
arm 1: Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, and dacarbazine IV on days 1 and 15. Patients also receive brentuximab vedotin IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.

Interventions: intervention 1: Brentuximab Vedotin intervention 2: Dacarbazine intervention 3: Doxorubicin Hydrochloride intervention 4: Pharmacological Study intervention 5: Vinblastine
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Correlative studies intervention 5: Given IV

Protocol document:
Prot_SAP_000.pdf: 
AMC-085 (Version 19.0) 15APR2019 
 
i 
NCI Version Date 15APR2019 
SUMMARY OF CHANGES 
A pilot trial of AVD and brentuximab vedotin (SGN-35) in the treatment of stage II-IV 
HIV-associated Hodgkin lymphoma 
Version 19.0 
 
NCI Protocol #: AMC-085 
Local Protocol #: AMC-085 
 
NCI Version Date: 15APR2019 
Protocol Date: 15APR2019 
 
I. 
Revisions in response to the updated RRA for brentuximab vedotin (SGN-35) from 
Dr. Elad Sharon (sharone@mail.nih.gov), dated 01 APR 2019 
# 
Section 
Description of Change 
1.  
6.1 
 
Appendix XV 
The CAEPR Version 2.4, January 31, 2018 was updated to CAEPR Version 2.5, 
February 13, 2019. 
 
The SPEER grades have been updated. 
 
Increase in Risk Attribution:  
• 
Changed to “Rare but Serious” from “Also Reported on SGN-35 Trials But With 
Insufficient Evidence for Attribution:”  Infusion related reaction 
 
Provided Further Clarification:   
• 
Infections and infestations - Other (herpes zoster) is now reported as Shingles 
(CTCAE 5.0 language). 
• 
Investigations - Other (blood LDH increased) is now reported as Blood lactate 
dehydrogenase increased (CTCAE 5.0 language). 
2.  
ICD 
The Risk Profile was updated to clarify a risk in the RARE, AND SERIOUS risk category 
for brentuximab vedotin (SGN-35). 
 
Provided Further Clarification:   
• 
“A tear or hole in the stomach that may require surgery” (under Rare) is now reported 
as “A tear or hole in internal organs that may require surgery” (under Rare). 
 
II. 
Administrative and Editorial Changes 
# 
Section 
Description of Change 
3.  
Global 
The U.S. protocol version number has been updated from 18.0 to 19.0 and the date has 
been updated from 06MAR2019 to 15APR2019. 
 
The LYSARC protocol version number has been updated from 5.0 to 6.0 and the date 
has been updated from 14/11/2016 to 15/04/2019. 
4.  
Global 
The protocol statistician has been changed from Page Moore to Milan Bimali. 
5.  
Appendix XV 
All remaining references to CTCAE version 4.0 in the LYSARC protocol were 
corrected to version 5.0. 


AMC-085 (Version 19.0) 15APR2019 
 
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AMC PROTOCOL #085: 
A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the 
treatment of stage II-IV HIV-associated Hodgkin Lymphoma 
A Trial of the AIDS Malignancy Consortium (AMC) 
 
Sponsored by: 
CTEP, Division of Cancer Treatment and Diagnosis, NCI 
and 
The Lymphoma Study Association (LYSA), conducted by 
The Lymphoma Academic Research Organisation 
(LYSARC), l’Institut National du Cancer 
 
Supported by: 
Office of HIV and AIDS Malignancy (OHAM) 
 
NCT Registration Number: 
NCT01771107 
 
CTEP IND Number: 
 
 
Protocol Chair: 
Paul G. Rubinstein, MD 
 
Protocol Co-Chair: 
Ariela Noy, MD 
Version 19.0, 15APR2019 
NCI Version Date: 15APR2019 


AMC-085 (Version 19.0) 15APR2019 
 
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AMC PROTOCOL SIGNATURE PAGE 
I,  
 
 
 
 
, Principal Investigator at site  
, agree to conduct and 
follow this protocol: AMC Protocol #085 - A Pilot Trial of AVD and Brentuximab Vedotin (SGN-
35) in the treatment of stage II-IV HIV-associated Hodgkin Lymphoma (Version 19.0, 
15APR2019), as written according to AMC, NCI and FDA guidelines. I understand that no 
deviations from the protocol eligibility criteria or waivers for protocol deviations will be permitted. 
 
_________________________________ 
 
 
_____________________ 
 
Signature 
Date (mm/dd/yyyy) 
 
 


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TABLE OF CONTENTS 
SUMMARY OF CHANGES ......................................................................................................... i 
I. 
Scientific and Substantive Changes ......................................................................... i 
II. 
Administrative and Editorial Changes ..................................................................... i 
AMC PROTOCOL SIGNATURE PAGE ...................................................................................2 
TABLE OF CONTENTS ..............................................................................................................3 
LIST OF TABLES .........................................................................................................................7 
PROTOCOL ROSTER .................................................................................................................8 
PROTOCOL SYNOPSIS ............................................................................................................10 
LIST OF ABBREVIATIONS .....................................................................................................13 
1.0 
OBJECTIVES ..................................................................................................................16 
1.1 
Primary Objective ..................................................................................................16 
1.2 
Secondary Objectives .............................................................................................16 
2.0 
BACKGROUND ..............................................................................................................18 
2.1 
Hodgkin Lymphoma ..............................................................................................18 
2.2 
Hodgkin Lymphoma in HIV Patients ....................................................................18 
2.3 
Current Treatment for HIV-Related HL ................................................................19 
2.4 
Study Agents ..........................................................................................................21 
2.5 
Study Design and Rationale ...................................................................................26 
2.6 
Rationale for Correlative Studies ...........................................................................27 
3.0 
PARTICIPANT SELECTION .......................................................................................28 
3.1 
Eligibility Criteria ..................................................................................................28 
3.2 
Exclusion Criteria ..................................................................................................30 
3.3 
Number of Participants to be Enrolled ...................................................................31 
3.4 
Recruitment Plan ....................................................................................................32 
3.5 
Participant Enrollment Procedures ........................................................................32 
4.0 
TREATMENT PLAN ......................................................................................................33 
4.1 
Phase I: AVD-Brentuximab Vedotin Therapy .......................................................33 
4.2 
Phase II: AVD-Brentuximab Vedotin Therapy .....................................................33 
4.3 
Radiation Therapy ..................................................................................................34 
4.4 
Supportive Therapy ................................................................................................34 
4.5 
Study Duration .......................................................................................................35 
4.6 
Criteria for Permanent Removal from Treatment ..................................................35 


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4.7 
Criteria for Early Study Termination .....................................................................36 
5.0 
DOSE MODIFICATIONS/TOXICITY MANAGEMENT..........................................38 
5.1 
Brentuximab Vedotin Dose Modifications ............................................................38 
5.2 
AVD-Brentuximab Vedotin Dose Modifications (applies to all cycles) ...............44 
6.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS .......................46 
6.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for 
Brentuximab Vedotin (SGN-35, NSC 749710) .....................................................46 
6.2 
Classification of AEs by Severity and Relationship to Study Drug 
Administration .......................................................................................................52 
6.3 
Expedited Adverse Event Reporting ......................................................................53 
6.4 
Routine Adverse Event Reporting .........................................................................55 
6.5 
Secondary Malignancy ...........................................................................................56 
7.0 
PHARMACEUTICAL INFORMATION ......................................................................57 
7.1 
Chemotherapy Medications ...................................................................................57 
7.2 
Drug Orders, Transfers, Returns, and Accountability ...........................................60 
7.3 
Reporting Requirements for Concomitant Medications ........................................60 
8.0 
STUDY PROCEDURES .................................................................................................62 
8.1 
Screening/Baseline Evaluations .............................................................................62 
8.2 
Evaluations During Treatment ...............................................................................64 
8.3 
Post Treatment Evaluation .....................................................................................65 
8.4 
Early Discontinuation of Therapy ..........................................................................67 
9.0 
EFFICACY AND SAFETY MEASUREMENTS .........................................................68 
9.1 
Efficacy Measurements ..........................................................................................68 
9.2 
Response Assessment ............................................................................................68 
10.0 
CORRELATIVE STUDIES ............................................................................................71 
10.1 
Pharmacokinetic/Immunogenicity Studies ............................................................71 
10.2 
Micro RNA Analysis of HIV-Associated Hodgkin Lymphoma ............................72 
10.3 
Effects of AVD-Brentuximab Vedotin on T-cell Subsets in vivo ..........................73 
11.0 
STATISTICAL CONSIDERATIONS ...........................................................................74 
11.1 
Study Design/Endpoints.........................................................................................74 
11.2 
Sample Size/Accrual Rate ......................................................................................75 
11.3 
Stratification Factors ..............................................................................................75 
11.4 
Analysis of Secondary Endpoints ..........................................................................75 


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12.0 
ROLE OF DATA MANAGEMENT ..............................................................................78 
12.1 
CRF Instructions ....................................................................................................78 
12.2 
Data Quality ...........................................................................................................78 
12.3 
Data Monitoring .....................................................................................................78 
13.0 
ETHICAL AND REGULATORY CONSIDERATIONS ............................................79 
13.1 
Good Clinical Practice ...........................................................................................79 
13.2 
Ethical Considerations ...........................................................................................79 
13.3 
IRB Approval and Informed Consent ....................................................................79 
13.4 
Research Authorization ..........................................................................................80 
13.5 
Participant Confidentiality .....................................................................................80 
13.6 
Protocol Compliance ..............................................................................................80 
13.7 
Changes to the Protocol .........................................................................................80 
13.8 
On-site Audits ........................................................................................................80 
13.9 
Women and Minorities ..........................................................................................81 
14.0 
REFERENCES .................................................................................................................82 
APPENDIX I: SCHEDULE OF EVALUATIONS ...................................................................89 
APPENDIX II: COLLABORATIVE RESEARCH AGREEMENT ......................................91 
APPENDIX III: PERFORMANCE STATUS SCALES ..........................................................93 
APPENDIX IV: FACT-GOG-NEUROTOXICITY QUESTIONNAIRE v4.0.......................94 
APPENDIX V: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) DONATION 
SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS ...................95 
APPENDIX VI: ACSR INFORMED CONSENT .....................................................................98 
APPENDIX VII: AMC DATA AND SAFETY MONITORING PLAN ...............................103 
APPENDIX VIII: CENTRAL PATHOLOGY REVIEW ......................................................106 
APPENDIX IX: PHARMACOKINETIC/IMMUNOGENICITY STUDIES ......................109 
APPENDIX X: ASSESSMENT OF CIRCULATING LEVELS OF PRO-
INFLAMMATORY AND ANGIOGENESIS-ASSOCIATED MOLECULES 
STUDY PLAN .........................................................................................................115 
APPENDIX XI: ASSESSMENT OF EBV DNA IN PLASMA ..............................................119 
APPENDIX XII: ASSESSEMENT OF HIV LATENT AND EXPRESSED HIV 
RESERVOIRS ........................................................................................................122 
APPENDIX XIII: PROHIBITED AND USE WITH CAUTION MEDICATIONS THAT 
ARE P-GLYCOPROTEIN AND CYP3A4 INHIBITORS .................................126 
APPENDIX XIV: ANALYSIS OF T-CELL SUBSETS AND CYTOKINES OVER TIME 


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IN SUBJECTS TREATED WITH AVD-BV .......................................................127 
APPENDIX XV: AMC-085 LYSARC PROTOCOL ..............................................................130 
 
 


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LIST OF TABLES 
 
Table 2-A:  
Summary of Retrospective and Prospective Trials of HIV-cHL ...............20 
Table 4-A:  
Phase 1 Dose Finding Schema for AVD-BV Regimen* ..............................33 
Table 5-A:  
Treatment Modification Guidelines for Brentuximab Vedotin for All 
Cycles ..............................................................................................................38 
Table 5-B:  
Treatment Modification Guidelines for AVD-Brentuximab Vedotin for 
All Cycles ........................................................................................................43 
Table 5-C:  
Total Bilirubin with Appropriate Doxorubicin and Vinblastine Dose 
Adjustments ....................................................................................................45 
Table 13-A:  
Accrual Targets ..............................................................................................81 
Table App IX-A: Pharmacokinetic Time Point and Immunogenicity Sampling Time Points
........................................................................................................................110 
 
 


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PROTOCOL ROSTER 
AMC Protocol #085 
A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the Treatment of  
Stage II-IV HIV-associated Hodgkin Lymphoma 
Protocol Chair: 
Paul G. Rubinstein, MD 
John H. Stroger Jr. Hospital of Cook 
County 
(Cook County Hospital) 
Section of Hematology/Oncology 
Administration Building 
1900 W. Polk Street, Suite 755 
Chicago, IL 60612 
Tel: 312-864-7277 
Fax: 312-864-9002 
Email: prubinstein@cookcountyhhs.org 
Protocol Statistician: 
Milan Bimali, PhD 
AMC Statistical Center 
University of Arkansas for Medical Sciences 
4301 West Markham Street 
Little Rock, AE 72205 
Tel: 501-686-8204 
Fax: 501-526-6729 
Email: mbimali@uams.edu 
Protocol Co-Chair: 
Ariela Noy, MD 
Memorial Sloan-Kettering Cancer Center 
Lymphoma Service 
1275 York Avenue 
New York, NY 10065 
Tel: 212-639-7423 
Fax: 646-422-2284 
Email: noya@mskcc.org 
Data Management/Operations: 
AMC Operations and Data Management Center 
The Emmes Corporation 
401 N. Washington Street, Suite 700 
Rockville, MD 20850 
Tel: 301-251-1161 
Fax: 240-238-2842 
Email: amcpm@emmes.com 
AMC Biorepository: 
Sylvia Silver, DA 
AMC Biorepository Director 
George Washington University Medical 
Center 
2300 I Street, NW 
Room 118 
Washington, DC 20037 
Tel: 202-994-2945 
Fax: 202-994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
 
 
 


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LYSARC sites (accrual concluded 30NOV2017): 
APHP - Hôpital Antoine Béclère (Bicêtre-
Béclère): 
Pr. François Boué 
157, Rue de la Porte de Trivaux, 
92140 Clamart, France 
Email: francois.boue@abc.aphp.fr 
APHP - Hôpital Henri Mondor: 
Pr. Corinne Haioun 
Unité Hémopathies Lymphoïdes 
51 avenue de Lattre de Tassigny  
94010 Créteil, France 
Email: corinne.haioun@hmn.aphp.fr 
APHP - Hôpital St Louis: 
Pr. Eric Oksenhendler 
Service d’immunologie Clinique - 
1 avenue Claude Vellefaux - 
Coquelicot 6 - 
75475 Paris 10, France 
Email: eric.oksenhendler@sls.aphp.fr 
APHP - Hôpital St Antoine: 
Pr. Paul Coppo 
Service hématologie 
Bâtiment Robert André 2ème étage 
184, rue du Fg. Saint Antoine 
75012 Paris, France 
Email: paul.coppo@sat.aphp.fr 
CHU de Nice: 
Pr. Nicolas Mounier 
Service d'onco hématologie 
151 route Saint Antoine de Ginestière 
06202 Nice, France 
Email: mounier.n@chu-nice.fr 
Hospice Civils de Lyon – Centre 
Hospitalier Lyon Sud: 
Pr. Gilles Salles 
Service Hématologie 
165 chemin du Grand Revoyet 
69495 Pierre Bénite cedex, France 
Email: gilles.salles@chu-lyon.fr 
CHU de Toulouse: 
Dr. Pierre Delobel 
Service des maladies infectieuses 
place Baylac 
Hôpital Purpan 
31059 TOULOUSE Cedex 9, France 
Email: delobel.p@chu-toulouse.fr 
 
 
 


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PROTOCOL SYNOPSIS 
Title: 
A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the 
treatment of stage II-IV HIV-associated Hodgkin Lymphoma 
Phase of Study: 
Phase I /II 
Participating Institutions: 
This protocol will be open to all AMC member sites. 
Accrual Target: 
Phase I/II: Minimum of 6 participants 
Phase I: Maximum of 18 participants 
Phase II: Maximum of 51 participants 
Population: 
 
Previously untreated individuals diagnosed with stage II-IV, 
HIV-associated, CD30-positive, classic Hodgkin Lymphoma 
(cHL), as defined by the 2008 WHO classification of 
hematological malignancies1. 
Regimen: 
Phase 1: This portion of the protocol will be a de-escalation 
design testing 3 dose levels of brentuximab vedotin in 
conjunction with standard, fixed doses of doxorubicin 25 mg/m2, 
vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 (AVD) on days 
1 and 15 of a 28-day cycle for a total of 6 cycles. The following 
dose schedule will be used to determine the maximum tolerated 
dose (MTD) of brentuximab vedotin. 
Dose levels: 
Dose - 0: 
1.2 mg/kg 
Dose - 1: 
0.9 mg/kg 
Dose - 2: 
0.6 mg/kg 
On the first cohort, 3 to 6 participants will begin at Dose level 0. 
If > 1 dose-limiting toxicity (DLT) is encountered, 3 to 6 
additional participants will be enrolled at the next lowest dose 
level. The MTD will be the dose level at which ≤ 1 of 6 
participants experience DLT. If more than one participant at any 
one dose level encounters a DLT, the dose will be de-escalated 
for all subsequent participants (see Section 4.1.1 for DLT 
definition). Once a MTD has been confirmed, the phase II portion 
of the study will commence at that dose level. The phase I MTD 
was determined to be 1.2 mg/kg. 
Phase 2: The MTD of brentuximab vedotin will be used in 
conjunction with doxorubicin, vinblastine, and dacarbazine at the 
same doses and times as stated above. 


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Duration: 
Participants will receive brentuximab vedotin, in conjunction 
with standard, fixed, doses of doxorubicin 25 mg/m2, vinblastine 
6 mg/m2, and dacarbazine 375 mg/m2 on days 1 and 15 of a 28-
day cycle for 6 cycles. Evaluation of disease response will be 
performed by PET/CT at the end of cycle 2 and cycle 6 and 
compared to the baseline PET/CT per the Lymphoma 
Harmonization criteria. Participants with progressive disease at 
the end of cycle 2 will be removed from study and those with 
stable disease can proceed with the study at the discretion of the 
principal investigator. Participants will be followed for a total of 
5 years after the completion of therapy: every 3 months for the 
first 2 years and every 6 months for years 3 to 5 of follow up. 
Primary Objective: 
Phase 1: To identify the MTD of brentuximab vedotin when 
combined with the AVD chemotherapy regimen in the treatment 
of HIV-associated stage II-IV Hodgkin lymphoma. 
Phase 2: To establish an estimate of the two-year progression-
free survival (PFS) for participants with HIV-associated stage II-
IV Hodgkin lymphoma when treated using brentuximab vedotin 
plus the AVD chemotherapy regimen. 
Secondary Objectives: 
 
Phase 1 and 2 
• To evaluate the toxicity of AVD and brentuximab vedotin 
with HAART. 
• To estimate the partial response (PR) rate, complete response 
(CR) rate, overall survival (OS), and event free survival 
(EFS) at 2 and 5 years. 
• To evaluate the effect of AVD and brentuximab vedotin on 
CD4 and CD8 counts after cycle 1, 4, at the end of therapy, 
and every 3 months after treatment completion for one year. 
• To investigate the prognostic value of FDG-PET/CT scans at 
baseline, after cycle 2, and at treatment completion, with 
respect to 2-year progression free survival. 
• To evaluate HAART status at baseline and to correlate this 
with tumor response to therapy and OS and PFS. 


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• To characterize the histologic subtypes in HIV-HL in the 
highly active antiretroviral therapy (HAART) era. 
• To assess the neurotoxicity of HAART in combination with 
AVD and brentuximab vedotin. 
• To evaluate effect of AVD and brentuximab vedotin on viral 
load after cycle 1, 4, at the completion of therapy, and every 
3 months after treatment completion for one year. 
• To perform pharmacokinetic and immunogenicity studies to 
determine drug levels during therapy (See Section 10.0 and 
Appendix IX). 
• To perform miRNA profile analysis on the HIV-HL tumor 
specimens and to correlate miRNA expression with OS, PFS, 
tumor response to therapy, histologic subtype of HIV-HL, 
and HIV disease characteristics (See Section 10.0 and 
Appendix VIII). 
• To perform tissue microarray analysis on HIV-HL tumor 
specimens and to correlate the markers studied with OS, PFS, 
and tumor response to therapy (See Section 10.0 and 
Appendix VIII). 
• To identify EBV-associated tumor derived DNA in the 
plasma of study participants and to correlate these levels 
during therapy with disease response and OS (See Section 
10.0 and Appendix XI). This objective will only be performed 
in the Phase II portion of the study. 
• To identify cytokines in the plasma of participants during 
therapy that can be used as tumor and prognostic markers. 
(See Section 10.0 and Appendix X). This objective will be 
done only in the Phase II portion of the study. 
• To assess latent and expressed HIV reservoirs before, during, 
and post chemotherapy. To understand how cytotoxic 
chemotherapeutic agents affect HIV expression (See Section 
10.0 and Appendix XII). 


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LIST OF ABBREVIATIONS 
AASD ....................................................................................... Assistance for AIDS Specific Drugs 
ABVD ............................................................. Doxorubicin, Bleomycin, Vinblastine, Dacarbazine 
ACSR ................................................................................... AIDS and Cancer Specimen Resource 
ACTG .................................................................................................... AIDS Clinical Trials Group 
ADC ........................................................................................................ Antibody-Drug Conjugate 
AdvantageEDCSM ........................................................................ AMC Internet Data Entry System 
AE .............................................................................................................................. Adverse Event 
AIDS .................................................................................. Acquired Immunodeficiency Syndrome 
ALCL .......................................................................................... Anaplastic Large Cell Lymphoma 
ALT ......................................................................................................... Alanine Aminotransferase 
AMC ................................................................................................ AIDS Malignancy Consortium 
ANC ........................................................................................................ Absolute Neutrophil count 
ART................................................................................................................. Antiretroviral therapy 
ASCT ........................................................................................... Autologous Stem Cell Transplant 
AST ............................................................................................................. Aspartate Transaminase 
AVD ..................................................................................... Adriamycin, Vinblastine, Dacarbazine 
AVD-BR .......................................... Adriamycin, Vinblastine, Dacarbazine-Brentuximab Vedotin 
AZT ................................................................................................................................. Zidovudine 
BCSAP .......................................................................................... B-cell Specific Activator Protein 
bDNA ........................................................................................................................Branched DNA 
cART ............................................................................................ Combined Antiretroviral Therapy 
CBC.............................................................................................................. Complete Blood Count 
CDUS .................................................................................................. Clinical Data Update System 
CFR ...................................................................................................... Code of Federal Regulations 
cHL ................................................................................................... Classical Hodgkin Lymphoma 
CI........................................................................................................................ Confidence interval 
cm ...................................................................................................................................... centimeter 
CR ...................................................................................................................... Complete Response 
CRADA.......................................................... Cooperative Research and Development Agreement 
CRF ...................................................................................................................... Case Report Form 
CSF .................................................................................................................... Cerebrospinal Fluid 
CT ...................................................................................................... Computed Tomography Scan 
CTA........................................................................................................... Clinical Trial Agreement 
CTCAE .............................................. Common Terminology Criteria for Adverse Event reporting 
CTEP ....................................................................................... Cancer Therapy Evaluation Program 
CTEP-AERS ..................................................................... CTEP Adverse Event Reporting System 
CTMS ......................................................................................... Clinical Trials Monitoring Service 
DARF ......................................................................................... Drug Accountability Record Form 


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DCTD ......................................................................... Division of Cancer Treatment and Diagnosis 
DDI ................................................................................................................................. Didanosine 
DFS ................................................................................................................ Disease Free Survival 
DHHS ............................................................................ Department of Health and Human Services 
DLCO .......................................................... Diffusing Capacity of the Lung for Carbon Monoxide 
DLT ............................................................................................................. Dose-Limiting Toxicity 
DMC .................................................................................................... Data Monitoring Committee 
DNA ............................................................................................................. Deoxyribonucleic Acid 
DTIC .............................................................................................................................. Dacarbazine 
EBV.......................................................................................... Epirubicin, Bleomycin, Vinorelbine 
EBVP ................................................................... Epirubicin, Bleomycin, Vinorelbine, Prednisone 
EFS .................................................................................................................... Event-Free Survival 
ELISA ................................................................................. Enzyme Linked Immunosorbent Assay 
ESA ............................................................................................ Erythropoiesis Stimulating Agents 
FDA.................................................................................................. Food and Drug Administration 
FDG-PET ...................................................... Fluorodeoxyglucose-Positron Emission Tomography 
GCSF.................................................................................. Granulocyte Colony-Stimulating Factor 
HAART ................................................................................. Highly Active Antiretroviral Therapy 
HBV ....................................................................................................................... Hepatitis B Virus 
HCV ....................................................................................................................... Hepatitis C Virus 
HIV ............................................................................................... Human Immunodeficiency Virus 
HL .................................................................................................................... Hodgkin Lymphoma 
HRS ................................................................................................................... Reed Stemberg Cell 
IDB ....................................................................................................... Investigational Drug Branch 
IDSA .................................................................................. Infectious Diseases Society of America 
IEC ................................................................................................... Independent Ethics Committee 
IND ...................................................................................... Investigational New Drug Application 
IPI ...................................................................................................... International Prognostic Index 
IPS ..................................................................................................... International Prognostic Score 
IRB ......................................................................................................... Institutional Review Board 
IV .................................................................................................................................... Intravenous 
JCV ............................................................................................................ John Cunningham Virus 
kg........................................................................................................................................ Kilogram 
LDH ............................................................................................................. Lactate Dehydrogenase 
LVEF........................................................................................... Left Ventricular Ejection Fraction 
mg ..................................................................................................................................... Milligram 
miRNA ................................................................................................................ Mature microRNA 
MMAE ..................................................................................................... Monomethyl Auristatin E 
MRI .................................................................................................... Magnetic Resonance Imaging 
MTD ........................................................................................................ Maximum Tolerated Dose 


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MUGA .......................................................................................... Multiple Gated Acquisition Scan 
NADC .................................................................................................. Non-AIDS Defining Cancer 
NCCN ............................................................................ National Comprehensive Cancer Network 
NCI ............................................................................................................ National Cancer Institute 
NCT............................................................................................. National Clinical Trials [Registry] 
NIH……………………………………………………………….. .... National Institutes of Health 
NHL………………………………………………………………… ..... Non-Hodgkin Lymphoma 
NLPHL ....................................................... Nodular Lymphatic Predominant Hodgkin Lymphoma 
NNRT .................................................................. Non-nucleoside Reverse Transcriptase Inhibitors 
NSC ............................................................................................................. National Service Center 
ODMC............................................................................. Operations and Data Management Center 
OHAM ......................................................................................... Office of HIV AIDS Malignancy 
OI ................................................................................................................ Opportunistic Infections 
OS ........................................................................................................................... Overall Survival 
PCR ....................................................................................................... Polymerase Chain Reaction 
PFS ........................................................................................................... Progression-Free Survival 
PFT ............................................................................................................ Pulmonary Function Test 
PI ..................................................................................................................... Principal Investigator 
PI ......................................................................................................................... Protease Inhibitors 
PIO ........................................................................................................ Protocol Information Office 
PML .......................................................................... Progressive Multifocal Leukoencephalopathy 
PO ...................................................................................................................... Per oral [by mouth] 
PR ............................................................................................................................ Partial Response 
RISC .............................................................................................. RNA-induced silencing complex 
RNA ................................................................................................................. Ribose Nucleic Acid 
SD .............................................................................................................................. Stable Disease 
SPD ......................................................................................... Sum of the Product of the Diameters 
SUV...................................................................................................... Standardized Uptake Values 
TLS ........................................................................................... Tumor Lysis Leukoencephalopathy 
TMA ........................................................................................................ Tissue Microarray Studies 
ULN ............................................................................................................. Upper Limit of Normal 
WHO ...................................................................................................... World Health Organization 
 
 
 


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1.0 
OBJECTIVES 
1.1 
Primary Objective 
1.1.1 Phase 1: To identify the MTD of brentuximab vedotin when combined with the 
AVD chemotherapy regimen in the treatment of HIV-associated stage II-IV 
Hodgkin lymphoma. 
1.1.2 Phase 2: Establish an estimate of the two-year progression free survival for 
participants with HIV-associated stage II-IV Hodgkin lymphoma when treated 
using brentuximab vedotin plus the AVD chemotherapy regimen. 
1.2 
Secondary Objectives 
1.2.1 To evaluate the toxicity of AVD and brentuximab vedotin with HAART. 
1.2.2 To estimate the partial response (PR) rate, complete response (CR) rate, overall 
survival (OS), and event free survival (EFS) at 2 and 5 years. 
1.2.3 To evaluate the effect of AVD and brentuximab vedotin on CD4 and CD8 counts 
after cycle 1, 4, at the end of therapy, and every 3 months after treatment completion 
for one year.  
1.2.4 To investigate the prognostic value of FDG-PET/CT scans at baseline, after cycle 
2, and at treatment completion, with respect to 2-year progression free survival. 
1.2.5 To evaluate HAART status at baseline and to correlate this with tumor response to 
therapy and OS and PFS. 
1.2.6 To characterize the histologic subtypes in HIV-HL in the highly active 
antiretroviral therapy (HAART) era. 
1.2.7 To assess the neurotoxicity of HAART in combination with AVD and brentuximab 
vedotin. 
1.2.8 To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, 
at completion of therapy, and every 3 months after treatment completion for one 
year. 
1.2.9 To perform pharmacokinetic and immunogenicity studies to determine drug levels 
during therapy (See Section 10.0 and Appendix IX). 
1.2.10 To perform miRNA profile analysis on the HIV-HL tumor specimens and to 
correlate miRNA expression with OS, PFS, tumor response to therapy, histologic 
subtype of HIV-HL, and HIV disease characteristics (See Section 10.0 and 
Appendix VIII). 
1.2.11 To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate 
the markers studied with OS, PFS, and tumor response to therapy (See Section 10.0 
and Appendix VIII). 
1.2.12 To identify EBV associated tumor derived DNA in the plasma of study participants, 
and to correlate these levels during therapy with disease response and OS (See 
Section 10.0 and Appendix XI). This objective will only be performed in the Phase 
II portion of the study. 


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1.2.13 To identify cytokines in the plasma of participants during therapy that can be used 
as tumor and prognostic markers. (See Section 10.0 and Appendix X). This 
objective will be done only in the Phase II portion of the study. 
1.2.14 To assess latent and expressed HIV reservoirs before, during, and post 
chemotherapy. To understand how cytotoxic chemotherapeutic agents affect HIV 
expression (See Section 10.0 and Appendix XII). 


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2.0 
BACKGROUND 
2.1 
Hodgkin Lymphoma 
Hodgkin lymphoma (HL) is a lymphoid neoplasm first described by Thomas Hodgkin in 
the 1890s2. The disease presents with or without splenomegaly, fevers, night sweats, 
weight loss, and occasionally pruritus. In 2008, 8,220 new cases of HL were diagnosed 
resulting in 1,350 deaths1,3. The transformed cell that defines classic Hodgkin lymphoma 
(cHL) is the Reed Sternberg cell (HRS), a large multinuclear cell expressing surface 
antigens CD15 and CD30 without B or T cell surface antigens1. The cell of origin was 
unclear until the mid-1990s, when it was shown that the tumor originated from germinal B 
cell lymphocytes, as demonstrated by the expression of PAX 5, B-cell Specific Activator 
Protein (BCSAP), and B cell clonality based on single cell PCR of the IgH gene4-8. Based 
on these data, the World Health Organization (WHO) changed the name from Hodgkin 
disease to Hodgkin lymphoma1. The four histological subtypes of cHL recognized by the 
WHO are mixed cellularity, nodular sclerosis, lymphocytic depletion, and lymphocyte 
predominant HL1. Nodular lymphocytic predominant HL (NLPHL) is quite different from 
cHL in that HRS present in NLPHL expresses mature B cell antigens, CD20, CD79a, does 
not express CD15 or CD30, and has a slow progressive course1. This trial will only include 
participants with HIV infection and cHL (HIV-cHL) in light the lack of CD30 expression, 
differences in disease biology, and the rarity of NLPHL in the HIV-positive population. 
2.2 
Hodgkin Lymphoma in HIV Patients 
HIV-cHL is one of the most common non-acquired immunodeficiency syndrome (AIDS)-
defining tumors9. Multiple large database studies of linked cancer and HIV/AIDS registries 
from 1992-2005 in the United States showed that HL represents the second to third most 
common non-AIDS defining cancer (NADC)9,10. One of these studies showed that the risk 
for HIV-cHL was 68% higher in 1996-2002, the post HAART era (SIR 13.6), than in 1990-
1995 (SIR 8.1)10. In a comparative study conducted from 1992 to 2003, the trend over time 
in cancer rates for the HIV-cHL was elevated despite stable rates of HL in the general 
population11. Studies on HRS microenvironment in non-HIV associated HL showed that 
the HRS were surrounded by B and CD4 cells, eosinophils, macrophages, and fibroblasts, 
all of which affect its survival and disease course12,13. This trophic effect, due in part to 
CD4 cells, has been postulated to explain the increase in incidence of HIV-cHL in the post 
HAART era12-14. In addition, many observational studies consistently showed that HIV-
HL patients present with higher CD4 counts compared to other HIV-associated 
lymphoproliferative disorders, with the exception of Burkitt’s lymphoma9-14. 
As a population, patients with HIV have a 10-25 -fold increase risk of developing HL, and 
they present with many high-risk characteristics that distinguish it from non-HIV cHL15. 
The differences are seen in patient presentation, histology, immunohistochemistry, 
molecular changes, and overall outcome15. The International Prognostic Score (IPS) for 
patients with advanced non- HIV-HL defined the following adverse risk factors: age over 
45 years, male gender, stage IV disease, low albumin, anemia, lymphopenia, and 
leukocytosis16. Eighty percent of patients with HIV-cHL present with stage III/IV disease, 
and 70-96% presents with B symptoms15. B symptoms, defined as one of the following: 1) 
drenching night sweats, 2) fever of over 100.4°F for 3 consecutive days, and 3) a weight 
loss exceeding 10% of body weight in 6 months. These are also poor prognostic signs in 


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stage I/II non-HIV HL. The two most aggressive histological forms of HL, mixed 
cellularity and lymphocytic depletion are predominate in HIV-cHL compared to the non-
HIV population15. In addition, histologically, the HRS is found in much higher 
concentrations in HIV-cHL than non- HIV-cHL15. HIV-cHL is associated in 80-100% of 
the cases with EBV co-infection of the HRS, though in the non-HIV cHL patients this 
occurs only with a frequency of 30-40%15,17,18. The expression of the Epstein-Barr Virus 
(EBV) has been identified by both single cell polymerase chain reaction (PCR) and co-
immunohistochemical analysis of the HRS in HIV-infected patients15,17,18. The HRS in 
non-HIV patients are derived from germinal center B cell lymphocytes, on the other hand, 
the origin of HIV-associated HRS have been linked to post germinal lymphocytes19. It is 
interesting to note that diffuse large B-cell lymphoma derived from non-germinal center 
have a worse prognosis than germinal cell derived large cell lymphoma in most studies. It 
is unclear the role each factor plays in disease outcome (i.e., HRS origin, EBV co-infection 
status, presentation, and histology) but it is clear that outcomes for patients with HIV-cHL 
are inferior to HIV-negative patients. 
For HIV-cHL, the median complete remission rate is about 58% with a median survival 8-
20 months in the pre HAART era, which is substantially lower than the median complete 
remission rate of approximately 90% with a median survival of 7 years for HIV-negative 
patients15,20,21. Retrospective data showed improved overall survival in the post HAART 
compared to treatment without HIV therapy21,22. Both studies showed an improved 2 year 
overall survival while taking HAART, ranging from 16 to 42% depending on the study21,22. 
Similarly, of the four HIV-HL trials completed while utilizing combined antiretroviral 
therapy (cART), the overall survival has varied from 86% at 2 years to 51% at 3 years, an 
improvement compared to the historical controls in the pre HAART era, but still lagging 
behind historical controls of non-HIV infected patients 23-26. Explanations for poorer 
survival are likely multifactorial, including treatment-related toxicity, EBV status, HRS 
non-germinal cell of origin, tumor biology, histology, and presentation. More prospective 
trials and newer treatments are needed to improve on the outcomes of HIV-positive patients 
to where they are comparable to the HIV-negative population. 
2.3 
Current Treatment for HIV-Related HL 
Currently, no standard of care exists for the upfront treatment of HIV-cHL. Outcomes of 
clinical trials for HIV-cHL in the pre- and post-HAART era are summarized in Table 2-A. 
In the pre-HAART era, the AIDS Clinical Trials Group (ACTG 149) performed a 
prospective multi-institutional clinical trial of ABVD with supportive GCSF27. 
Antiretroviral therapy was not used. Among 21 patients enrolled between 1992 and 1996, 
90% had B symptoms at presentation, and 67% had stage IV disease. Complete remission 
(CR) was attained in only 9 patients (43%; 95% CI: 24%-63%), a partial remission (PR) in 
4 participants (19%), resulting in a 2-year OS was 48%27. Even with routine GCSF use, 10 
patients developed severe neutropenia and opportunistic infections (OIs) occurred in 6 
patients (29%) during the study. A similar study with EBVP utilizing only zidovudine 
(AZT) or didanosine (DDI) as HIV therapy showed an equivalent 2-year OS of 40%28. 
Retrospective data showed a positive effect of HAART on OS, disease free survival (DFS), 
and infectious complications, though these benefits have been limited to studies 
implementing HAART. As illustrated above, the difference between no HAART and single 
agent antiretroviral therapy is minimal27,28. Comparing sequential HIV-cHL studies with 


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ABVD with cART and without HAART, the OS improved from 48% at 2 years to 76% at 
5 years27,24. 
In the post HAART era, only 5 prospective studies have been completed all with cART23-
26,30. A study of therapy with ABVD regimen in patients with advanced stage HIV-HL 
assessed the outcome in 62 patients (1996-2005) with advanced stage HL from multiple 
centers in Spain24. Six patients died during induction, 54 (87%) achieved CR and 2 had 
resistant disease. After a median follow up of 39 and 47 months, 5-year EFS probability 
was 71% and OS was 76%24. An immunological response was observed in 56% and a 
virological response in 68%. The immunological response to HAART had a positive 
impact on OS and EFS24.  
The VEBEP, Stanford V, and BEACOPP standard studies included all stages of HIV-cHL, 
and despite the inclusion of earlier stages, OS in each study did not compare well to ABVD, 
(see Table 2-A)23-33. The BEACOPP regimen did show an improved CR rate compared to 
ABVD (100% vs. 87%), but only 66% of participants were able to tolerate the 6 courses 
of BEACOPP compared to 82% in the ABVD trial. Also, 3 of the 12 participants in the 
BEACOPP trial died during chemotherapy (25%). Thus, based on OS, adverse events, and 
PFS, ABVD currently is the most promising regimen studied for advanced stage HIV-
cHL23-30. 
Table 2-A: Summary of Retrospective and Prospective Trials of HIV-cHL 
Regimen abbreviations: ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), VEBEP (vinorelbine, epirubicin, 
bleomycin, cyclophosphamide, prednisone), EBVP (epirubicin, bleomycin, vinorelbine, prednisone), EBV (epirubicin, 
bleomycin, vinorelbine), BEACOPPstd (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, 
prednisone), MOPP (mechlorethamine, vincristine, procarbazine, and prednisone), and RT (radiation therapy). 
 
 
Regimen 
Trial Type 
HAART 
# Patients 
Year 
Stage 
III/IV% 
OS% (Months) 
MOPP or ABVD or 
MOPP/ABVD +/- RT31 
Retrospective 
Pre-HAART 
71 
1992 
80% 
Median Survival (14) 
MOPP or ABVD or 
MOPP/ABVD +/- RT32 
Retrospective 
Pre-HAART 
45 
1993 
75% 
Median Survival (20) 
MOPP or ABVD or 
MOPP/ABVD +/- RT28 
Retrospective 
Pre-HAART 
46 
1994 
89% 
Median Survival (15) 
MOPP or ABVD or 
MOPP/ABVD +/- RT28 
Retrospective 
Pre-HAART 
24 
1991 
92% 
Median Survival (15) 
MOPP or ABVD or 
MOPP/ABVD +/- RT28 
Retrospective 
Pre-HAART 
23 
1991 
74% 
Median Survival (8) 
MOPP/ABVD +/- RT28 
Retrospective 
Pre-HAART 
13 
1988 
92% 
Median Survival (14) 
EBV29 
Prospective 
No- HAART 
17 
1994 
88% 
11 months 
ABVD27 
Prospective 
No-HAART 
21 
1992-6 
67% 
48% (24) 
EBVP28 
Prospective 
AZT or DDI 
35 
1993-7 
66% 
40% (24) 
ABVD30 
Prospective 
HAART 
8 
2002 
75% 
43 Months 
Stanford V23 
Prospective 
HAART 
56 
2005 
71% 
59% (60) 
BEACOPPstd26 
Prospective 
HAART 
12 
2002 
92% 
75% (36) 
VEBEP25 
Prospective 
HAART 
28 
1996-05 
71% 
69% (24) 
ABVD24 
Prospective 
HAART 
62 
2007 
100% 
76% (60) 


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2.4 
Study Agents 
2.4.1 Rationale for the use of brentuximab vedotin in HIV-cHL 
Brentuximab vedotin (SGN-35) is a CD30-directed antibody-drug conjugate 
(ADC) consisting of three components: (a) the antibody cAC10, specific for human 
CD30, (b) the highly potent anti-microtubule agent, monomethyl auristatin E 
(MMAE), and (c) a protease-cleavable linker that covalently attaches MMAE to 
cAC1034. The biological activity of brentuximab vedotin results from a multi-step 
process. Binding of the ADC to CD30 on the cell surface initiates internalization of 
the ADC-CD30 complex, which then traffics to the lysosomal compartment. Within 
the cell, a single defined active species, MMAE, is released via proteolytic 
cleavage34. Binding of MMAE to tubulin prevents its polymerization, thus 
disrupting the microtubule network within the cell, inducing cell cycle arrest, and 
apoptotic death of the CD30-expressing tumor cell34. MMAE was found to be a 
quasi-irreversible, mechanism-based CYP3A inhibitor, and, to the limited extent 
that metabolism occurred, the primary metabolites were formed by CYP3A434,35. 
CD30, a member of the TNF-receptor (TNF-R) super family, is a transmembrane 
glycoprotein receptor normally found on the surface of activated T cells but present 
on a variety of cell types of hematopoietic origin. The CD30 antigen has a very low 
expression on normal cells but is found on the HRS cells of HL, anaplastic large 
cell lymphoma (ALCL), and other T cell lymphoproliferative disorders. While the 
function of CD30 has not been clearly defined, CD30 has been implicated both in 
cell death and proliferation34,35. The utility of CD30 as a diagnostic marker for 
malignancies (including HL and ALCL), its limited normal tissue expression 
profile, and its apoptosis-inducing characteristics have led to the investigation of 
this antigen as a target for immunotherapy. Brentuximab vedotin has been studied 
and is FDA approved in the relapsed/refractory setting for ALCL and non-HIV 
cHL36-40. In the frontline setting, a phase I study is currently ongoing with 
brentuximab vedotin for non-HIV-cHL in combination with AVD41. 
A phase 1 study of brentuximab vedotin was performed in relapsed and refractory 
CD30 positive malignancies, including ALCL and HL. Patients had a median of 3 
prior chemotherapy regimens (range 1-7) with 73% of patients having previously 
received an autologous stem cell transplant (ASCT)36. The brentuximab vedotin 
dose levels ranged from 0.1 to 3.6 mg/kg (2-hr outpatient IV infusion) every 3 
weeks. Brentuximab vedotin was generally well-tolerated in the study. The most 
common adverse events, which occurred in 20% of patients or more, were fatigue, 
pyrexia, nausea, and diarrhea. The neutropenia observed appeared to be dose-
related. The maximum tolerated dose was 1.8 mg/kg every 3 weeks. One patient 
treated at 3.6 mg/kg developed febrile neutropenia and presumed sepsis, and died 
14 days after the first dose of brentuximab vedotin. Neuropathy was also observed 
in some patients, especially after repeated dosing. Approximately 75% of patients 
reporting B symptoms at baseline experienced symptom resolution while on study. 
Despite a median 3 prior chemotherapy regimens per patient including 75% with 
prior ASCT, 88% of the patients in the study experienced tumor reductions. The 
objective response rate (CR+PR) was 46% (n=13), with a CR rate of 25% (n=7). 


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Two additional PRs were observed in the 0.6 mg/kg cohort. Median response 
duration to date was 22 weeks (range, 0.1+ to 38+ weeks) 39-41. 
A phase 2 study of brentuximab vedotin (SGN-35) studied 102 patients with 
relapsed or refractory HL post autologous stem cell transplant41. Patients received 
brentuximab vedotin every three weeks at a dose of 1.8 mg/kg. The median duration 
of brentuximab vedotin treatment was 27 weeks (range 3-54). The most common 
treatment-related adverse events (AEs) of any grade in >15% of patients were 
peripheral sensory neuropathy (43%), fatigue (40%), nausea (35%), neutropenia 
(19%), diarrhea (18%), and pyrexia (16%). Most events were Grade 1 or 2. The 
Grade 3 treatment-related AEs reported in more than 1 patient were neutropenia 
(14%), peripheral sensory neuropathy (5%), thrombocytopenia and hyperglycemia 
(3% each), and fatigue (2%). The only Grade 4 treatment-related events were 
neutropenia (4%), and thrombocytopenia, abdominal pain, and pulmonary 
embolism (1% each). There we no related Grade 5 events. Eighteen patients 
discontinued treatment due to an adverse event41. While no interim analysis was 
presented with respect to overall response rate, there was a 95% reduction of tumor 
size and an 83% resolution of B symptoms41. 
2.4.2 Rationale for substitution of brentuximab vedotin for bleomycin in ABVD regimen 
Bleomycin is associated with significant pulmonary toxicity, particularly in the 
setting of radiation involving lung fields as is typically prescribed in the context of 
bulky mediastinal Hodgkin lymphoma. There are no large studies addressing the 
incidence of bleomycin-associated pneumonitis in the setting of HIV-HL. Outside 
of HIV, the incidence of bleomycin-associated pneumonitis with ABVD in HL has 
been reported in the range 10-15%. A randomized trial comparing ABVD to 
Stanford V (25% of the bleomycin dose) reported a 10% versus 2% incidence of 
pulmonary toxicity, respectively, requiring early discontinuation of bleomycin in 
20/23 participants42,80. A separate, single institution retrospective study 
demonstrated a 15% incidence in bleomycin pneumonitis in 184 HL patients treated 
with ABVD43. In this study, low albumin and use of GCSF were the factors most 
predictive of bleomycin toxicity. These factors are both likely to occur with high 
incidence in the HIV HL population where more advanced HL presentation is 
typical and the increased risk of marrow suppression with chemotherapy, use of 
GCSF is often required to maintain or approximate optimal chemotherapy dose 
density in the setting of HIV and aggressive lymphomas. 
The substitution of brentuximab vedotin for bleomycin is being explored in the 
general HL population. A phase 1, open-label, multicenter study is currently 
underway to evaluate the safety of brentuximab vedotin when administered in 
combination with standard therapy with AVD (ClinicalTrials.gov #NCT01060904) 
as the combination with ABVD had intolerable pulmonary toxicity41. Patients have 
received doses of 0.6, 0.9, or 1.2 mg/kg brentuximab vedotin with standard doses 
of ABVD or 1.2 mg/kg brentuximab vedotin with AVD, depending upon cohort 
assignment. The combination regimens were administered on Days 1 and 15 of 
each 28-day cycle for up to 6 cycles of therapy. Each regimen evaluated a dose 
limiting toxicity (DLT) period, defined as any Cycle 1 toxicity requiring a delay of 
≥7 days in standard ABVD or AVD therapy41. This is the first trial to dose 


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brentuximab vedotin every two weeks and in combination with multi-agent 
chemotherapy. Interim data of the first 31 patients treated were recently presented41. 
Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 received 1.2 mg/kg 
with ABVD; 6 patients received 1.2 mg/kg with AVD. Patient baseline 
characteristics included: Stage IV, 55%; IPS score ≥4, 29%; male, 77%; median 
age, 35 years (range, 19-59). The combination of chemotherapy and brentuximab 
vedotin treatment had no DLT observed up to 1.2 mg/kg in either regimen41. AEs 
reported in ≥45% of patients, regardless of severity, were nausea and neutropenia 
(77% each); peripheral sensory neuropathy (48%); and fatigue (45%). Infusion-
related reactions occurred in 23% of patients. Grade 3/4 AEs observed in >10% of 
patients were neutropenia (74%), febrile neutropenia (16%), and anemia (13%). No 
Grade 5 AEs were observed. Overall, 6 patients discontinued combination 
treatment due to an adverse event. In the ABVD cohorts (n=25), AEs of pulmonary 
toxicity, dyspnea, and interstitial lung disease that could not be distinguished from 
bleomycin toxicity led to discontinuation of bleomycin in 7 patients. Five of these 
7 patients continued treatment with AVD and brentuximab vedotin41. The 
expansion cohort of approximately 20 patients is currently enrolling at the 1.2 
mg/kg brentuximab vedotin dose combined with AVD therapy41. An international 
phase III study comparing ABVD versus AVD in combination with brentuximab 
vedotin is currently under development. This AMC trial will help define more 
clearly how this regimen can be used in the HIV-infected population. 
While it is desirable to replace bleomycin with a less toxic alternative in the general 
HL population, the argument is even more compelling in the HIV-HL population 
with a higher prevalence of risk factors associated with bleomycin toxicity, i.e., 
intercurrent infection, and a higher prevalence of tobacco use. In replacing 
bleomycin, risk of reduced efficacy exists. Given this, as well as the preliminary 
efficacy data of brentuximab vedotin + AVD in the general HL population, a dose 
de-escalation design is chosen for this study to maximize anti-tumor activity of the 
regimen for each cohort. 
2.4.3 Considerations regarding brentuximab vedotin, CD30, and HIV 
CD30 has also been studied in HIV replication, in addition to lymphoma. In fact, 
increased levels of the soluble form of CD30, sCD30, are predictors of progression 
to AIDS44-47. Levels of sCD30 also have been shown to correlate with HIV viremia 
levels and clinical outcome in patients with primary HIV infection in the pre-
HAART era47. Furthermore, CD30 stimulation directly induces HIV expression 
through activation of the transcription factor NF-kB45-47. In addition, CD30/CD30L 
interactions lead to virus production also in primary CD4+ T cells from HIV-
positive patients47. Both agonistic anti-CD30 antibodies and CD30L-expressing, 
glutaraldehyde-fixed CD8+ human T cell clones significantly enhanced HIV 
expression in human CD4+ T cells obtained from HIV-infected individuals44-47. 
This data suggests that the activation of CD30 expression in HIV-infected CD4+ T 
cells may allow the interaction of these cells with CD30L-expressing cells and, 
therefore, favor HIV replication44-47. The result of the use of the brentuximab 
vedotin and its effects on HIV replication will be monitored closely in this study. 
All participants on study must be on concurrent HAART therapy. We will test for 


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a multiplexed inflammatory marker panel that includes sCD30, as well as several 
other molecules (several soluble cytokine receptors and BAFF/BLyS and CXCL13 
(BLC/BCA-1) for changes with the use of brentuximab vedotin and correlate this 
with changes in HIV viral load as well as clinical outcome. See Section 2.6 for a 
description of all correlative studies. 
2.4.4 Considerations regarding progressive multifocal leukoencephalopathy associated 
with HIV, brentuximab vedotin, and HIV-cHL 
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of 
the central nervous system caused by the lytic replication of the John Cunningham 
Virus (JCV). It typically occurs in immunocompromised individuals and is nearly 
uniformly fatal48-54. In a clinical study conducted by Koralnik et al, 80% of reported 
PML patients had AIDS, 13% had hematologic malignancies, 5% were transplant 
recipients, and 2% had chronic inflammatory diseases49. Presenting features 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 PML patients (approximately 20%)48. The onset of 
neurological deficits may occur over weeks to months48. In a retrospective study, 
data showed the incidence of PML in patients with NHL is 8 per 100,000 patient 
years, though the incidence in cHL or HIV-cHL is not known. In the onset of the 
HIV epidemic, the incidence of the PML was 3.4 per 1000 patient years at risk with 
HIV50,51. But in the era of HAART, the incidence has decreased to 1.3 patients per 
1000 patient years51. In a Swiss HIV cohort study, a multivariate analysis showed 
that of the 226 patients diagnosed with PML from 1998 to 2007, HAART was 
associated with a hazard ratio of 0.22 (p<0.01). A trend was seen for decreased 
incidence with elevated CD4 counts52. Compared to patients with CD4 counts 
below 50 cells/µl, the hazard ratio for patients with CD4 counts above 100 cells/µl 
was 0.75 (p<0.38)52.  
Recently PML has been reported in HIV negative patients receiving antibody based 
immunomodulatory therapies for lymphoma, multiple sclerosis, and collagen 
vascular diseases treated with antibodies rituximab, efalizumab, and natalizumab53. 
To date 3 patients treated with brentuximab vedotin have developed PML, each in 
the relapsed refractory setting, with 3 to 6 chemotherapeutic regimens before 
treatment with brentuximab vedotin54. To curtail the risk of PML in this study, no 
patients with a CD4 count below 50 cells/µl will be permitted on study, all 
participants will be required to take HAART, and MRI scans pre-study will be 
required. In addition, we will incorporate stopping rules should any patient develop 
PML with a CD4 count > 50 at the time of PML diagnosis. 
2.4.5 Rationale for use of concurrent HAART with HL treatment 
The improvement in outcomes of HIV-cHL patients to standard treatment in the 
HAART era is partially related to the HAART therapy itself. Given this and 
concerns above regarding HIV viremia with CD30 perturbation and PML, we will 
require participants to be on HAART. Chemotherapy-HAART interactions have 
become more pronounced in the transition from single agent HIV therapies to the 
era of cART as protease inhibitors (PI) and non-nucleoside reverse transcriptase 


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inhibitors (NNRT) are potent inhibitors or inducers of the cytochrome p450 
system55. In early studies with HIV-cHL treated with EBVP, where only AZT or 
DDI was used as antiviral therapy, 1% neurotoxicity all grades, 7% Grade 3/4 
leukopenia, and 3% G3/4 anemia were observed. However, in a single institution 
retrospective study of 23 patients treated with ABVD, while taking HAART, 31% 
were found to have neuropathy (all grades), 68% G3/4 neutropenia, and 57% G3/4 
anemia56. Correlations were then made comparing all adverse events with HAART 
therapy. Of the patients with neuropathy, 13% had grade 3 sensory neuropathy and 
each developed the symptoms before cycle 2 of ABVD. Many had symptoms years 
after therapy. One hundred percent of the patients with neuropathy were taking 
ritonavir based HAART56. Similarly, 75% of the patients who were taking ritonavir 
based HAART developed G3/4 neutropenia, as opposed to only 21% taking non- 
ritonavir-based HIV-therapy. Lastly, it was noted that 82% of the patients with 
Grade 3/4 anemia were taking ritonavir and or AZT in some combination. Based 
on these data, at this institution made a policy to utilize only non-ritonavir and non-
AZT based HAART regimens during treatment for HIV-cHL57. Twelve patients 
were subsequently treated, and neuropathy, febrile neutropenia, G4 neutropenia, 
and G4 anemia had decreased by 100%, 100%, 20%, and 15% respectivly57. 
One concern to be managed in the current study is the overlapping toxicities of 
brentuximab vedotin and vinblastine, both of which have been shown to cause 
neuropathy and neutropenia. To prevent potentiating any adverse events, we will 
require participants’ HAART regimens to exclude ritonavir or AZT. Cobicistat, 
another potent inhibitor of the CYP 3A4 enzyme system, will also be excluded from 
the study. Any new forthcoming CYP 3A4 inhibitors will be excluded.  
Despite these changes, many of the HAART drugs undergo metabolism by and can 
induce or inhibit various CYP450s enzyme systems. Therefore, all participants will 
be closely monitored for AEs throughout the entire study. In addition, 
pharmacokinetics will be studied in a subset of participants to confirm whether 
alterations in exposure correlate with the AEs. 
2.4.6 Rational for use of PET scans in HIV patients and HIV-HL 
The use of FDG-PET scans in HL patients is increasingly being used for prognostic 
significance in during treatment in the HIV negative setting. Data by Galamini et 
al. showed a FDG-PET scan done at the completion of cycle 2 was more prognostic 
than the IPS score for advanced Hodgkin lymphoma58,59. A negative PET scan after 
two cycles of ABVD predicted a 96% 2-year PFS. Similar data reported in abstract 
form regarding ABVD and rituximab showed a negative PET correlated with a 5-
year EFS of 93% vs. 75% for those who remained PET positive (p=0.05)58-60. The 
prognostic significance of PET scanning in the HIV patients with HL is unknown. 
At issue is FDG-PET scanning in the setting of HIV alone without malignancy is 
frequently positive. One report suggested FDG activity might correlate with 
detectable HIV viral loads61. Thus, it is important to correlate FDG-PET in 
combination with CT scans (FDG-PET/CT scan). Experience with PET scanning 
in the HIV setting with malignancy requires further study. Therefore, we plan to 
use baseline, post cycle #2 interim, and post-treatment FDG-PET/CT scans 
prospectively in this study, to correlate scan positivity with PFS and OS. The 


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Deauville 5-point criteria will be used to record the interim FDG-PET scan91,92. The 
Deauville criteria capture gradations of FDG uptake from no uptake (1 point) to 
new disease (5 points). For the purposes of this study, we will record the Deauville 
score and determine whether scores of 3-5 or 4-5 are predictive of relapse. Notably, 
SUVs can be affected by inflammation related to therapy as in the case of rituximab 
or HIV related inflammation. 
2.4.7 Brentuximab vedotin relevant preclinical data 
Little to no data exists on the dosing of 1.2mg/kg of brentuximab vedotin to be used 
in this study, and no information exists on its interactions with anti-HIV 
medications. The data summarized below were obtained using 1.8mg/kg.  
Pharmacokinetic parameters for individual patients were determined using 
concentrations of serum brentuximab vedotin ADC, plasma MMAE, serum TAb, 
and actual sampling times relative to the start of the infusion. The maximum 
concentrations for the serum PK of brentuximab vedotin ADC following an IV dose 
of 1.8 mg/kg were typically observed at the end of infusion. A multi-exponential 
decline in ADC serum concentrations was observed with a terminal half-life (t1/2) 
of approximately 4 to 6 days. Exposures were approximately dose proportional. 
After administration of multiple doses of brentuximab vedotin, steady-state was 
achieved by 21 days, consistent with the t1/2 estimate. Minimal to no accumulation 
was observed with multiple doses with the q3wk regimen, and ADC exposure did 
not decrease with subsequent doses. 
The plasma PK profile of MMAE following an IV dose of 1.8 mg/kg brentuximab 
vedotin appeared to follow metabolite kinetics, with the elimination of MMAE 
appearing to be limited by its rate of release from ADC. Tmax ranged from 
approximately 1 to 3 days. Exposures were linear and approximately dose 
proportional with MMAE exposures decreasing after multiple doses with 
approximately 50% to 80% of the exposure of the first dose observed at subsequent 
doses. After administration of multiple doses of brentuximab vedotin, MMAE 
steady-state was achieved by 21 days, similar to ADC. Total antibody exposures 
were approximately dose proportional and higher than brentuximab vedotin ADC 
exposures while Tmax was similar. 
2.5 
Study Design and Rationale 
Based on the evidence presented above, specifically the remarkably high response of 
brentuximab vedotin in the relapse setting, we will conduct a phase 1 clinical trial with a 
de-escalation design evaluating 3 doses of brentuximab vedotin (1.2 mg/kg, 0.9 mg/kg, and 
0.6 mg/kg) given every 2 weeks with AVD in a 28-day cycle. Three to six participants will 
be enrolled at dose level 0 (1.2 mg/kg). If > 1 DLT is encountered, up to six additional 
participants will be enrolled at the next lowest dose level. If no more than 1/6th of the 
participants at dose level 0 encounter a DLT, this dose (1.2 mg/kg) will be used in the phase 
II portion. If dose de-escalation is required, we will follow the algorithm presented in Table 
4-A in Section 4.1. 
Bleomycin is omitted, due to the pulmonary toxicity of ABVD plus brentuximab vedotin 
demonstrated in the phase I trial for non-HIV cHL. Based on the bleomycin omission, and 


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based on phase I efficacy data, a dose de-escalation design was chosen for this study to 
maximize anti-tumor activity of the regimen for the initial cohort in a curable disease. Fifty-
one participants in the phase II trial will be treated for 6 cycles for a 5-year follow up. The 
primary end point of the phase II portion will estimate the two-year progression free 
survival for AVD-brentuximab vedotin. The secondary endpoints of both phases will be to 
evaluate AVD-brentuximab vedotin with regard to 1) the toxicity of participants taking 
concurrent HAART, 2) the effects on viral load, CD4, and CD8 counts, and 3) PR, OS, 
EFS. Other non-treatment related endpoints for both phases will be the predictive value of 
FDG-PET on 2-year PFS and a characterization of HIV-cHL subtypes in the post HAART 
era.  
We hypothesize that AVD-brentuximab vedotin will 1) improve HIV-cHL OS to be more 
consistent with the non-HIV population 2) be administered safely with cART regimens 
lacking ritonavir or AZT. We also anticipate cycle 2 FDG/PET-CT will be prognosticate 
OS in the HIV population.  
We will perform immunological, viral, and molecular correlative studies to monitor the 
effects brentuximab vedotin will have on the viral replication of HIV. With respect to HIV 
replication, we will assess viral loads and CD4 counts every 2 cycles during therapy and 
every 3 months for 1 year post treatment. We will also perform pharmacokinetic and 
immunogenicity to help understand the interaction between brentuximab vedotin and 
HAART. Studies will determine drug and anti-brentuximab vedotin antibody levels during 
treatment. 
2.6 
Rationale for Correlative Studies 
Improving the ability to predict which participants with HIV-HL will respond best to 
therapy is an important goal of this clinical trial and in its correlative studies as well. As 
stated earlier, Galamini et al., was able to correlate a negative cycle 2 FDG-PET scan with 
improved OS and PFS in non-HIV cHL58,59. A negative cycle 2 FDG-PET scan was more 
prognostic than the IPS itself58,59. Thus, to validate this in the HIV population is an 
important goal to help identify which patients can maybe benefit from chemotherapy 
intensification to improve outcomes. We hypothesize that the biological features of a 
participant's tumor, identified as immunohistochemical markers, circulating cytokines, and 
tumor DNA and microRNA (miRNA), can also be more predictive than the IPS. In addition 
to their prognostic significance, we believe that these markers can also help us gain insight 
into tumor biology. See Section 10.0 below for a detailed description of each correlative 
study (also see Appendix VIII, IX, X, and XI). The final correlative study will be to assess 
the chemotherapy effects on the latent and HIV reservoirs, an area in need of investigation. 
The changes in the viral copy numbers in both the plasma and the peripheral blood 
mononuclear cells (PBMC) will be studied before, during, and after chemotherapy, to 
correlate the effects chemotherapy with viral expression (Appendix XII). 


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3.0 
PARTICIPANT SELECTION 
A rostered AMC investigator (CTEP-registered physician investigator) must document that 
each protocol participant meets all stated eligibility criteria. Participating sites must have 
documentation that each eligibility requirement is satisfied prior to participant enrollment. 
In compliance with CTEP policy, no exceptions to eligibility criteria will be granted under 
any circumstance. 
NOTE: Institutions may use this section of the protocol as an eligibility checklist for source 
documentation if it has been reviewed, signed, and dated before registration/randomization 
by the study investigator. If used as source documentation, this checklist must be printed, 
the investigator must check each item to document their assessment that the participant 
meets each eligibility criterion, and the completed checklist must be maintained in the 
participant’s chart. NOTE: All questions regarding eligibility should be directed to the 
study chair. 
Participant ID Number: 085 - ___ ___ ___ - ___ ___ ___ 
Patient’s Initials (L, F, M): ___ ___ ___ 
3.1 
Eligibility Criteria 
___ 
3.1.1 Age ≥ 18 years. Because no dosing or adverse event data are currently available on 
the use of brentuximab vedotin in combination with AVD in patients <18 years of 
age, children are excluded from this study. 
___ 
3.1.2 HIV positive. Documentation of HIV-1 infection by means of any one of the 
following: 
• Documentation of HIV diagnosis in the medical record by a licensed health care 
provider; 
• Documentation of receipt of ART by a licensed health care provider; 
• HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating > 1000 
RNA copies/mL; 
• Any licensed HIV screening antibody and/or HIV antibody/antigen 
combination assay confirmed by a second licensed HIV assay such as a HIV-1 
Western blot confirmation or HIV rapid multispot antibody differentiation 
assay. 
NOTE: A “licensed” assay refers to a US FDA-approved assay, which is required 
for all IND studies. 
___ 
3.1.3 Histologic diagnosis of CD30-positive classical HL as defined by the 2008 WHO 
Classification of Hematological diseases. Nodular lymphocyte predominant 
Hodgkin Lymphoma is not eligible. 
___ 
3.1.4 Stage II, III, or IV disease as defined by the Ann Arbor Staging System. 
___ 
3.1.5 Participants must have previously untreated HIV-cHL, with the exception of up to 
14 consecutive days of steroids, emergency radiation, or 1 prior cycle of 
cyclophosphamide to reduce tumor burden and improve hyperbilirubinemia in the 
setting of lymphoma related liver involvement. 
___ 
3.1.6  Normal baseline cardiac ejection fraction ≥ 50%. 


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___ 
3.1.7 Serum creatinine of ≤ 1.5 mg/dL. If creatinine >1.5 mg/dL, creatinine clearance 
must be ≥ 60 mL/minute. 
___ 
3.1.8 ANC ≥ 1000/µL and platelets ≥ 75,000/µL unless related to bone marrow 
involvement by HIV-cHL. 
___ 
3.1.9 Total bilirubin must be < 1.5 x the upper limit of normal, unless the elevation of 
bilirubin is thought to be secondary to Gilbert’s syndrome or cART. If, however, 
the elevated bilirubin is felt to be secondary to antiretroviral therapy, the total 
bilirubin must be ≤ 3.5 mg/dL, provided that the direct bilirubin is normal and the 
AST and ALT ≤ 3 x the upper limit of normal. Also, if the elevated bilirubin is 
thought to be secondary to cHL the same criteria for hyperbilirubinemia should be 
applied; however 1 prior cycle of cyclophosphamide is permitted in attempt to 
make the participant eligible (see Section 3.1.5). Patients should not be excluded 
from study participation unless dosing cannot be safely established as per Section 
5.2.5. 
___ 
3.1.10 Female participants must have a negative pregnancy test within 1 week of 
enrollment and all participants must agree to use two reliable methods of 
contraception simultaneously if conception is possible during the study and for 6 
months after stopping treatment. Should a woman participant become pregnant or 
suspect she is pregnant while the participant is participating in this study, she should 
inform her treating physician immediately. The participant will then be removed 
from protocol therapy. Participants who father a child while participating in the 
study will be permitted to continue with the protocol. The participant, however, is 
required to notify the investigator if he fathers a child. 
___ 
3.1.11 Ability to understand and the willingness to sign a written informed consent 
document. 
___ 
3.1.12 Karnofsky performance status > 30% (given the aggressiveness of this disease and 
the often severely debilitated nature of the patients at initial presentation). See 
Appendix III. 
___ 
3.1.13 Measurable or non-measurable (evaluable) tumor parameter(s). Non-measurable 
tumor parameters will be defined as not having bi-dimensional measurements (i.e., 
gastric or marrow involvement) but can be followed for response by other 
diagnostic tests such as gallium, PET imaging and/or bone marrow biopsy. 
___ 
3.1.14 Patients already receiving erythropoietin or GCSF for treatment of HIV-related 
cytopenia are eligible. 
___ 
3.1.15 CD4 count ≥ 50 cells/µL. 
___ 
3.1.16 Participants are required to be on antiretroviral regimens that are in accordance with 
the current International AIDS Society guidelines concurrently with chemotherapy. 
The specific agents are at the discretion of the Investigator and the use of 
investigational agents currently available on an expanded access basis is allowed. 
Use of experimental antiretroviral agents or those containing zidovudine (including 
Combivir and Trizivir) or ritonavir (includes Norvir® or Kaletra®), Cobicistat, 
Didanosine (Videx® or Videx EC®), or similar potent CYP3 inhibitors are 


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prohibited, as explained in Section 2.4.5. In order to be eligible, participants taking 
zidovudine or ritonavir, Cobicistat, Didanosine, or other CYP3 inhibitors must 
change to a different regimen 7 days prior to therapy initiation. Changes to HAART 
therapy during the study may be made if medically necessary (toxicity, failure of 
regimen, etc.). Participants must be on HAART for at least 7 days prior to therapy. 
___ 
3.1.17 Negative for Hepatitis B, or if infected with Hepatitis B, receiving anti-Hepatitis B 
therapy. All participants will be required to be screened for Hepatitis B. Per IDSA 
and AASD guidelines, those participants that show no immunity, defined by the 
lack of Hepatitis B surface antibody, and show evidence of chronic infection (i.e., 
HBsAg+, HBcore+, HBsAB-) will be required to be on anti-Hepatitis B therapy 
during the study in order to be eligible. Patients will be permitted to enroll in the 
study provided normal liver function tests (see Section 3.1.9) and no evidence of 
cirrhosis. The exact Hepatitis B therapy will be at the discretion of the infection 
disease specialist or investigator. However, all patients who present with acute 
hepatitis B or show normal transaminases and are HBsAg+ and IgM+ for Hepatitis 
core antigen will not be eligible for trial enrollment. 
___ 
3.1.18 Patients diagnosed with Hepatitis C who are Hepatitis C antibody positive, whether 
Hepatitis C RNA level is measurable or not, must have no evidence of cirrhosis and 
have liver function tests that conform to Section 3.1.9. 
___ 
3.1.19 Brentuximab vedotin is partially metabolized via the CYP3A4 pathway and is 
cleared from the cells via the P-glycoprotein pump. Therefore, participants must 
discontinue use of the following agents within 7 days prior to therapy as per 
Appendix XIII. 
• Strong CYP 3A4 inhibitors that treat HIV, see 3.1.16. 
• Other strong CYP3A inhibitors. 
• Moderate CYP3A4 inhibitors should be Used with Caution but are not 
excluded. If 2 moderate CYP3A4 inhibitors are used concurrently, one must 
be discontinued at least 7 days (1 week) prior to the initiation of 
chemotherapy. 
• P-glycoprotein inhibitors. 
• If patients are taking any of these excluded medications, they must be 
discontinued at least 7 days (1 week) prior to the initiation of chemotherapy. 
All concomitant medications must be reviewed by the study chair or co-chair 
prior to enrollment by email. 
Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of. 
3.2 
Exclusion Criteria 
Patients who do not fulfill the criteria as listed in Section 3.1 above, are ineligible. 
Additionally, the presence of any of the following conditions will exclude a participant 
from study enrollment: 
___ 
3.2.1 Patients with prior anthracycline therapy will be excluded. 
___ 
3.2.2 Female participants who are pregnant or breast-feeding. Confirmation that the 


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participant is not pregnant must be established by a negative serum b-human 
chorionic gonadotropin (b-hCG) or urine pregnancy test result obtained during 
screening. Pregnancy testing is not required for post-menopausal or surgically 
sterilized women. 
___ 
3.2.3 Medical illness unrelated to HL, which in the opinion of the study physician will 
preclude administration of chemotherapy safely. This includes patients with 
uncontrolled infection (including opportunistic), chronic renal failure, myocardial 
infarction (MI) within the past 6 months, unstable angina, cardiac arrhythmias other 
than chronic atrial fibrillation, or second malignancy requiring active treatment. 
___ 
3.2.4 Prior malignancy within 2 years before enrollment other than curatively treated 
cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, 
anal intraepithelial neoplasia, or cutaneous Kaposi’s sarcoma (KS). Participants 
with prior malignancies must have completed all therapy at least 2 years before 
enrollment with no evidence of disease since therapy completion. 
___ 
3.2.5 Grade 2 or greater peripheral neuropathy. 
___ 
3.2.6 Evidence of PML identified on the pretreatment MRI. 
___ 
3.2.7 Central nervous system disease. 
___ 
3.2.8 Patients with history of JC Virus identified in the CSF or previous history of PML 
will be excluded from the study. 
___ 
3.2.9 Cirrhosis secondary to any cause will be excluded. 
 
Physician Signature: ______________________________ Date: ___________________ 
(Optional unless this section is used as an eligibility checklist) 
 
3.3 
Number of Participants to be Enrolled 
3.3.1 Proposed Sample Size 
• For Phase I/II, this study will enroll a minimum of 6 participants. 
• For Phase I, this study will enroll a maximum of 18 participants. 
• For Phase II, this study will enroll a maximum of 51 participants. 
• If there are no DLTs observed in the Phase 1 portion of the study, and if 100% 
of all of the Phase 1 participants are treated identically to participants in Phase 
2, accrual from the Phase 1 and 2 portions can be combined to complete the 
phase 2 portion of the study. 
3.3.2 Accrual Rate 
• Approximately 2 participants per month. 
3.3.3 Replacement of inevaluable participants 
A participant who does not complete cycle 1 can be replaced if, based on a review 
of the available safety for that dose level, the principal investigator agrees that the 
events leading to participant withdrawal are unlikely to constitute a safety risk for 
further participant enrollment and dose escalation. This means that as long as 


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participant safety is not compromised, a participant who withdraws from the study 
for administrative reasons prior to experiencing DLT during cycle 1 of therapy can 
be replaced by another participant to complete the number of participants evaluable 
per dose level required by the protocol. Similarly, as long as participant safety is 
not compromised, if an eligibility criterion or protocol violation occurs that 
substantially impairs evaluation of DLT during cycle 1, another participant can 
enter the cohort to complete the number of participants evaluable per dose level 
required by the protocol. Any replacement participant will be enrolled into the same 
dosing cohort as that for the participant who withdrew. Participants withdrawn 
because of brentuximab vedotin -related DLT may not be replaced. 
3.4 
Recruitment Plan 
Participants seen in the inpatient or outpatient setting who meet eligibility criteria will be 
recruited to this study. Participation is voluntary. The participant will be made aware of his 
or her diagnosis and current nature of this treatment program. All participants will be 
required to sign a statement of informed consent that conforms to FDA regulations and 
Institutional Review Board (IRB) guidelines. IRB-approved advertisements to local 
periodicals, participant groups, or physicians may be used by each participating site. 
3.5 
Participant Enrollment Procedures 
Sites must have this protocol approved by their Institutional Review Boards (IRB) and be 
registered for study participation with the AMC Operations and Data Management Center 
(ODMC) before they may enroll participants. 
After it has been determined that the participant is eligible and an informed consent has 
been signed by the participant, the participant must be registered on-line via the AMC 
AdvantageEDCSM Internet Data Entry System (AdvantageEDC). Enrollment and data 
collection will occur via the AMC Internet Data Entry System. 
The participating site will ensure a participant meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist in AdvantageEDC for enrollment. 
Participants will be enrolled on-line via AdvantageEDC no more than 1 week prior to the 
initiation of treatment (enrollment 1 day prior to or on the day of treatment is strongly 
encouraged). Once the eligibility checklist is submitted a system-generated confirmation 
email will be sent to the enroller upon successful completion of the participant enrollment. 
If the on-line system is inaccessible, the site should notify the AMC ODMC (via email at 
amcpm@emmes.com or via phone at 301-251-1161) for further instructions. 


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4.0 
TREATMENT PLAN 
4.1 
Phase I: AVD-Brentuximab Vedotin Therapy 
AVD will be given in conjunction with the brentuximab vedotin on days 1 and 15 on a 28-
day cycle for 6 cycles. Standard, fixed-doses of AVD (doxorubicin 25 mg/m2, vinblastine 
6 mg/m2, dacarbazine 375 mg/m2) will be administered intravenously. Brentuximab 
Vedotin will be administered after AVD (doxorubicin 25 mg/m2, vinblastine 6 mg/m2, 
dacarbazine 375 mg/m2). Brentuximab vedotin dosing will be determined by the phase I 
dose de-escalation schema with the starting dose of 1.2 mg/kg (See Table 4-A). For 
participants with weight exceeding 100kg, the dosage of Brentuximab vedotin will be 
calculated based on a weight of 100kg. 
On the first cohort, three to six participants will begin at dose level 0. If > 1 dose-limiting 
toxicities (DLT) are encountered, 3 to 6 additional participants will be enrolled at the next 
lowest dose level. This will then be the MTD as long as no more than 1/6th of the 
participants experience DLT (1 participant of the 6 enrolled at that particular dose level). 
If more than one participant at any one dose level encounters a DLT, the dose will be de-
escalated for all subsequent participants (see Section 4.1.1 for DLT definition). Once a 
MTD has been confirmed, this will be the standard dose used in the phase II portion of the 
study. The phase I MTD was determined to be 1.2 mg/kg. 
Table 4-A: Phase 1 Dose Finding Schema for AVD-BV Regimen* 
 
Doxorubicin 
Vinblastine 
Dacarbazine 
Brentuximab 
Vedotin** 
Dose 
Level 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day cycle 
0 
25 mg/m2 
6 mg/m2 
375 mg/m2 
1.2 mg/kg** 
-1 
25 mg/m2 
6 mg/m2 
375 mg/m2 
0.9 mg/kg** 
-2 
25 mg/m2 
6 mg/m2 
375 mg/m2 
0.6 mg/kg** 
*See Section 4.4.1 for instructions on GCSF supportive treatment.  
**For participants with weight exceeding 100kg, the dosage of Brentuximab Vedotin will be calculated 
based on a weight of 100kg. 
4.1.1 Definition of Dose-Limiting Toxicity (DLT) 
During cycle 1, any AE resulting in a dose delay in AVD-BV therapy of ≥ 7 days 
is considered a DLT, which requires discontinuation of protocol-specified therapy 
and withdrawal from the study. Please refer to Table 5-A in Section 5.1 for specific 
guidelines. In subsequent cycles, the brentuximab vedotin dose may be withheld or 
reduced according to the guidelines provided in Section 5.1. If two sequential doses 
of AVD+BV or AVD alone are held due to unresolved toxicity, leading to a 
treatment delay of an additional 2 weeks (i.e., 4 weeks between doses), protocol 
treatment will be discontinued. Please see Section 4.6.1 for criteria for permanent 
treatment discontinuation. 
4.2 
Phase II: AVD-Brentuximab Vedotin Therapy 
AVD dosing will be as described in Table 4-A, in conjunction with brentuximab vedotin 
at the MTD determined in the phase 1 portion of the study. The phase I MTD was 
determined to be 1.2 mg/kg. As in phase 1, drugs will be given on days 1 (+/- 2 days) and 


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15 (+/- 2 days) on a 28-day cycle for a total of 6 cycles. Brentuximab vedotin will be 
administered after AVD (doxorubicin 25 mg/m2, vinblastine 6 mg/m2, dacarbazine 375 
mg/m2). 
If treatment is delayed (<7 days if during cycle 1, or <2 weeks if occurring during 
subsequent cycles), once treatment is resumed the next dose will be scheduled two weeks 
after treatment is restarted. 
4.3 
Radiation Therapy 
Involved field radiotherapy should be given at the discretion of the investigator after 
chemotherapy if there was bulky (> 10cm) disease at diagnosis as suggested in the NCCN 
guidelines. Radiation therapy initiation will be within 2 weeks after protocol therapy. 
Radiotherapy may be performed during the follow-up period according to institutional 
standards. 
4.4 
Supportive Therapy 
4.4.1 Growth Factor 
GCSF will be administered on Days 2-10 and 16-24 throughout each 28-day cycle 
using standard doses. Pegfilgrastim may be substituted for GCSF and be 
administered on days 2 and 16, either by clinical staff or via autoinjector applied 
on the day of protocol treatment. 
4.4.2 HAART 
HAART is a requirement for the duration of the study. Participants must be on 
HAART therapy for at least 7 days before therapy. The specific agents are at the 
discretion of the Investigator and use of agents currently available on an expanded 
access basis is allowed. Use of experimental antiretroviral agents or those 
containing zidovudine (including Combivir® and Trizivir®), ritonavir (including 
Kaletra®), Cobicistat (Stribild®), or another potent CYP3 inhibitor are prohibited. 
In order to be eligible, participants taking zidovudine- or ritonavir-based HAART 
must change to a different regimen 7 days prior to therapy initiation. Changes to 
HAART therapy may be made if medically necessary (toxicity, failure of regimen, 
etc.). 
4.4.3 Pneumocystis prophylaxis 
Trimethoprim sulfamethoxazole (Bactrim) must be given at the onset of therapy for 
Pneumocystis and Toxoplasmosis prophylaxis, according to current CDC 
guidelines 
which 
can 
be 
found 
here:  
https://aidsinfo.nih.gov/guidelines/html/4/adult-and-adolescent-opportunistic-
infection/0 
Alternatively, dapsone (50 mg PO twice daily), atovaquone, or aerosolized 
pentamidine may be substituted for Pneumocystis prophylaxis in participants 
allergic to sulfonamides. Pneumocystis prophylaxis will be continued once therapy 
has been discontinued. 
4.4.4 Mycobacterium avium complex (MAC) prophylaxis 
Azithromycin 1,200 mg PO once weekly must be initiated for prophylaxis if the 


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CD4 count falls below 50 cells/µL or is expected to drop below 50 cells/µl while 
on chemotherapy. Prophylaxis may be discontinued once the CD4 count is deemed 
reliably above 50 cells/µL by the treating investigator. 
Due to the glycoprotein P inhibition properties of azithromycin, this may increase 
the chemotherapy drug exposure and contribute to increased toxicity. Sections 
3.1.19, 7.3.7, and Appendix XIII state that P-glycoprotein inhibitors, including 
azithromycin, are disallowed medications on protocol. This limited exception is 
permitted in the case of MAC prophylaxis. 
Based on the pharmacokinetics of azithromycin and brentuximab vedotin, the study 
team recommends giving the azithromycin on Days 5, 12, 19, and 26 of each cycle. 
4.4.5 Pre-infusion prophylaxis 
Pre-infusion prophylaxis (e.g., diphenhydramine) may be administered per 
institutional guidelines. 
4.4.6 Quinolone antibacterial prophylaxis 
For participants with a CD4+ T cell count of < 100/mm3 at baseline or whose CD4 
count decreases below 100/mm3 during protocol therapy, antibiotic prophylaxis 
covering the nadir is recommended with quinolone or equivalent. Ciprofloxacin is 
not preferred due to being a moderate CYP3A4 inhibitor and caution should be 
exercised due to drug-drug interactions (See Appendix XIII). 
4.5 
Study Duration 
Participants will receive brentuximab vedotin in conjunction with standard, fixed, doses of 
doxorubicin 25 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 on days 1 and 15 
of a 28-day cycle for 6 cycles. Participants will be followed for a total of 5 years, every 3 
months for the first 2 years and every 6 months for years 3 to 5 of follow up. 
Participants who discontinue all protocol therapy after having a CR or PR are followed for 
up to 5 years after treatment for recurrence and survival. Participants who discontinue 
protocol therapy due to disease progression or other reasons (Section 4.6) are followed for 
survival only for up to 5 years after treatment or until death, whichever occurs first. 
Participants who cross over to non-protocol therapy (if PR or stable disease at physician 
discretion), or other reasons will be followed for survival for up to 5 years after treatment. 
Participants removed from study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
4.6 
Criteria for Permanent Removal from Treatment 
After enrollment, participants will be permanently withdrawn from study treatment for any 
of the following reasons. In the event of withdrawal from treatment, the reason for study 
treatment removal and the date the participant was removed must be documented in the 
Off Protocol Treatment Form in AdvantageEDCSM. See Section 8.4 on evaluations to be 
performed at early discontinuation of therapy. 
4.6.1 Participants who experience a delay of over 7 days in cycle 1 will be removed from 
protocol therapy. For subsequent cycles, if two sequential doses of AVD + BV or 
AVD alone are held due to unresolved toxicity, leading to a treatment delay of an 


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additional 2 weeks (i.e., 4 weeks between doses), the participant will be taken off 
protocol therapy. The participant will be followed for survival and may resume 
AVD treatment off study. 
4.6.2 Severe toxicities as outlined in Section 5.0. 
4.6.3 Progressive lymphoma at any time while on study. 
4.6.4 Voluntary withdrawal. 
4.6.5 The investigator has the right to remove participants from study for clinical reasons 
which he or she believes to be life threatening or resulting in significant morbidity 
to the participant. 
4.6.6 Any participant who develops HBV reactivation or acute Hepatitis B as defined by 
the reappearance of a previously suppressed hepatitis B surface antigen, a positive 
IgM hepatitis B core antibody, and a positive viral load. Any participant with 
Hepatitis B or C who has worsening liver function as defined by Section 5.2.5 will 
also be removed from study. 
4.6.7 Participants who become pregnant or breast-feed. 
4.6.8 Participants with progressive disease at the end of cycle 2 will be removed from 
study treatment, while participants with stable disease may be removed from the 
study treatment at the discretion of the local responsible investigator. Progressive 
or stable disease defined at cycle 2 will be based by CT criteria only, as FDG-PET 
has yet to be validated in HIV-associated HL. 
4.6.9 If found by central pathology review to not have the diagnosis of HIV-HL. 
4.6.10 If the participant has had two cycles of AVD + brentuximab vedotin and develops 
recurrent Grade 3 peripheral neuropathy despite dose reductions of brentuximab 
vedotin and vinblastine, the participant may continue the study receiving AVD with 
dose adjustments in vinblastine as clinically necessary, keeping in mind to maintain 
the dose and schedule as in standard therapy, or may be removed from protocol 
treatment. This decision will be at the discretion of the investigator. 
4.7 
Criteria for Early Study Termination 
4.7.1  An early stopping rule will be established such that the trial will be terminated if 
either or both of the following conditions hold:  
1. If the highest dose, the 1.2mg/kg dose, moves forward into the phase II portion 
of the study, and if more than 10% of the participants experience a grade 3 
motor or sensory neurotoxicity lasting for more than 4 weeks, the trial will be 
terminated. The first 10 participants in the phase II portion of the study at the 
1.2 mg/kg dose will be monitored for this outcome. If more than 3 out of the 10 
participants experience grade 3 neurotoxicity, this will be considered sufficient 
to stop the trial. With an underlying probability of grade 3 neuropathy of no 
more than 10%, the probability of observing > 3 participants with grade 3 
neuropathy is less than 5%. 
2. If any PML case is diagnosed when the CD4 count is above 50, the trial will be 
terminated. 


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4.7.2 Request by the protocol chairs, AMC, IRB, NCI, OHRP, or pharmaceutical 
sponsors. 


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5.0 
DOSE MODIFICATIONS/TOXICITY MANAGEMENT 
5.1 
Brentuximab Vedotin Dose Modifications 
Intrapatient Dose Reductions for Starting Dose of 1.2 mg/kg Every 2 Weeks. 
No further dose reductions will be permitted beyond 0.6 mg/kg of brentuximab vedotin. 
Participants not tolerating a dose of 0.6mg/kg will continue with standard dose AVD at the 
discretion of the investigator. 
Dose Level 
1.2 mg/kg 
0.9 mg/kg 
0.6 mg/kg 
 
Table 5-A:  Treatment Modification Guidelines for Brentuximab Vedotin for All Cycles 
Event 
CTCAE v5.0 
Grade 
Action to be Taken 
Allergic reactions, or 
Acute infusional 
reactions/ cytokine 
release syndrome 
Grade 1-2 
For first reaction: 
• Hold the infusion and wait 30 to 60 minutes 
(depending upon the reaction severity). 
• Treat reactions with diphenhydramine 1 mg/kg 
(max 50 mg), or follow local institution 
guidelines. Depending on the reaction severity, 
dexamethasone 0.2mg/kg (max 10mg) IV should 
be used or follow local institution guidelines. 
• 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. 
Brentuximab vedotin may be administered at half 
of the previously administered rate at the 
discretion of the investigator. 
For subsequent doses: 
• Utilize 
diphenhydramine 
with 
or 
without 
acetaminophen 
as 
pre-treatment 
for 
all 
subsequent infusions. 
• Dosing will be administered over the shortest 
infusion period that was well tolerated. 
If Grade 1-2 infusion reactions recur despite the 
above measures, either during re-challenge or 
subsequent treatments: 


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Event 
CTCAE v5.0 
Grade 
Action to be Taken 
• Take the measures outlined above. 
• With subsequent dosing, add dexamethasone 0.2 
mg/kg (max 10mg) IV or equivalent to 
medications above prior to infusion. 
Grade 3 
• Stop infusion immediately. 
• Administer diphenhydramine hydrochloride 1 
mg/kg IV (max 50 mg), dexamethasone 
0.2mg/kg (max 10mg) IV (or equivalent), 
bronchodilators for bronchospasms, and other 
medications as medically indicated. 
• Once symptoms recover, brentuximab vedotin 
should not be resumed for that course. 
Subsequent courses of brentuximab vedotin may 
be considered at physicians’ discretion. 
• All subsequent infusions will use the following 
premedications 
prior 
to 
infusion, 
diphenhydramine hydrochloride 1 mg/kg IV 
(max 50 mg), dexamethasone 0.2mg/kg (max 
10mg) IV (or equivalent). In addition, the 
infusion will be administered at 50% of the 
previous infusion rate. 
Grade 4 
• Stop infusion immediately. 
• Administer diphenhydramine hydrochloride 1 
mg/kg (max 50mg) IV, dexamethasone 0.2 
mg/kg (max 10mg) IV (or equivalent), and other 
anaphylaxis medications as indicated. 
• Epinephrine or bronchodilators at the discretion 
of the investigator will be administered as 
indicated. 
• Hospital admission for observation may be 
indicated 
• Discontinue brentuximab vedotin. 
Anaphylaxis 
Any grade 
If anaphylaxis occurs, immediately and permanently 
discontinue administration of brentuximab vedotin 
and administer appropriate medical therapy. 
Pancreatitis 
Grade 2 
• Withhold dose until toxicity has returned to 
baseline, then continue on protocol therapy but 
resume at one dose reduction. 
• If Grade 2 pancreatitis recurs after one dose 
reduction, the participant must be removed from 
protocol therapy. 
Grades 3-4 
• Permanently discontinue brentuximab vedotin. 
Peripheral 
Grade 1 
Continue at same dose level. 


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Event 
CTCAE v5.0 
Grade 
Action to be Taken 
Neuropathy 
Grade 2 
• Treatment is to be delayed until neuropathy 
improves to Grade 1 or baseline. 
• Brentuximab vedotin will be reduced by one dose 
level for subsequent treatments once peripheral 
neuropathy returns to baseline or returns to a 
grade 1. 
• Participants who experience a delay of over 7 
days in cycle 1 will be removed from the study. 
For subsequent cycles, if two sequential doses of 
brentuximab vedotin are held due to unresolved 
toxicity, leading to a treatment delay of an 
additional 2 weeks (i.e., 4 weeks between doses), 
participant will discontinue brentuximab vedotin. 
Participants will have the option to discontinue 
protocol therapy or continue study with AVD 
with dose adjustments in vinblastine as clinically 
necessary based on the level of neuropathy on the 
day of treatment as per standard label/summary 
product characteristics. 
Grade 3 
• Treatment is to be delayed until neuropathy 
improves to Grade 1 or baseline. Brentuximab 
vedotin will be reduced by one dose level for 
subsequent 
treatments 
once 
peripheral 
neuropathy returns to baseline or returns to a 
grade 1. 
• Participants who develop grade 3 neuropathy 
after dose reduction will have to discontinue 
brentuximab vedotin. Participants will have the 
option to be taken off protocol or continue study 
with AVD with dose adjustments as clinically 
necessary. 
• Participants who experience a delay of over 7 
days in cycle 1 will be removed from the study. 
For subsequent cycles, if two sequential doses of 
brentuximab vedotin are held due to unresolved 
toxicity, leading to a treatment delay of an 
additional 2 weeks (i.e., 4 weeks between doses), 
the participant will discontinue brentuximab 
vedotin. Participants will have the option to 
discontinue protocol therapy or continue study 
with AVD with dose adjustments in vinblastine 
as clinically necessary, based on the level of 
neuropathy on the day of treatment as per 
standard label/Summary product characteristics. 


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Event 
CTCAE v5.0 
Grade 
Action to be Taken 
Grade 4 
Discontinue brentuximab vedotin. 
Neutropenia 
Occurring on the Day 
of Treatmentb 
Grade 1-2 
Continue at same dose level. 
Grade 3-4  
• Reinstitute growth factor support (GCSF) for 
treatment of neutropenia until recovery to ANC 
≥1,000/mm3. 
• If 
myeloid 
growth 
factor 
support 
was 
inadvertently omitted in the previous dose, 
participants should receive the same full dose of 
brentuximab vedotin in the next treatment dose, 
along with myeloid growth factor support. 
• If, as per protocol, the participant was on myeloid 
growth factor support with the previous dose and 
presents 
with 
treatment 
day 
neutropenia, 
reinstitute daily growth factor support (GCSF) 
until recovery to ANC ≥1,000/mm3 and reduce 
brentuximab vedotin one dose level for all 
remaining cycles. 
• Dose reduction below brentuximab vedotin 0.6 
mg/kg is not allowed. Brentuximab vedotin 
should not be given for any subsequent cycles. 
• If participants have febrile neutropenia, please 
see Section 5.1.3 for dose modifications. 
Thrombocytopenia 
Grade 1-2 
Continue at same dose level. 
Grade 3-4 
• Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline, then continue on protocol 
therapy but at one dose reduction. 
• Participants 
who 
experience 
Grade 
3-4 
thrombocytopenia after dose reduction must be 
removed from protocol therapy. 
• Participants who experience a delay of over 7 
days in cycle 1 will be removed from the study. 
For subsequent cycles, if two sequential doses of 
brentuximab vedotin are held due to unresolved 
toxicity, leading to a treatment delay of an 
additional 2 weeks (i.e., 4 weeks between doses), 
the participant will be taken off protocol therapy. 
Lymphopenia 
Grade 1-4 
Continue at same dose level. 


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Event 
CTCAE v5.0 
Grade 
Action to be Taken 
Non-hematologica 
events (not including 
electrolyte 
abnormalities or 
febrile neutropenia) 
(See Section 5.1.3 for 
treatment modifications 
for febrile neutropenia) 
Grade 1-2 
Continue at same dose level. 
Grade 3-4 
• Withhold dose until toxicity is ≤ Grade 2 or has 
returned to baseline, then continue on protocol 
therapy but resume at one dose reduction of 
brentuximab vedotin. 
• If non-hematological Grade 3-4 toxicity recurs 
after one dose reduction, the participant must be 
removed from protocol therapy. 
• Participants who experience a delay of over 7 
days in cycle 1 will be removed from protocol 
therapy. For subsequent cycles, if two sequential 
doses of brentuximab vedotin are held due to 
unresolved toxicity, leading to a treatment delay 
of an additional 2 weeks (i.e., 4 weeks between 
doses), the participant will be taken off protocol 
therapy, and brentuximab vedotin will be 
discontinued. Participants will have the option to 
be taken off protocol or continue study with just 
AVD without brentuximab vedotin. 
Electrolyte 
Abnormalities 
Grade 1-4 
• Continue at same dose level, provided electrolyte 
toxicity is not medically consequential and has 
been readily corrected. 
• If 
electrolyte 
abnormality 
is 
medically 
consequential, refer to guidelines above for non-
hematologic events. 
a Participants who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption but should receive appropriate medical therapy at the discretion of the investigator. 
b See Section 4.4.1 for instructions on GCSF supportive treatment. 
5.1.1 Dose Modifications for Progressive Multifocal Leukoencephalopathy (PML) 
PML is a rare demyelinating disease of the brain that is caused by the John 
Cunningham virus (JCV). It typically occurs in immunocompromised individuals 
and can be fatal. Presenting features 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 PML 
patients (approximately 20%). Cognitive decline without accompanying deficits in 
motor or sensory function is uncommon. Optic nerve involvement, fever, and spinal 
cord disease are not typically associated with PML. In addition, peripheral 
neuropathy, which has been reported with brentuximab vedotin treatment, is not 
commonly reported with PML. 
If PML is suspected, a diagnostic work-up must be performed. The work-up may 
include, but is not limited to the following: 
• Neurologic examinations and neurology consultation, as warranted. 


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• 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. 
• PCR analysis. JCV DNA, detectable in CSF or in a brain biopsy, is suggestive 
of PML. 
Brentuximab vedotin dosing must be held if PML is suspected. If PML is 
confirmed, brentuximab vedotin must be permanently discontinued. 
5.1.2 Dose Modifications for Pulmonary Toxicity 
Pulmonary toxicity will be defined by grade 3 or 4 dyspnea, pneumonitis, and/or 
hypoxia that persists for at least three days. There must be no evidence of other 
etiologies, including left atrial hypertension, congestive heart failure, infection, 
metabolic abnormalities, or cancer related causes (e.g., malignant pericarditis). 
Participants who develop pulmonary toxicity associated with brentuximab vedotin 
may benefit from treatment with corticosteroids. However, there are no published 
guidelines to suggest the most appropriate dosing or duration of treatment. 
Administration of 100 mg of oral or intravenous prednisolone in single daily or two 
divided doses has been reported to improve symptoms in adults with pulmonary 
toxicity secondary to gemcitabine. The suggested dose for participants who develop 
pulmonary toxicity is methylprednisolone 1 mg/kg IV every 12 hours for a 
minimum of seven days. Participants who develop pulmonary toxicity meeting the 
above definition will be taken off protocol therapy (brentuximab vedotin). 
5.1.3 Dose Modifications for Febrile Neutropenia 
For participants already dosed reduced for reasons other than febrile neutropenia 
(e.g., neuropathy), dose reduction must start from the level at which the febrile 
neutropenia occurs. 
Table 5-B: Treatment Modification Guidelines for AVD-Brentuximab Vedotin for 
All Cycles 
Episode of Febrile Neutropenia 
Action 
First Episode of Febrile 
Neutropenia 
Maintain current brentuximab vedotin dose 
with quinolone prophylaxis, or reduce one 
dose level (investigator’s discretion). 
Second Episode of Febrile 
Neutropenia 
Quinolone prophylaxis and reduce one dose 
level. 
Third Episode of Febrile 
Neutropenia 
Quinolone prophylaxis and reduce one dose 
level. 
Fourth Episode of Febrile 
Neutropenia 
Quinolone prophylaxis and reduce one dose 
level. 
 
Dose Level 
Brentuximab 
Vedotin 
AVD 
1 
1.2 mg/kg 
Full dose 


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-1 
0.9 mg/kg 
Full dose 
-2 
0.6 mg/kg 
Full dose 
-3 
0 
Full dose 
-4 
0 
0.75 
 
Quinolone prophylaxis: antibacterial therapy is required for all cycles after an initial 
episode of febrile neutropenia. Suggested regimen can be altered based on 
availability, allergies, or ANC trends (e.g., levofloxacin 750 mg PO daily, Days 6-
13 and Days 20-27). Ciprofloxacin is not preferred due to being a moderate 
CYP3A4 inhibitor and caution should be exercised due to drug-drug interactions 
(See Appendix XIII). 
Participants who are unable to receive at least 4 doses of brentuximab vedotin will 
not receive further therapy on study. 
See Section 6.1 for a complete listing of potential adverse events and Section 6.1.1 for 
special precautions and safety issues. 
5.2 
AVD-Brentuximab Vedotin Dose Modifications (applies to all cycles) 
5.2.1 Hematologic Toxicity 
Although it is common practice to attenuate doses or delay treatment due to 
cytopenias alone, recent studies have shown that in the non-HIV setting for cHL 
patients receiving delays results in suboptimal treatment outcomes77,78. Participants 
will 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. 
5.2.2 Febrile Neutropenia 
See Section 5.1.3 for AVD-brentuximab vedotin dose modification instructions for 
febrile neutropenia. 
5.2.3 Transfusions 
Erythrocyte and platelet transfusions will be administered as needed at the 
discretion of the treating physician. 
5.2.4 Severe Infection 
Severe infection (NCI CTC Version 5.0, Grade 3 or 4) due to chemotherapy-related 
neutropenia requires a decrease in 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. 
 
 


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5.2.5 Impaired Hepatic Function 
Please see Table 5-C below for the appropriate dose adjustments based on total 
bilirubin and AST. In cases of obstruction of the biliary duct by a tumor mass, a 
biliary drainage stent may be placed prior to chemotherapy. Values must be within 
protocol eligibility at treatment initiation. 
Table 5-C: 
Total Bilirubin with Appropriate Doxorubicin and Vinblastine 
Dose Adjustments 
Drug1 
Total Bilirubin: 
< 1.5 
AST: < 60 
Total Bilirubin: 
1.5 – 3 
AST: 60 - 180 
Total Bilirubin: 
3.1 – 3.5 
AST: > 180 
Total 
Bilirubin: 
> 3.5 
Doxorubicin 
Administer 
100% 
Administer 
50% 
Administer 
25% 
Safety Not 
Established 
Vinblastine 
Administer 
100% 
Administer 
50% 
Administer 
25% 
Safety Not 
Established 
1. 
If participants are receiving atazanavir, please use only the direct bilirubin as an indicator 
for dose reduction of doxorubicin or vinblastine, following the dose reduction guidance 
identically as for total bilirubin 
5.2.6 Neuropathy 
Once brentuximab vedotin has been discontinued, participants experiencing Grade 
3 vinblastine-neuropathy (e.g., obstipation, weakness) may continue the study 
receiving AVD with dose adjustments in vinblastine as clinically necessary, based 
on the level of neuropathy on the day of treatment. Participants experiencing Grade 
4 vinblastine neuropathy will have this drug omitted from all future cycles of AVD. 
5.2.7 If a participant's weight has changed more than 10% from baseline or the prior dose, 
the new BSA must be used on the next cycle. For a weight change of 10% or less, 
doses may be adjusted according to the BSA or remain the same in conjunction 
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6.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of expected AEs (Section 6.1) and the characteristics of an observed AE 
(Section 6.2) will determine whether the event requires expedited (via CTEP-AERS) in 
addition to routine reporting (via AdvantageEDCSM). 
CTCAE term (AE description) and grade: The descriptions and grading scales found in the 
revised NCI Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 will 
be utilized for AE reporting beginning April 1, 2018. All appropriate treatment areas should 
have access to a copy of the CTCAE version 5.0. A copy of the CTCAE version 5.0 can be 
downloaded from the CTEP web site  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. This study 
will be monitored by the Clinical Data Update System (CDUS). Cumulative CDUS data 
will be submitted quarterly to CTEP by electronic means. Reports are due January 31, April 
30, July 31, and October 31. 
A monthly conference call between all participating institutions will be conducted to 
discuss all adverse events encountered. 
6.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for 
Brentuximab Vedotin (SGN-35, NSC 749710) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a single 
list of reported and/or potential adverse events (AE) associated with an agent using a 
uniform presentation of events by body system. In addition to the comprehensive list, a 
subset, the Specific Protocol Exceptions to Expedited Reporting (SPEER), appears in a 
separate column and is identified with bold and italicized text. This subset of AEs (SPEER) 
is a list of events that are protocol specific exceptions to expedited reporting to NCI (except 
as noted below).  Refer to the 'CTEP, NCI Guidelines: Adverse Event Reporting 
Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines.pd
f for further clarification. Frequency is provided based on 798 patients. Below is the 
CAEPR for SGN-35 (brentuximab vedotin).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in parentheses 
next to the AE in the SPEER.  If this CAEPR is part of a combination protocol using 
multiple investigational agents and has an AE listed on different SPEERs, use the lower of 
the grades to determine if expedited reporting is required. 
 
 


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Version 2.5, February 13, 20191 
 
 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
 
 
 Specific Protocol 
Exceptions to Expedited 
Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%)  
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
 
 Colitis2 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
 
 Enterocolitis 
  
 
 
Gastrointestinal hemorrhage3 
  
 
 
Gastrointestinal obstruction4 
  
 
 
Gastrointestinal perforation5 
  
 
 
Gastrointestinal ulcer6 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatotoxicity)7 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
  
  
Upper respiratory infection 
 
 Upper respiratory infection 
(Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
Neutrophil count decreased  
 
 Neutrophil count decreased 
(Gr 4) 
 
Platelet count decreased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 


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


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gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic hemorrhage, Rectal 
hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal hemorrhage under 
the GASTROINTESTINAL DISORDERS SOC. 
4Fatal and/or serious gastrointestinal obstructions have been observed in SGN-35 
(brentuximab vedotin) treated patients. Gastrointestinal obstruction includes Colonic 
obstruction, Duodenal obstruction, Esophageal obstruction, Ileal obstruction, Jejunal 
obstruction, Obstruction gastric, Rectal obstruction, Small intestinal obstruction, and 
other sites under the GASTROINTESTINAL DISORDERS SOC. 
5Fatal and/or serious gastrointestinal perforations have been observed in SGN-35 
(brentuximab vedotin) treated patients.  Gastrointestinal perforation includes Colonic 
perforation, Duodenal perforation, Esophageal perforation, Gastric perforation, Ileal 
perforation, Jejunal perforation, Rectal perforation, and Small intestinal perforation under 
the GASTROINTESTINAL DISORDERS SOC.  Lymphoma with preexisting GI 
involvement may increase the risk of perforation. 
6Fatal and/or serious gastrointestinal ulcers have been observed in SGN-35 (brentuximab 
vedotin) treated patients.  Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, 
Duodenal ulcer, Esophageal ulcer, Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, 
and Small intestine ulcer under the GASTROINTESTINAL DISORDERS SOC. 
7Hepatotoxicity may manifest as increased ALT/AST, bilirubin, alkaline phosphatase, 
and/or GGT. 
8Pulmonary toxicity, which may manifest as pneumonitis, interstitial lung disease, or 
adult respiratory distress syndrome (ARDS), has been observed in patients treated in 
brentuximab vedotin monotherapy trials as well as in combination with bleomycin. 
 
Adverse events reported on SGN-35 (brentuximab vedotin) trials, but for which 
there is insufficient evidence to suggest that there was a reasonable possibility that 
SGN-35 (brentuximab vedotin) caused the adverse event: 
BLOOD AND LYMPHATIC SYSTEM DISORDERS - Blood and lymphatic system 
disorders - Other (lymphadenopathy) 
CARDIAC DISORDERS - Myocardial infarction; Pericardial effusion; Sinus 
tachycardia 
GASTROINTESTINAL DISORDERS - Dyspepsia; Esophagitis 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS - Non-
cardiac chest pain 
INFECTIONS AND INFESTATIONS - Meningitis; Pharyngitis; Sepsis; Shingles; 
Sinusitis; Skin infection; Soft tissue infection; Thrush; Urinary tract infection 
INVESTIGATIONS - Blood lactate dehydrogenase increased; Carbon monoxide 
diffusing capacity decreased; Creatinine increased; Lipase increased; Lymphocyte count 
decreased 
METABOLISM AND NUTRITION DISORDERS - Dehydration; Hypercalcemia; 
Hyperkalemia; Hypertriglyceridemia; Hyperuricemia; Hypocalcemia; Hypoglycemia; 
Hypokalemia; Hypomagnesemia; Hypophosphatemia 
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS - Bone pain; 
Generalized muscle weakness; Myositis; Neck pain 
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND 
POLYPS) - Myelodysplastic syndrome 


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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. 
6.1.1 Special Precautions/Safety Issues 
Infusion-Related Reactions 
Some patients experienced an infusion-related reaction during or soon after SGN-
35 treatment. Symptoms of infusion-related reactions included chills, nausea, 
cough, itching, and shortness of breath. Two patients experienced a serious allergic 
reaction (wheezing/difficulty breathing, hives, itching, swelling) that required 
immediate medical attention and treatment discontinuation. 
Peripheral Neuropathy 
Some patients who received SGN-35 developed peripheral neuropathy. Symptoms 
reported by these patients included burning sensation, pain, weakness, numbness 
and tingling of hands and/or feet, and severe abnormal nerve function that caused 
difficulty walking. 
Neutropenia 
Some patients experienced neutropenia that was related to treatment with SGN-35. 
This could result in an increased risk of infection. 
Infection Risk 
SGN-35 may cause patients to be less resistant to infections, including severe 
infections. 
Other Important Side Effects 
The following important or potentially life-threatening side effects have been 
reported infrequently in patients treated with SGN-35: 
• Serious allergic reaction (wheezing/difficulty breathing, hives, itching, 
swelling) during or soon after SGN-35 treatment, which requires immediate 
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• Severe leukopenia, fever, and possible infection that resulted in death 
• Stevens-Johnson syndrome (unexplained widespread skin pain, blisters on skin 
and mucous membranes, hives, tongue swelling, a red or purple skin rash that 
spreads, or unexplained shedding of skin) 
• Tumor lysis syndrome (TLS) is a potentially life-threatening complication. TLS 
usually occurs within a few days of the start of cancer treatment and may result 
in metabolic complications. Potential complications may include nausea, 
vomiting, edema (swelling), shortness of breath, heart rhythm disturbances, and 
acute renal failure. 
• Progressive Multifocal Leukoencephalopathy (PML) is a rare, serious brain 
infection caused by a certain virus. People with a weakened immune system can 
experience PML. PML can result in death or severe disability. Care providers 
should be mindful of confusion or problems thinking, loss of balance or 
problems walking, difficulty speaking, decreased strength or weakness on one 
side of your body, blurred vision or loss of vision. 
Pregnancy and Breastfeeding 
Brentuximab vedotin is pregnancy category D; therefore, participants should not 
receive SGN-35 if they are pregnant because of the risk to the fetus. SGN-35 affects 
the testes in animals; therefore, men should not get their partner pregnant while 
being treated with SGN-35. 
• Female study volunteers of reproductive potential (defined as girls who have 
reached menarche and pre-menopausal women who have not had a sterilization 
procedure such hysterectomy, bilateral oophorectomy, or salpingectomy) must 
have a negative serum or urine pregnancy test performed within 48 hours before 
initiating the protocol-specified medication(s). Women are considered 
menopausal if they have not had a menses for at least 12 months and have a 
FSH of greater than 40 IU/L or, if FSH testing is not available, they have had 
amenorrhea for 24 consecutive months. 
• All study volunteers, male and female, must agree not to participate in a 
conception process (e.g., active attempt to become pregnant or to impregnate, 
sperm donation, or in vitro fertilization). 
• If participating in sexual activity that could lead to pregnancy, all study 
volunteers must agree to use two reliable methods of contraception 
simultaneously while receiving protocol-specified medication(s) and for 6 
months after stopping the medication(s). 
• If the female volunteer is not of reproductive potential (defined above) or the 
man has documented azoospermia, contraception is not required. 
Participants who could become pregnant or who have partners who could become 
pregnant must use birth control during the study and for 6 months after stopping 
treatment. If a participant or a participant’s partner becomes pregnant while taking 
part in this study or within 6 months after stopping treatment, the participant should 
inform the study doctor right away. Seattle Genetics will follow the pregnancy to 
term. In addition, the resultant progeny will be followed for potential side effects 
for some period of time after birth. 


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It is not known whether SGN-35 or its breakdown products end up in breast milk. 
If it does end up in breast milk, it could cause harm to a nursing baby. Therefore, 
breast feeding is prohibited while on study drug and for 6 months after the last dose 
of study drug. 
Possible Risks in Combination with Other Therapies 
Concomitant use of SGN-35 and bleomycin is contraindicated due to pulmonary 
toxicity. In a clinical trial that studied SGN-35 with bleomycin as part of a 
combination regimen (ABVD), the rate of noninfectious pulmonary toxicity was 
higher than the historical incidence reported with ABVD. Monotherapy with SGN-
35 has not been associated with a clinically meaningful risk of pulmonary toxicity. 
An ongoing phase 1 study is investigating the combination of SGN-35 with ABVD 
or AVD as front-line therapy for HL. Noninfectious pulmonary toxicity was 
observed in some patients treated with SGN-35 in combination with ABVD. The 
incidence of pulmonary toxicity in the ABVD + SGN-35 arm of the trial was 
approximately 40% (10 of 25 patients), compared to an incidence of 10% to 25% 
most commonly reported in the literature with bleomycin-based regimens79-81. 
Patients presented with cough and dyspnea. Interstitial infiltration and/or 
inflammation were observed on X-ray and computed tomography of the chest. Five 
patients had a maximum severity ≥ Grade 3 (3 with Grade 3 and 2 with Grade 4). 
Most patients responded favorably to corticosteroid therapy. 
6.2 
Classification of AEs by Severity and Relationship to Study Drug Administration 
6.2.1 Adverse Event: Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a 
medical treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite). 
6.2.2 Life-threatening Adverse Event: Any AE that places the participant or participant, 
in view of the Investigator, at immediate risk of death from the reaction. 
6.2.3 Serious Adverse Event (SAE): Any AE occurring at any dose that results in any of 
the following outcomes: Death, a life-threatening AE, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/ 
incapacity, or a congenital anomaly/birth defect. 
6.2.4 Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or unexpected, 
and attribution. For example, do not report an admission for pharmacokinetic 
sampling, but do report an admission for a myocardial infarction. 
6.2.5 Toxicity: Toxicity is a term NOT clearly defined by regulatory organizations. 
Toxicity has been described as an AE that has an attribution of possibly, probably 
or definitely related to investigational treatment. To minimize confusion the NCI 
would recommend that the term toxicity NOT be utilized for AE reporting 
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6.2.6 Unexpected Adverse Event: Any AE that is not listed in available sources including 
the package insert, the Investigator’s Brochure, or the protocol. 
6.2.7 CTEP Adverse Event Reporting System (CTEP-AERS): An electronic system for 
expedited submission of AE reports. 
6.2.8 Attribution: The determination of whether an AE is related to a medical treatment 
or procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent. 
Probable – The AE is likely related to the investigational agent. 
Possible – The AE may be related to the investigational agent. 
Unlikely – The AE is doubtfully related to the investigational agent. 
Unrelated – The AE is clearly NOT related to the investigational agent. 
6.3 
Expedited Adverse Event Reporting 
6.3.1 Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse Event 
Reporting System) accessed via the CTEP home page (http://ctep.cancer.gov). The 
reporting procedures to be followed are presented in the “CTEP, NCI Guidelines: 
Adverse Event Reporting Requirements” which can be downloaded from the CTEP 
home page (http://ctep.cancer.gov). These requirements are briefly outlined in the 
table below (Section 6.3.3). 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497 only 
when Internet connectivity is disrupted. Once Internet connectivity is restored, a 
24-hour notification phoned in must be entered electronically into CTEP-AERS by 
the original submitter at the site. 
6.3.2 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Protocol Chair, Principal Investigator at the local AMC 
treating institution and AMC Operations and Data Management Center. CTEP-
AERS provides a copy feature for other e-mail recipients.  
6.3.3 Phase 1 and Early Phase 2 Studies: Expedited Reporting Requirements for Adverse 
Events that Occur on Studies under an IND/IDE within 30 Days of the Last 
Administration of the Investigational Agent/Intervention1, 2 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “General disorders 
and administration site conditions - Disease Progression.” Evidence that the death 
was a manifestation of underlying disease (e.g., radiological changes suggesting 
tumor growth or progression: clinical deterioration associated with a disease 
process) should be submitted. 


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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 and Grade 2 
Timeframes 
Grade 3-5 
Timeframes 
Resulting in Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar 
Days 
Not resulting in Hospitalization ≥ 24 hrs 
Not required 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are 
found in the Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the 
CAEPR. 
Expedited AE reporting timelines are defined as: 
• “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 
hours of learning of the AE, followed by a complete expedited report within 5 calendar days 
of the initial 24-hour report. 
• “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: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 
radioactive half-lives, rounded UP to the nearest whole day, after the agent/intervention was 
last administered. Footnote “1” above applies after this reporting period. 
Effective Date: May 5, 2011 
 
• Expedited AE reporting timelines defined: 


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o “24 hours; 5 calendar days” – The investigator must initially report the AE 
via CTEP-AERS within 24 hours of learning of the event followed by a 
complete CTEP-AERS report within 5 calendar days of the initial 24-hour 
report. 
o “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the event. 
• Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse event 
reporting exclusions. 
• Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if the 
event occurs following treatment with an agent under a CTEP IND. 
• Use the NCI protocol number and the nine-digit AMC participant ID assigned 
during trial registration on all reports. 
6.3.4 Clinical Laboratory Results 
Clinical laboratory results that are outside of the institution’s reference ranges must 
be reported as adverse events if they are deemed clinically significant by the 
investigator(s). 
6.3.4.1 A clinical laboratory abnormality should be deemed clinically significant if 
any one of the following conditions is met: 
• The laboratory abnormality is not otherwise proved false by a repeat 
confirmation test. 
• The abnormality suggests a disease and/or organ toxicity that is new or 
has worsened from baseline. 
• The abnormality is of a degree that requires additional active 
management, e.g., change of dose, discontinuation of the drug(s), close 
observation, more frequent follow-up assessments, or further diagnostic 
investigation. 
6.3.4.2 In this protocol the following clinical laboratory abnormalities are expected 
and will not be considered AEs: 
• HIV viral load 
• T Cell subsets 
• LDH 
6.4 
Routine Adverse Event Reporting 
All AEs that require expedited reporting via CTEP-AERS must also be reported in routine 
study data submissions (Adverse Event Form CRF). Routine reporting of all AEs attributed 
to therapy (possible, probable or definitely), regardless of grade, should be reported on the 
Adverse Event Form CRF. Similarly, if participants require radiotherapy, post-treatment 
AEs related to radiation therapy do not require routine reporting. All Grade 5 events, 
regardless of attribution to therapy, must be reported in the Adverse Event and Death Forms 


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in AdvantageEDCSM. 
6.4.1 Timeline for routine adverse event reporting 
All adverse events will be assessed by the investigator in the study source from 
the first dose of protocol therapy through the post-treatment discontinuation visit 
(one month if discontinuing treatment early; 6-8 weeks at scheduled protocol 
therapy completion). After this evaluation, assessment and reporting of AEs will 
only be required for all grade 5 AEs and any SAE that the investigator considers 
related to AMC-085 protocol therapy. 
6.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) events must be 
reported via CTEP-AERS (in addition to your routine AE reporting mechanisms). In 
CTCAE v5.0, the event(s) may be reported as either: 1) Leukemia secondary to oncology 
chemotherapy, 2) MDS, or 3) Treatment-related secondary malignancy. Whenever 
possible, the CTEP-AERS report should include the following: tumor pathology; history 
of prior tumors; prior treatment/current treatment including duration; any associated risk 
factors or evidence regarding how long the tumor may have been present; when and how 
the tumor was detected; molecular characterization or cytogenetics of the original tumor 
(if available) and of any new tumor; and tumor treatment and outcome, if available. These 
events should be reported for the duration of the study treatment and during the protocol-
specified follow-up period. 


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7.0 
PHARMACEUTICAL INFORMATION 
7.1 
Chemotherapy Medications 
7.1.1 Doxorubicin 
Doxorubicin is an anthracycline antibiotic that binds tightly with DNA, inhibits 
nucleic acid synthesis and causes DNA strand breaks. Although active throughout 
the cell cycle, cells in S phase are most sensitive. Common side effects include 
myelosuppression, alopecia, and stomatitis, which is dose related and may be 
severe. Drug-induced cardiomyopathy, which may result in congestive heart 
failure, is a cumulative dose-dependent effect and risk becomes considerable at 
total doses exceeding 500 mg/m2. Doxorubicin is given intravenously and is a 
vesicant causing severe local necrosis at the site of injection if extravasation occurs. 
Nausea and vomiting are frequent. Please refer to the approved package insert for 
complete prescribing and toxicity information. 
Doxorubicin will be commercially supplied and please refer to institutional 
guidelines for administration. Additional information on this medication including 
all adverse events can be obtained from the approved FDA package insert found at: 
http://dailymed.nlm.nih.gov/dailymed/archives/fdaDrugInfo.cfm?archiveid=1389
4 
7.1.2 Vinblastine 
Vinblastine is the salt of an alkaloid derived from Vinca rosea Linn, a common herb 
known as the periwinkle. 
Mechanism of Action: Tissue culture studies suggest an interference with metabolic 
pathways of amino acids leading from glutamic acid to the citric acid cycle and to 
urea. A number of studies in vitro and in vivo have demonstrated its stathmokinetic 
effect and various atypical mitotic figures. Other studies indicate an effect on cell 
energy production required for mitosis and the interference with nucleic acid 
synthesis. Reversal of antitumor effect by glutamic acid and tryptophan has been 
observed. 
Leukopenia is the usual dose-limiting side effect, with the nadir falling four to 
seven days post-injection. Thrombocytopenia and anemia may occur. 
Gastrointestinal toxicities include nausea, vomiting, diarrhea or constipation, 
abdominal pain, ileus, peptic ulcer, rectal bleeding and anorexia. Fever and 
phlebitis have also been seen when the drug is given as an infusion. Extravasation 
may lead to tissue necrosis. Ten percent of the participants will experience 
peripheral neuropathy. Alopecia can also occur. 
Vinblastine will be commercially supplied and please refer to institutional 
guidelines for administration. Additional information on this medication including 
all adverse events can be obtained from the approved FDA package insert found at: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=17060 
 
 


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7.1.3 Dacarbazine (DTIC) 
Three hypotheses have been offered as the mechanism(s) of action of DTIC: 
inhibition of DNA synthesis by acting as a purine analog, action as an alkylating 
agent, and/or interaction with SH groups. 
Myelosuppression is the dose-limiting toxicity. The predominant side effect 
observed in humans has been anorexia, nausea, and vomiting. This occurs with 
maximal intensity on the first day of a five-day course, and in many patients, it is 
less with each subsequent day. Myelosuppression consisting of thrombocytopenia 
and leukopenia occurs in approximately one-quarter of patients after a five-day 
course of 250 mg/m2. The time course for this myelosuppression is generally 
maximal approximately three weeks after administration with the period of 
recovery variable. Other reported side effects include infrequent flu-like syndrome 
associated with fever and myalgia, phlebitis, liver necrosis, hepatic toxicity, 
anaphylaxis, photosensitivity, alopecia, and facial flushing. Rarely, DTIC has 
caused diarrhea. 
Dacarbazine is pregnancy category D, please follow the same guidelines stated in 
Section 6.1.1 under the pregnancy and breastfeeding section. 
Dacarbazine will be commercially supplied and please refer to institutional 
guidelines for administration. Additional information on this medication including 
all adverse events can be obtained from the approved FDA package insert found at: 
http://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?id=17060 
7.1.4 Brentuximab Vedotin (NSC 749710) 
Other Names: AdcetrisTM, Brentuximab vedotin 
Classification: Monoclonal Antibody 
CAS Registry Number: 914088-09-8 
M.W.: 153 kDa 
Mode of Action: 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. 
How Supplied: Seattle Genetics supplies and CTEP/DCTD distributes SGN-35 as 
a single use, preservative free vial containing 50 mg of white to off-white 
lyophilized powder for Injection. Inactive ingredients are trehalose, sodium citrate, 
and polysorbate 80. The pH is 6.6 once reconstituted in Sterile Water for Injection. 
Preparation: Consists of 2 steps: dilution of the stock solution and dilution of the 
final solution. 


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Step 1: To make a 5 mg/mL concentration. 
1. Reconstitute the 50 mg lyophilized powder SGN-35 with 10.5 mL Sterile Water 
for Injection, USP. Final concentration is 5 mg/mL (Note: total volume is 11 
mL). 
2. Swirl the vial gently. Do not shake. 
3. Let the reconstituted vial settle for one minute to eliminate bubbles. The 
reconstituted solution should be colorless, clear to slightly opalescent and should 
NOT have visible particulates. 
4. Store the reconstituted vial under refrigeration (2° – 8°C), protect from light if 
not used immediately. Discard after 8 hours. 
Step 2: Further dilute the IV solution. Use vials from the same Lot number for 
each dose. 
1. Withdraw the calculated amount of drug from the 5 mg/mL reconstituted vial in 
step 1. 
2.  Inject the required amount of drug into a 50 mL to 250 mL of 0.9% NS, 
Lactated Ringer’s Solution, USP, or dextrose 5% in Water (D5W), USP to a 
final concentration between 0.4 – 1.8 mg/mL. 
3. SGN-35 solution is compatible in polyvinylchloride (PVC), ethylene vinyl 
acetate (EVA), polyolefin, or polyethylene. 
4. Do not shake. Gently invert the bag. 
5. The prepared IV bag is to be stored at 2-8° C and must be used within 24 hours 
of initial product reconstitution. Protect the prepared IV solution from direct 
sunlight if not used immediately. 
6. Prior to administration, inspect the IV bag for discoloration or floating 
particulates. Do not use the IV solution if the solution is discolored or/and have 
particulates. 
Storage: Store the intact vials refrigerated at 2-8° C. Protect from direct sunlight. 
Stability: The stability testing of the intact vials is ongoing. Reconstituted agent 
must be diluted and administer within 24 hours. 
CAUTION: The single-use lyophilized dosage form contains no antibacterial 
preservatives. Therefore, it is advised that the reconstituted product be discarded 8 
hours after initial entry. 
Route(s) of Administration: Intravenous. Do not administer as an IV Push or 
bolus. 
Method of Administration: Infuse the prepared IV solution over 30 minutes. Do 
not mix with other medications. Do not use an in-line filter for the IV 
administration. The IV bag does NOT need light protection during the IV 
administration. 
Potential Drug Interactions: In vitro data, one of SGN-35 active metabolites, 
monomethyl auristatin E (MMAE) is a substrate and an inhibitor of CYP3A4 but 
is not a sensitive substrate nor a strong inhibitor/inducer of CYP3A4. However, 
participants should be monitored for potential drug-interaction when administered 
drugs known to be a strong CYP 3A4 inhibitor/inducer with SGN-35. In vitro, 


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MMAE is a substrate of P-gp transporter and is not an inhibitor of P-gp. 
Participant Care Implications: 
• New signs and symptoms of CNS system abnormalities may indicate 
progressive multifocal leukoencephalopathy (PML). 
• Tumor lysis syndrome, particularly in participants with highly proliferative 
tumors or high tumor burden prior to treatment. 
• Infusion-related reactions, including anaphylaxis, may occur. Refer to protocol 
for the management of infusion-related reactions. 
• Signs and symptoms of peripheral neuropathy such as tingling or numbness of 
the hands, feet, or any muscles weakness. 
• Steven-Johnson syndrome 
• High fever (≥100.5F) or other signs of potential infection. 
7.2 
Drug Orders, Transfers, Returns, and Accountability 
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 participant 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), Curriculum Vitae, 
Supplemental Investigator Data Form (IDF), 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. 
Active CTEP-registered investigators and investigator-designated shipping designees and 
ordering designees can submit agent requests through the PMB Online Agent Order 
Processing (OAOP) application (https://eapps-ctep.nci.nih.gov/OAOP/pages/login.jspx). 
Access to OAOP requires the establishment of a CTEP Identity and Access Management 
(IAM) account (https://eapps-ctep.nci.nih.gov/iam/) and the maintenance of an “active” 
account status and a “current” password. For questions about drug orders, transfers, returns, 
or accountability, call (240) 276-6575 Monday through Friday between 8:30 am and 4:30 
pm (ET) or email PMBAfterHours@mail.nih.gov anytime. 
Agent Inventory Records - The investigator, or a responsible party designated by the 
investigator, must maintain a careful record of the inventory and disposition of all agents 
received from DCTD using the NCI Drug Accountability Record Form (DARF). (See the 
NCI Investigator’s Handbook for Procedures for Drug Accountability and Storage.) 
Seattle Genetics will be responsible for supplying Brentuximab vedotin to all of the 
LYSA/LYSARC sites in France. Agent orders, transfers, and returns will be conducted 
according to the agreement between LYSA/LYSARC and Seattle Genetics. 
7.3 
Reporting Requirements for Concomitant Medications 
All medications must be reported in the site’s source documents at baseline. All 


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medications will be reviewed and updated in the site’s source documents at all visits where 
indicated in the schedule of evaluations (Appendix I). Only a subset of medications will be 
reported in the Concomitant Medications CRFs after study entry, as listed below: 
7.3.1 Anti-seizure medications 
7.3.2 Prophylactic medications 
• Antiviral 
• Antifungal 
• Quinolone/Antibiotic therapy (See Section 4.4.6) 
• Any other medications used for prophylaxis of opportunistic infections 
7.3.3 Hepatitis medications 
7.3.4 Growth colony stimulation factors (GCSF) 
7.3.5 Erythropoiesis Stimulating Agents (ESA) 
7.3.6 Anti-retroviral medications. Note: Antiretroviral therapy will be collected in the On 
Study Form. If the participant remains on the same anti-retroviral medications 
throughout study participation that have already been reported in the On Study 
Form, then do not report them in the Concomitant Medications Form. If the 
participant changes or discontinues anti-retroviral therapy for any reason, then 
update the Concomitant Medication Form with the start and stop date of the 
discontinued medication(s) and start date of the new (if applicable) medication(s). 
7.3.7 Receipt of disallowed medications (CYP3A4 or P-glycoprotein inhibitors) after 
study enrollment, as per Appendix XIII 


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8.0 
STUDY PROCEDURES  
Schedule of Evaluations is provided in Appendix I. 
8.1 
Screening/Baseline Evaluations 
Unless otherwise specified, the following evaluations must be performed within 6 weeks 
prior to participant registration: 
8.1.1 AIDS and Cancer Specimen Resource (ACSR) Consent for optional donation. It is 
required that AMC sites present the ACSR donation option to participants. (See 
Appendix VI for ACSR Informed Consent Form and Appendix V for ACSR 
Specimen Preparation and Shipping Instructions). 
8.1.2 Medical history, history of drug allergies, history of current and past anti-retroviral 
regimens, if available; and history of any prior AIDS-defining conditions. Date of 
initial lymphoma diagnosis is required, with a copy of the pathology report in the 
medical record. Presence of systemic “B” symptoms should be noted, as well as 
other symptoms of cHL. Current concomitant medication list, including all anti-
retroviral, anti-viral, antibiotics, and opportunistic prophylaxis should be obtained. 
8.1.3 Physical examination, including performance status (see Appendix III Performance 
Status Scale), vital signs (weight, height, body surface area), neurological 
examination, and if possible, two dimensional measurement of all palpable, 
peripheral lymph nodes and measurement of other sites of disease present on 
physical exam. 
8.1.4 A combined FDG-PET/CT or FDG-PET + CT scan with and without IV contrast is 
required for this study. If a participant has an allergy to IV contrast, a non-IV 
contrast CT scan will be permitted. To ensure consistency between all centers, 
FDG-PET/CT scans at diagnosis should be conducted no more than 28 days before 
enrollment. 
If the CT scan of a PET/CT hybrid is performed with both oral and IV contrast with 
contrast enhancement in the arterial and/or portal venous phase, with at least a 2-
slice CT, and is acquired with at least 80 mAs and CT scans are obtained with 
contiguous sections (with a maximum of 5 mm slice thickness), then the pre-
treatment PET/CT scan alone will suffice for participants enrolled on this trial. If 
no contrast is used in the FDG-PET/CT, an additional CT scan with contrast is 
required of the neck, chest, abdomen, and pelvis, see 8.1.5 below. 
8.1.5 CT scan of the neck (if palpable lymphadenopathy only), chest, abdomen and pelvis 
with and without IV contrast will be required. If the CT portions of the FDG-
PET/CT combination scan is a non-contrast CT scan, then a separate CT scan with 
and without IV contrast will be required. 
8.1.6 MRI of the brain with and without IV gadolinium contrast, to look for early 
evidence of PML. 
8.1.7 Determination of LVEF by MUGA scan or echocardiogram. 
8.1.8 Bone marrow biopsy for histology and determination of percent bone marrow 
involvement. If bone marrow involvement by lymphoma has already been 


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documented after bone marrow biopsy performed more than 6 weeks prior to 
registration, the biopsy does not have to be repeated. 
8.1.9 Central pathology review for confirmation of histology of lymphoma specimen: 
Biopsy material at diagnosis will be sent to confirm HIV-HL and histologic 
subtype. When possible, biopsy tissue blocks should be sent. If not, one 
hematoxylin and eosin (H&E) stained slide and ten 5 µm blank (unstained) paraffin 
sections can be used instead. The tissue block will be returned to the sites. (See 
Appendix VIII for the acceptable specimens required for central review and for 
handling instructions). 
All specimens will be reviewed by a panel of pathologists and must be submitted 
within 30 days of study enrollment. Participants who are found not to have HIV-
HL will be withdrawn from the study 
8.1.10 Three 1.0 mm cores from the initial biopsy tissue block will be required to be sent 
for miRNA analysis. If biopsy block is unavailable, 10 unstained sections at 20 
microns can be submitted (See Appendix VIII for the acceptable specimens 
required for miRNA analysis and for handling and shipping instructions). 
8.1.11 Three 1.0 mm cores from the initial biopsy tissue block will be required to be sent 
for tissue microarray analysis. (See Appendix VIII for the acceptable specimens 
required for TMA construction and analysis and for handling and shipping 
instructions). 
8.1.12 Laboratory tests, including: 
8.1.12.1 CBC with differential and sedimentation rate (within 2 weeks prior to 
participant registration). Sedimentation rate is only required at 
screening/baseline. 
8.1.12.2 Serum chemistries: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, and 
phosphorus), glucose, blood urea nitrogen (BUN), creatinine, total 
bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, AST 
and ALT (within 2 weeks prior to participant registration). 
8.1.12.3 CD4 and CD8 cell count. 
8.1.12.4 HIV-1 RNA viral load to be assessed by any FDA-approved viral load 
assay (evaluated at the local laboratory). This must be performed within 
21 days prior to Cycle 1, Day 1. (The HIV viral load assay must detect 
at minimum viremia > 200 copies/mL to be consistent with the DHHS 
HIV treatment guidelines). 
8.1.12.5 Assessment for Hepatitis C antibody, Hepatitis B core antibody, 
Hepatitis B surface antigen (HBsAg), and Hepatitis B surface antibody. 
8.1.12.6 Serum or urine pregnancy test for women of childbearing potential 
(within 7 days prior to Cycle 1 chemotherapy). (See Section 6.1.1 under 
pregnancy and breastfeeding for guidelines on the use of pregnancy 
category D medications, which includes brentuximab vedotin and 
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8.1.12.7 Blood samples to be taken for EBV tumor DNA studies. See Section 10.0 
and Appendix XI for time points needed, sample processing, and 
shipping instructions. This will be done only in the Phase II portion of 
the study. 
8.1.12.8 Blood samples to be taken for cytokine studies. See Section 10.0 and 
Appendix X for time points needed, sample processing, and shipping 
instructions. This will be done only in the Phase II portion of the study. 
8.1.12.9 Blood samples will be taken for analysis of latent and HIV reservoirs. 
See Section 10.0 and Appendix XII for time points needed, sample 
processing, and shipping instructions. Only for participants who are 
found to have undetectable plasma HIV-1 RNA by the standard assay 
performed at the clinical site within 21 days of C1 Day 1. 
8.2 
Evaluations During Treatment 
Evaluations are to occur in both Phase 1 and 2 and all study arms unless otherwise 
specified. 
8.2.1 Update medical history prior to each cycle of chemotherapy. History to include 
concomitant medication changes and any signs and symptoms. Reportable adverse 
events must be recorded in AdvantageEDC. To be performed within 48 hours prior 
to or on first day of each cycle. 
8.2.2 Physical examination prior to each cycle of chemotherapy. Examination to include 
performance status (Appendix III). All participants will be evaluated for clinical 
response by physical examination prior to receiving treatment on each cycle. The 
exam should occur within 2 days prior to the start of each cycle but may occur on 
Day 1 of cycle. Disease measurable by physical examination will be recorded in 
two dimensions if possible. To be performed within 48 hours prior to or on first day 
of each cycle. 
8.2.3 FDG-PET/CT. Combined FDG-PET/CT or FDG-PET + CT scans with and without 
IV contrast are required for this study. If a participant has an allergy to IV contrast, 
a CT scan without contrast will be permitted.  
Restaging evaluation by a full body FDG-PET/CT within Day 22-28 of Cycle 2 
(i.e., 7-13 days after the Cycle 2 Day 15 doses of AVD-BV). If the CT portion of 
the PET/CT is a non-contrast CT, an additional CT scan with and without contrast 
must be obtained. Tumor measurements and SUVs must be documented. A neck 
CT must be included if palpable neck nodes were present at baseline and a 
diagnostic CT is being performed. 
As the false positive rate of FDG-PET scans may be higher in the HIV population, 
a biopsy of an unexpected FDG-PET avid lesion is recommended but remains at 
the discretion of the investigator. 
8.2.4 Neuropathy evaluation by completing the FACT/GOG-neurotoxicity questionnaire 
at the beginning of each cycle. To be performed once within 48 hours prior to or on 
first day of each cycle (Appendix IV). 
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be known prior to treatment. 
8.2.6 Serum chemistries within 48 hours of day 1 and 15 of each cycle: electrolytes (Na, 
K, Cl, bicarbonate, Ca, Mg, and phosphorus), glucose, blood urea nitrogen (BUN), 
creatinine, total bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, 
AST and ALT. Results do not need to be known prior to treatment unless clinically 
indicated. 
8.2.7 CD4/CD8 count will be performed within 48 hours of cycle 2 and cycle 5 day 1 
along with the CBC evaluation. 
8.2.8 HIV-1 RNA viral load, to be assessed by any FDA-approved viral load assay 
(evaluated at the local laboratory). This will be performed within 48 hours of cycle 
2 and cycle 5 day 1 along with the CBC evaluation. (The HIV viral load assay must 
detect at minimum viremia >200 copies/mL to be consistent with the DHHS HIV 
treatment guidelines). 
For participants with undetectable HIV viral at baseline: If the viral load rises above 
200 copies per mL, HIV resistance testing will be required. Both viral load and 
resistance testing information must be shared in real time with the primary HIV 
provider if different from the protocol investigator. (The HIV viral load assay must 
detect at minimum viremia >200 copies/mL to be consistent with the DHHS HIV 
treatment guidelines). 
8.2.9 Serum or urine pregnancy test for women of childbearing potential will be 
performed per institutional guidelines during the study. 
8.2.10 Plasma samples to be taken for EBV tumor DNA studies at the end of cycles 1 and 
3. See Section 10.0 and Appendix XI for time points needed, sample processing, 
and shipping instructions. This will be done only in the Phase II portion of the study. 
8.2.11 Plasma samples to be taken for cytokine studies. See Section 10.0 and Appendix X 
for time points needed, sample processing, and shipping instructions. This will be 
done only in the Phase II portion of the study. 
8.2.12 Pharmacokinetic/Immunogenicity studies in select Phase II participants only. See 
Appendix IX for details on time points, sample processing, and shipping. 
8.2.13 Blood samples will be taken for analysis of latent and HIV reservoirs. See Section 
10.0 and Appendix XII for time points needed, sample processing, and shipping 
instructions. 
8.3 
Post Treatment Evaluation 
The studies listed below will be performed post-therapy within 6-8 weeks of the last 
treatment dose (6-8 weeks after Cycle 6 Day 15; all follow up time points for post-treatment 
evaluations should be calculated in reference to this treatment discontinuation visit). 
Studies will then be repeated every 3 months (+/- 7 days) thereafter for 2 years; every 6 
months (+/- 7 days) for the third through the fifth years unless otherwise specified. All 
study participants should be followed for up to 5 years after treatment discontinuation or 
until death if occurring before 5 years of treatment discontinuation. Participants who 
discontinue all protocol therapy after a CR or PR are followed for up to 5 years after 
treatment for recurrence and survival. Participants who discontinue protocol therapy due 


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to disease progression or other reasons are followed for survival for up to 5 years after 
treatment discontinuation. No additional studies except follow up for survival are required 
after disease progression. In those instances in which a third party payer denies payment 
for some or all of these laboratory analyses, absence of these test results will not be 
considered a protocol violation. 
8.3.1 Medical history. 
8.3.2 Physical examination, including performance status (see Appendix III, 
Performance Status Scale), vital signs (weight, height, body surface area), 
neurological examination, and if possible, two dimensional measurement of all 
palpable, peripheral lymph nodes and measurement of other sites of disease present 
on physical exam. 
8.3.3 At the conclusion of chemotherapy, a full body FDG-PET/CT scan will be done 
between 6-8 weeks post the final treatment dose, Cycle 6 Day 15. This will be the 
final FDG-PET/CT needed for the study. A combined FDG-PET/CT or FDG-PET 
+ CT scans with and without IV contrast are required for the post-treatment scan. 
If a participant has an allergy to IV contrast, a CT scan without contrast will be 
permitted. As the false positive rate of FDG-PET scans may be higher in the HIV 
population, a biopsy of an unexpected FDG-PET avid lesion is recommended but 
remains at the discretion of the investigator. 
8.3.4 CT scan with oral/IV contrast every 6 months for 5 years. To begin 6 months from 
the post treatment FDG-PET/CT scan, obtained 6-8 weeks post the final 
chemotherapy dose (See Section 8.3.3). 
8.3.5 Bone marrow biopsy need only be performed to confirm a CR if positive at baseline 
(only once, within 8 weeks of the last treatment dose). 
8.3.6 CBC with differential. 
8.3.7 Serum chemistries: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, and phosphorus), 
glucose, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline 
phosphatase (ALP), LDH, total protein, albumin, AST and ALT.  
8.3.8 CD4 and CD8 cell count beginning with the first follow up visit and every 3 months 
after treatment completion for one year. 
8.3.9 HIV-1 RNA viral load, to be assessed by any FDA-approved viral load assay 
(evaluated at the local laboratory) beginning with the first follow up visit and every 
3 months after treatment discontinuation visit for one year. (The HIV viral load 
assay must detect at minimum viremia >200 copies/mL to be consistent with the 
DHHS HIV treatment guidelines). 
8.3.10 Plasma samples to be taken for EBV tumor DNA studies at treatment 
discontinuation visit and 3, 6, and 12 months after treatment discontinuation visit. 
See Appendix XI for time points, sample processing, and shipping instructions. 
This will only be performed on the Phase II portion of the study. 
8.3.11 Plasma samples to be taken for and cytokine studies. See Appendix XI for time 
points needed, sample processing, and shipping instructions. This will only be 
performed on the Phase II portion of the study. 


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8.3.12 Pharmacokinetic/Immunogenicity studies in select Phase II participants only. See 
Section 10.1 and Appendix IX for time points and sample processing post therapy. 
8.3.13 Blood samples will be taken for analysis of latent and HIV reservoirs. See Section 
10.0 and Appendix XII for time points needed, sample processing, and shipping 
instructions. 
8.4 
Early Discontinuation of Therapy 
8.4.1 Participants discontinuing therapy early (i.e., PD or stable disease, administrative 
reasons, participant non-compliance, etc.) will have a medical history update and 
complete physical examination. The examination will include performance status 
and blood drawn for the following studies within 1 month after treatment 
discontinuation, unless otherwise noted. See Section 4.7 for a list of reasons for 
study termination. Participants will be followed for survival only for 5 years after 
the last date of treatment: 
8.4.1.1 CBC with differential. 
8.4.1.2 Serum chemistries: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, and 
phosphorus), glucose, blood urea nitrogen (BUN), creatinine, total 
bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, AST 
and ALT. 
8.4.1.3 CD4 and CD8 cell count (do not repeat if done within 1 month from 
removal from treatment). 
8.4.1.4 HIV-1 RNA viral load to be assessed by any FDA-approved viral load 
assay (evaluated at the local laboratory, do not repeat if done within 1 
month from removal from treatment). 
8.4.1.5 Pharmacokinetic/Immunogenicity studies in select Phase II participants 
only. See Section 10.1 and Appendix IX for time points and sample 
processing. 
8.4.1.6 Blood samples will be taken for analysis of latent and HIV reservoirs. See 
Section 10.0 and Appendix XII for time points needed, sample processing, 
and shipping instructions (do not repeat if done within 1 month from 
removal from treatment). 
8.4.1.7 Plasma samples to be taken for EBV tumor DNA studies. See Appendix 
XI for sample processing and shipping instructions. This will only be 
performed on the Phase II portion of the study. 
8.4.1.8 Plasma samples to be taken for and cytokine studies. See Appendix XI for 
sample processing and shipping instructions. This will only be performed 
on the Phase II portion of the study. 


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9.0 
EFFICACY AND SAFETY MEASUREMENTS 
9.1 
Efficacy Measurements 
All participants will be evaluated for clinical response by physical examination prior to 
receiving treatment on each cycle. The exam should occur within 3 days prior to the start 
of each cycle, but may occur on Day 1 of cycle. 
All participants will be evaluated for clinical response by imaging studies after by FDG-
PET/CT at the completion of cycle 2 and at the completion of therapy (See Section 5.0). 
9.2 
Response Assessment 
Response is currently assessed on the basis of clinical, radiologic, and pathologic (i.e., bone 
marrow) criteria. 
Definition of Response: 
The response definitions used for this study are the 2007 Cheson criteria. A major 
distinction in the 2007 criteria is that PET/Gallium studies are used to facilitate the 
distinction between persistent tumor and scar/fibrosis. 
Complete Response (CR): 
1. 
Complete disappearance of all detectable clinical evidence of disease and disease-
related symptoms if present before therapy. 
2a. 
Typically FDG-avid lymphoma: In participants with no pretreatment PET scan or 
when the PET scan was positive before therapy, a post-treatment residual mass of 
any size is permitted as long as it is PET negative. 
2b. 
Variably FDG-avid lymphomas/FDG avidity unknown: In participants without a 
pretreatment PET scan, or if a pretreatment PET scan was negative, all lymph nodes 
and nodal masses must have regressed on CT to normal size (1.5 cm in their greatest 
transverse diameter for nodes > 1.5 cm before therapy). Previously involved nodes 
that were 1.1 to 1.5 cm in their long axis and more than 1.0 cm in their short axis 
before treatment must have decreased to 1.0 cm in their short axis after treatment. 
3. 
The spleen and/or liver, if considered enlarged before therapy on the basis of a 
physical examination or CT scan, should not be palpable on physical examination 
and should be considered normal size by imaging studies, and nodules related to 
lymphoma should disappear. However, determination of splenic involvement is not 
always reliable because a spleen considered normal in size may still contain 
lymphoma, whereas an enlarged spleen may reflect variations in anatomy, blood 
volume, the use of hematopoietic growth factors, or causes other than lymphoma. 
4. 
If the bone marrow was involved by lymphoma before treatment, the infiltrate must 
have cleared on repeat bone marrow biopsy. The biopsy sample on which this 
determination is made must be adequate (with a goal of > 20 mm unilateral core). 
If the sample is indeterminate by morphology, it should be negative by 
immunohistochemistry. 
Partial Response (PR) Requires all of the Following: 
1. 
At least a 50% decrease in sum of the product of the diameters (SPD) of up to six 
of the largest dominant nodes or nodal masses. These nodes or masses should be 
selected according to all of the following: they should be clearly measurable in at 


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least two perpendicular dimensions; if possible they should be from disparate 
regions of the body; and they should include mediastinal and retroperitoneal areas 
of disease whenever these sites are involved. 
2. 
No increase should be observed in the size of other nodes, liver, or spleen. 
3. 
Splenic and hepatic nodules must regress by 50% in their SPD or, for single 
nodules, in the greatest transverse diameter. 
4. 
With the exception of splenic and hepatic nodules, involvement of other organs is 
usually assessable and no measurable disease should be present. 
5. 
Participants who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial responders. 
When the bone marrow was involved before therapy and a clinical CR was 
achieved, but with no bone marrow assessment after treatment, participants should 
be considered partial responders. 
6. 
No new sites of disease should be observed. 
7. 
Typically FDG-avid lymphoma: for a participant with no pretreatment PET scan or 
if the PET scan was positive before therapy, the post-treatment PET should be 
positive in at least one previously involved site. 
8. 
Variably FDG-avid lymphomas/FDG-avidity unknown: if a pretreatment PET scan 
was negative, CT criteria should be used. 
Stable Disease (SD) is Defined as the Following: 
1. 
A participant is considered to have SD when he or she fails to attain the criteria 
needed for a CR or PR, but does not fulfill those for progressive disease (see 
Relapsed Disease [after CR]/Progressive Disease [after PR, SD]) below. 
2. 
Typically FGD-avid lymphomas: the PET should be positive at prior sites of 
disease with no new areas of involvement on the post- treatment CT or PET. 
3. 
Variably FDG-avid lymphomas/FDG-avidity unknown: if the pretreatment PET 
was negative, there must be no change in the size of the previous lesions on the 
post-treatment CT scan. 
Relapsed Disease (after CR)/Progressive Disease (after PR, SD): 
1. 
Lymph nodes should be considered abnormal if the long axis is more than 1.5 cm 
regardless of the short axis. If a lymph node has a long axis of 1.1 to 1.5 cm, it 
should only be considered abnormal if its short axis is more than 1.0. Lymph nodes 
1.0 x 1.0 cm will not be considered as abnormal for relapse or progressive disease. 
2. 
Appearance of any new lesion more than 1.5 cm in any axis during or at the end of 
therapy, even if other lesions are decreasing in size. Increased FDG uptake in a 
previously unaffected site should only be considered relapsed or progressive 
disease after confirmation with other modalities. In participants with no prior 
history of pulmonary lymphoma, new lung nodules identified by CT are mostly 
benign. Thus, a therapeutic decision should not be made solely on the basis of the 
PET without histologic confirmation. 
3. 
At least a 50% increase from nadir in the SPD of any previously involved nodes, 
or in a single involved node, or the size of other lesions (e.g., splenic or hepatic 
nodules). To be considered progressive disease, a lymph node with a diameter of 
the short axis of less than 1.0 cm must increase by 50% and to a size of 1.5 x 1.5 
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diameter of any single previously identified node more than 1 cm in its short axis. 
Lesions should be PET positive if observed in a typical FDG-avid lymphoma or the 
lesion was PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (< 1.5 cm in its long axis by CT). 
Recurrent Disease is defined as the appearance of tumor following documentation of a 
complete remission. 
Time to Response is defined as time from the first dose of chemotherapy until 
documentation of first response. 
Time to Progression is defined as time from initiation of chemotherapy to documentation 
of first progression. 
Response Duration is defined as the time from first documentation of response to 
documentation of first progression. 
Safety Measures 
All AE will be monitored by ongoing review of reported adverse events by the protocol 
chair and the AMC Operations and Data Management Center, and will be discussed during 
the monthly investigators’ Lymphoma Working Group conference calls (see Section 4.7 
for rules for early study termination). 


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10.0 
CORRELATIVE STUDIES 
For this protocol, we propose three correlative studies: miRNA analysis (see Section 10.2 
and Appendix VIII), Tissue Microarray Studies (TMA) (see Appendix VIII), and 
Pharmacokinetic studies (PK) (see Section 10.1 and Appendix IX). We will collect either 
the paraffin blocks or Cores from these tissue and multiple unstained slides as a 
requirement for study entry to perform the miRNA and the TMA studies in addition to 
central pathology diagnosis confirmation. We will then correlate findings with the 
outcomes of participants enrolled on this trial in addition to their HIV infection 
characteristics. Please see Section 10.1 and Appendix IX for a detailed description of the 
PK studies to be performed in this clinical trial using serum isolated from participants 
during therapy. 
In addition, upon acquisition of funding, we propose 3 more correlative studies. 1) We will 
analyze the Granzyme B to FoxP3 ratio on paraffin sections, to determine if these values, 
which have been reported to be prognostic indicators in non-HIV associated cHL, also 
correlate with outcome in HIV-HL62 (see Appendix VIII). 2) We will also screen 
participant’s plasma for molecules associated with immune activation and inflammation, 
specifically sCD30, CXCL13, IL-6 and IL-10. In a prior study in the AMC, we also 
assessed the effect of treatment for AIDS-associated NHL on plasma levels of these 
biomarkers, finding that treatment resulted in a marked decrease in many of these 
molecules, and that pre-treatment initiation plasma levels of CXCL13, IL-6 and IL-10 were 
predictive of subsequent CR to treatment63,64. In fact, in multivariate analysis, CXCL13 
levels proved to be better predictors of subsequent clinical response that IPI or other 
established prognostic markers63,64. We will confirm if these molecules are prognostic in 
HIV-HL as well as these molecules were also found to be elevated in these participants65,66 
(see Appendix X). 3) As HIV-HL is co-infected with EBV, an attempt will be made to 
detect levels EBV derived tumor DNA in the plasma and use this as a tumor marker and a 
prognostic one. To do these last two studies, we will also collect plasma samples over time 
throughout therapy and post therapy to see how these biomarkers change over time (see 
Appendix XI). 
10.1 
Pharmacokinetic/Immunogenicity Studies 
Chemotherapy-HAART interactions have become more pronounced in the transition from 
single agent HIV therapies to the era of cART as protease inhibitors (PI) and non-
nucleoside reverse transcriptase inhibitors (NNRT) are potent inhibitors (i.e., ritonavir) or 
inducers (i.e., efavirenz) of the cytochrome P450 system, in particular CYP3A4. As 
described in Section 7.1.4, brentuximab vedotin is an ADC whose conjugate MMAE is 
also metabolized via CYP3A4. As pharmacokinetic interactions between HAART and 
brentuximab vedotin are unknown, these interactions will be carefully monitored. Drug 
levels will be determined by assaying brentuximab vedotin, total antibody, and the free 
drug MMAE concentration over time. The formation of anti-brentuximab vedotin 
antibodies will be also assessed at the time points summarized below in Appendix IX. As 
the use of most potent inhibitor of CYP3A4 (i.e., ritonavir) is prohibited in this study, the 
pharmacokinetic data will compare two patient populations, those taking chemotherapy 
with concurrent efavirenz and non-efavirenz-based HAART. The pharmacokinetic data of 
6 participants from each group will be assessed in the phase II portion of the clinical trial, 
once the maximum tolerated dose has been determined. Please see Appendix IX for a 


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detailed description of sample processing, time points that need to be assayed, shipping, 
and the assays involved. 
10.2 
Micro RNA Analysis of HIV-Associated Hodgkin Lymphoma 
Mature microRNAs (miRNAs) are small non-coding RNAs that act as negative regulators 
of protein synthesis by covalently binding to the single stranded mRNA67-71. Once bound, 
the RNA-induced silencing complex (RISC) is formed67-71. Over 800 miRNAs have been 
identified in humans. These miRNAs play important roles in every cell function including 
cell proliferation/differentiation and can act as tumor suppressor and/or oncogenes72,73. 
Viruses also encode miRNA, and interactions between viral and host miRNAs affect host 
protein expression in specific manners to either promote viral replication or, in certain 
instances, cellular transformation1-4. The most common viruses identified to play a role in 
HIV-associated cancer tumorigenesis, HHV-8, HPV, and EBV together express over 40 
miRNAs67,68. Viral miRNAs transform cells by various mechanisms. MiR-BHRF1-1 and 
miR-BART1, EBV expressed miRNAs, inhibit the tumor suppressor p53 and activate 
BCL-2 (an anti-apoptotic protein), respectively67,68. These miRNA combinations found in 
profile analysis are so specific that they define specific cancers as precisely as mRNA gene 
profiling74. Since many of the targets of the miRNAs are known, clues into the mechanisms 
of transformation and potential targets for therapy can be obtained67-70. Unfortunately, little 
data exist on the miRNA profiles on HIV-associated lymphoma, and no data exist on HIV-
HL. It is known that hRS cell, can be co-infected in non-HIV participants, hRS cells are 
co-infected in 30-40% of the cases15,17,18. In HIV-HL the infection rate of the hRS cells 
with EBV range from 80-100%15,17,18. The molecular basis of transformation is unclear. In 
HIV-HL, the lymphocytic depleted histologic subtype of HL is more common than the 
non-HIV or the non-HIV EBV-associated HL. HIV-HL also is the most aggressive form 
of HL, imparting the worst prognosis. MiRNA profiling of HL in non-HIV-infected 
population identified unique molecular signatures so specific that just looking at the 
miRNA profile, a 100% correlation was made as to which tumors were infected with 
EBV75. Which types of EBV miRNA are expressed in HIV-HL vs. non-HIV HL and 
whether HIV effects the expression of different miRNAs in HL have never been assessed. 
Because the clinical course and histology differ from classic HL and EBV-associated 
HL in non-HIV infected individuals, we speculate that HIV-associated Hodgkin 
Lymphoma has a different molecular signature. 
To this end, as a correlative study in this clinical trial, we will analyze the miRNA profiles 
of the paraffin-embedded tumor samples of the study participants. This analysis will be 
performed using high throughput sequencing to comprehensively define the miRNA 
expression, as described previously. As controls, reactive lymph nodes from HIV-infected 
and uninfected participants, as well as non-HIV HL samples that are EBV positive will be 
used. 
We will also correlate miRNA expression with overall survival, tumor response to therapy, 
histologic subtype of HIV-HL, and HIV disease characteristics to identify miRNAs that 
could act as prognostic and diagnostic markers. 
Please see Appendix VIII for a detailed description of specimens required, sample 
processing, and shipping. 
 
 


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10.3 
Effects of AVD-Brentuximab Vedotin on T-cell Subsets in vivo 
Brentuximab vedotin has the potential to destroy all cells that are CD30 positive as seen in 
the HRS cell. Heiser et al. investigated the distribution of CD30 expression across all T-
cell subsets and demonstrated CD30 expression was identified mostly in the T-regulatory 
cells.93 While these cells have many roles, one of their main functions is to suppress CD8 
and CD4+ T-cell proliferation. When CD8+ and FOX-P3+ T-Regulatory cells were co-
incubated in vitro, brentuximab vedotin challenge resulted in a decrease in T-regulatory T-
cell number, and an increase in CD8+ T-cells number.93 Preliminary data from AMC-085 
identified that CD4+ T-cells as well as CD8+ T-cells increased about 1 month after AVD-
BV treatment in nearly all subjects enrolled to date (unpublished data). 
To see if this was a brentuximab vedotin effect, we compared data with 54 patients with 
HIV-associated Hodgkin Lymphoma treated with ABVD alone at County Hospital in 
Chicago (unpublished data). To exclude the possibility that uncontrolled HIV was a cause 
for a drop in the CD4+ T-cell counts in these subjects, patients with undetectable viral 
loads were identified. In this ABVD comparison group, 80% of the subjects had drops in 
CD4+ T-cell counts about 1-2 months post chemotherapy, the opposite of the effect seen 
in AMC 085. Additionally, when CD8+ T-cell counts were analyzed in subjects treated 
with ABVD, 100% had drops in CD8+ T-cell counts. 
The fact that patients with ABVD had drops in CD8 and CD4+ T-cell counts while trial 
participants receiving AVD-BV had elevations suggests brentuximab vedotin is the 
causative agent of the elevation, possibly due to T-regulatory T-cell destruction. The 
hypothesis of this correlative study is that brentuximab vedotin achieves T-regulatory 
T-cells destruction causing CD8 and CD4+ T-cell count elevation The purpose of this 
correlative study is to evaluate whether this is the mechanism seen in vivo in 
participants with HIV-associated cHL. 
To prove this mechanism, we will use cytokine analysis via multiplex, flow cytometry and 
CyTOF (cytometry by time of flight) to confirm which cytokines and T-cell subsets are 
altered over time. Cytokine analyses will be performed on all participants enrolled at Dr. 
Otto Martinez-Maza’s laboratory (AMC Core Biomarkers Laboratory), on existing 
samples for cytokine analysis. The T-cell subset and cytokine assays performed by CyTOF 
and flow cytometry will be performed by Dr. Robert Baiocchi’s laboratory (Ohio State 
University AMC site) for up to 10 participants. The cells required will be aliquots from 
blood samples already collected from participants in the optional HIV viral reservoir 
studies in Appendix XII, who have also consented for the additional use of his/her 
specimens in future research by the ACSR. Please see Appendix XIV for a detailed 
description of sample processing, time points that need to be assayed, shipping, and 
the assays involved. 


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11.0 
STATISTICAL CONSIDERATIONS 
11.1 
Study Design/Endpoints 
This multicenter, Phase I/II open label study will determine the safety and tolerability of 
participants with stage II/IV HIV-associated Hodgkin Lymphoma and evaluate the 
treatment effect of AVD in addition to brentuximab vedotin (SGN-35). The primary 
objective of the Phase I portion of the study is to identify the maximal tolerated doses of 
brentuximab vedotin when combined with the AVD chemotherapy regimen in HIV 
participants with advanced stage Hodgkin lymphoma. The primary objective of the Phase 
II portion of the study is to establish an estimate of the two-year progression-free survival 
for participants using brentuximab vedotin plus AVD regimen with HIV-associated 
advanced stage Hodgkin lymphoma. 
Secondary objectives include: 
1. To evaluate toxicity of AVD and brentuximab vedotin with HAART. 
2. To estimate the partial response (PR) rate, complete response (CR) rate, overall 
survival (OS), event free survival at 2 and 5 years. 
3. To evaluate effect of AVD and brentuximab vedotin on CD4 and CD8 counts after 
cycle 1, 4, at the end of therapy, and every 3 months after treatment completion for 
one year. 
4. To investigate the prognostic value of FDG-PET/CT scans at baseline, after cycle 2, 
and at treatment completion, with respect to 2-year progression free survival. 
5. To evaluate HAART status at baseline and to correlate this with tumor response to 
therapy and OS and PFS. 
6. To characterize the histologic subtypes in HIV-HL in the highly active antiretroviral 
therapy (HAART) era. 
7. To assess the neurotoxicity of HAART in combination with AVD and brentuximab 
vedotin. 
8. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, at 
completion of therapy, and every 3 months after treatment completion for one year. 
9. To perform pharmacokinetic and immunogenicity studies to determine drug levels 
during therapy (see Section 10.0 and Appendix IX). 
10. To perform miRNA profile analysis on the HIV-HL tumor specimens and to correlate 
miRNA expression with OS, PFS, tumor response to therapy, histologic subtype of 
HIV-HL, and HIV disease characteristics (see Section 10.0 and Appendix VIII). 
11. To perform tissue microarray analysis on HIV-HL tumor specimens and to correlate 
the markers studied with OS, PFS, and tumor response to therapy (see Section 10.0 
and Appendix VIII). 
12. To identify EBV associated tumor derived DNA in the plasma of study participants, 
and to correlate these levels during therapy with disease response and OS (see Section 
10.0 and Appendix XI). This objective will only be performed in the Phase II portion 
of the study. 
13. To identify cytokines in the plasma of participants during therapy, that can be used as 
tumor and prognostic markers. (see Section 10.0 and Appendix X). This objective 
will be done only in the Phase II portion of the study. 


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14. To assess latent and expressed HIV reservoirs before, during, and post chemotherapy. 
To understand how cytotoxic chemotherapeutic agents effect HIV expression (see 
Section 10.0 and Appendix XII). 
The Phase I portion of the clinical trial is a de-escalation design evaluating 3 doses of 
brentuximab vedotin (1.2mg/kg, 0.9 mg/kg, and 0.6mg/kg) given every 2 weeks with AVD 
in a 28-day cycle. Three to six participants will be enrolled at dose level 0. If > 1 DLT are 
encountered, an additional three to six participants will be enrolled at the next lowest dose 
level. If no more than 1/6th of the participants at the 0 dose level encounter a DLT, this 
dose (1.2 mg/kg) will be used in the phase II portion. If dose de-escalation is required, we 
will follow the algorithm presented in Table 4-A in Section 4.1.1. 
The primary objective of the Phase I portion of the study is to identify the maximal tolerated 
doses of brentuximab vedotin when combined with the AVD chemotherapy regimen in 
HIV participants with advanced stage Hodgkin lymphoma. No formal statistical hypothesis 
testing is planned for the primary analysis on the Phase I safety parameters; results will be 
presented descriptively. Continuous data will be summarized for each cohort using 
descriptive statistics (N, mean, median, standard deviation, minimum, maximum, 
geometric mean, and percentage coefficient of variation [CV]). Categorical data will be 
summarized for each cohort using frequency tables (frequencies and percents). 
The primary endpoint of the phase II portion will estimate the two-year progression-free 
survival for AVD-brentuximab vedotin which will be done using a one sample 
nonparametric survival analysis. 
11.2 
Sample Size/Accrual Rate 
No formal statistical hypothesis testing is planned for the primary analysis of the Phase I 
portion of the study. In the Phase II portion of the study, 51 participants will be enrolled to 
estimate the 2-year progression free survival. Sample size calculation is based on providing 
an estimate of the PFS with a 95% confidence interval ±10% under the hypothesis that 2-
year PFS is 85%. 
If there are no DLTs in the Phase 1 portion of the study, and if 100% of the Phase 1 
participants are treated identically to those in the Phase 2, data from the Phase 1 and 2 
portions can be combined to complete the phase 2 portion of the study. 
The primary endpoint of the phase II portion will be to estimate the two-year progression-
free survival for AVD-brentuximab vedotin which will be done using Kaplan-Meier 
estimates and corresponding 95% confidence intervals based on standard errors using 
Greenwood’s formula.  
11.3 
Stratification Factors 
No stratification is planned for this study. 
11.4 
Analysis of Secondary Endpoints 
Descriptive summaries and exploratory analyses for secondary objectives will be 
conducted. Significance for comparisons will be at the p<0.05 level. 
Secondary objectives include: 
1. To evaluate toxicity of AVD and brentuximab vedotin with HAART. 


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2. To estimate the partial response rate, complete response rate, overall survival (OS), 
event free survival at 2 and 5 years. To evaluate effect of AVD and brentuximab vedotin 
on CD4 and CD8 counts after 2 cycles, 6 cycles, and every 3 months after treatment 
completion for one year. 
3. To evaluate effect of AVD and brentuximab vedotin on viral load after 2 cycles, 6 
cycles, and every 3 months after treatment completion for one year 
4. To investigate the prognostic value of FDG-PET scans at baseline and after 2 cycles in 
participant with HIV and HL with respect to 2 year progression free survival. 
5. To evaluate HAART status at baseline for difference in outcome. 
6. The characterization of histologic subtypes in HIV-HL in the HAART era. 
7. To assess additional neurotoxicity in combination with HAART and AVD and 
brentuximab vedotin. 
The frequency of AEs and their severity will be tabulated to evaluate tolerance of AVD 
and brentuximab vedotin with HAART. Further, binomial probabilities and their 95% 
confidence intervals will be used to estimate the response rates (i.e., partial response rate, 
complete response rate, overall response rate) and event free survival at 2 and 5 years of 
AVD and brentuximab vedotin for a treatment of participants with stage III/IV HIV-
associated Hodgkin Lymphoma. 
Repeated measures analysis of variance (ANOVA) models will be used to evaluate the 
effect of AVD and brentuximab vedotin on CD4 counts, CD8 counts and viral load after 
1, 4, and 6 cycles, and every 3 months after treatment completion for one year. 
Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans at 
baseline, after 2 cycles and post-therapy in participants with HIV and HL with respect to 
progression free survival. 
After cycle 2 and post-therapy, progression-free survival will be estimated for participants 
whose FDG-PET findings were negative and those whose findings were positive using 
Kaplan-Meier estimates and corresponding 95% confidence intervals based on standard 
errors using Greenwood’s formula. Positive predictive value after 2 cycles and post-
therapy will be estimated as the proportion of PET-positive participants who progress or 
die before two years; negative predictive value after 2 cycles and post-therapy will be 
estimated as the proportion of PET-negative participants who are progression-free and 
alive at two years. Sensitivity of FDG-PET at cycle 2 and post-therapy will be estimated 
as the proportion of participants who progressed or died prior to year 2 whose FDG-PET 
was positive. Specificity of FDG-PET at cycle 2 and post-therapy will be estimated as the 
proportion of participants who are alive and progress-free at 2 years whose FDG-PET was 
positive. Exact two-sided 95% confidence intervals will be used for all estimates. 
Log-rank analysis will be used to evaluate HAART status at baseline for difference in 
outcome in terms of overall survival and progression free survival. The frequency and 
proportion of different histologic subtypes will be calculated. 
The frequency of neurotoxicity in participants taking AVD and brentuximab vedotin in 
combination with/without HAART will be tabulated. A binomial test of proportions will 
be used to test the difference in additional toxicity between those participants taking AVD 


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and brentuximab vedotin on HAART vs. those participants not on HAART. 


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12.0 
ROLE OF DATA MANAGEMENT 
12.1 
CRF Instructions 
Access to the internet data entry system for this study, AdvantageEDCSM, and instructions 
for recording of study data on CRFs will be provided by the AMC ODMC at 
www.AIDScancer.org. Participating institutions are responsible for submitting data and/or 
data forms via AdvantageEDC in accordance with the AMC Data Entry Guide and specific 
form instructions, within the timelines specified by the AMC’s Standards of Procedure for 
Site Performance Measures. 
12.2 
Data Quality 
It is the responsibility of the AMC ODMC to assure the quality of data for the study (see 
Appendix IX, AMC Data and Safety Monitoring Plan). This role extends from protocol 
development to generation of the final study database. 
12.3 
Data Monitoring 
This study will be monitored in compliance with AMC policies and by the Clinical Data 
Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific CDUS 
data will be submitted electronically to CTEP on a quarterly basis. Reports are due January 
31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can 
be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review. 


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13.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
13.1 
Good Clinical Practice 
The study will be conducted in accordance with the International Conference on 
Harmonisation (ICH) for Good Clinical Practice (GCP) and the appropriate regulatory 
requirement(s). The Investigator will be thoroughly familiar with the appropriate use of the 
drug as described in the protocol and Investigator’s Brochure. Essential clinical documents 
will be maintained to demonstrate the validity of the study and the integrity of the data 
collected. Master data files should be established at the beginning of the study, maintained 
for the duration of the study, and retained according to the appropriate regulations. 
13.2 
Ethical Considerations  
The study will be conducted in accordance with ethical principles founded in the 
Declaration of Helsinki (see Appendix VII). The IRB/IEC will review all appropriate study 
documentation in order to safeguard the rights, safety, and well-being of the participants. 
The study will only be conducted at sites where IRB/IEC approval has been obtained. The 
protocol, Investigator’s Brochure, informed consent, advertisements (if applicable), written 
information given to the participants (including diary cards), safety updates, annual 
progress reports, and any revisions to these documents will be provided to the IRB/IEC by 
the Investigator. 
13.3 
IRB Approval and Informed Consent 
The principles of Institutional Review Board (IRB) approval and informed consent 
described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 
56) and/or Department of Health and Human Services (DHHS) regulations for the 
Protection of Human Subjects (45 CFR Part 46) must be followed. IRB approval of the 
protocol and the informed consent form must be given in writing. 
The sponsor’s designee (AMC ODMC) must receive a copy of the letter of approval from 
the IRB, which specifically approves the protocol and informed consent, before participant 
enrollment. The IRB must also approve any significant changes to the protocol and 
documentation of this approval must be sent to the AMC ODMC. The IRB must review 
the research project at least once every 365 days during the duration of the project. 
Continuing approval of the project must also be given in writing and provided to the AMC 
ODMC. 
Records of all study review and approval documents must be kept on file by the 
Investigator and are subject to inspection during or after completion of the study. AEs must 
be reported to the IRB according to local procedures. The IRB should receive notification 
of completion of the study and final report within 3 months of study completion and 
termination. The Investigator will maintain an accurate and complete record of all 
submissions made to the IRB, including a list of all reports and documents submitted. 
Written informed consent will be obtained from the participant. The nature, significance, 
and risks associated with the study must be explained to the participant. The informed 
consent will describe the purpose of the study, the procedures to be followed, the risks and 
benefits of participation, all risks of the investigational agent(s) and/or study participation 
as listed in the model informed consent form, and all other elements of informed consent 


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as required by regulation. A copy of the consent form will be given to the participant to 
keep. 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and national laws and regulations governing the 
confidentiality and disclosure of health information. 
13.4 
Research Authorization  
Each institution should insert the appropriate research authorization sections into the 
informed consent document. 
13.5 
Participant Confidentiality 
In order to maintain participant privacy, all data capture records, drug accountability 
records, participant number. The Investigator will grant monitor(s) and auditor(s) from 
Seattle Genetics, AMC or the NCI and regulatory authorities (FDA) access to the 
participant’s original medical records for verification of data gathered on the data capture 
records and to audit the data collection process. The participant’s confidentiality will be 
maintained and will not be made publicly available to the extent permitted by the applicable 
laws and regulations. 
13.6 
Protocol Compliance 
The Investigator will conduct the study in compliance with the protocol given 
approval/favorable opinion by the IRB/IEC and the appropriate regulatory authorities. 
Changes to the protocol will require approval from CTEP and written IRB/IEC 
approval/favorable opinion prior to implementation, except when the modification is 
needed to eliminate an immediate hazard(s) to participants. The IRB/IEC may provide, if 
applicable regulatory authorities permit, expedited review and approval/favorable opinion 
for minor change(s) in ongoing studies that have the approval /favorable opinion of the 
IRB/IEC. The Investigator will submit all protocol modifications to Seattle Genetics and 
the regulatory authorities in accordance with the governing regulations. 
Any departures from the protocol must be fully documented in the source documents. 
13.7 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by CTEP and the Investigator before implementation. All amendments require 
approval by the IRB/IEC of the treating institution. A copy of the written approval of the 
IRB/IEC must be sent to the ODMC. 
13.8 
On-site Audits 
Regulatory authorities, the IEC/IRB, the AMC ODMC, and/or Seattle Genetics clinical 
quality assurance group may request access to all source documents, data capture records, 
and other study documentation for on-site audit or inspection. Direct access to these 
documents must be guaranteed by the investigator, who must provide support at all times 
for these activities. 
 
 


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13.9 
Women and Minorities 
This study is being conducted by the NCI-sponsored AIDS Malignancy Clinical Trials 
Consortium (AMC). As part of their contractual obligations, each participating site within 
the AMC and the AMC as a whole is required to assure that the participation of women 
and minority participants reflects the percentage representation of these populations in their 
geographic region and, for the AMC, the United States as a whole. As such, it is expected 
that the representation of participants on this trial will reflect the constitution of the 
respective populations. 
Table 13-A:  Accrual Targets 
Ethnic Category 
Sex/Gender 
Females 
 
Males 
 
Total 
Hispanic or Latino 
1 
+ 
2 
= 
3 
Not Hispanic or Latino 
3 
+ 
45 
= 
48 
Ethnic Category: Total of all 
participants 
4 
+ 
47 
= 
51 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
1 
+ 
1 
= 
2 
Black or African American 
1 
+ 
10 
= 
11 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
1 
= 
1 
White 
2 
+ 
35 
= 
37 
Racial Category: Total of all 
participants 
4 
+ 
47 
= 
51 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 


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14.0 
REFERENCES 
1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues (ed. 4th). Lyon, France: IARC Press; 2008. 
2. Hodgkin T (1832). On some morbid experiences of the absorbent glands and spleen. Med 
Chir Trans 17: 69–97. 
3. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008: 57; 43-66. 
4. Kuppers R, Rajewsky K, Zhao M et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells 
picked from histological sections show clonal immunoglobulin gene rearrangements and 
appear to be derived from B cells at various stages of development. Proc Natl Acad Sci 
USA 1994; 91:10962. 
5. Hummel M, Ziemann K, Lammert H et al. Hodgkin’s disease with monoclonal and 
polyclonal populations of Reed-Sternberg cells. N Engl J Med 1995; 333:901. 
6. Kanzler H, Küppers R, Hansmann M-L et al. Hodgkin and Reed-Sternberg cells in 
Hodgkin’s disease represent the outgrowth of a dominant tumor clone derived from 
(crippled) germinal center B cells. J Exp Med 1996; 184:1495 
7. Marafioti T, Hummel M, Anagnostopoulos I et al. Origen of nodular lymphocyte-
predominant Hodgkin’s disease from a clonal expansion of highly mutated germinal- 
center B cells. N Engl J Med 1997; 337:459. 
8. Carbone A, Gloghini A, Gaidano G et al. Expression status of BCL-6 and syndecan-1 
identifies distinct histogenetic subtypes of Hodgkin’s disease. Blood 1998; 92:2220. 
9. Shiels MS, Pfeiffer RM, Gail MH et al. Cancer burden in the HIV-infected population in the 
United States. J Natl Cancer Inst. 2011; 103(9):753-62. 
10. Patel, P., D. L. Hanson, et al. Incidence of types of cancer among HIV-infected persons 
compared with the general population in the United States, 1992-2003. Ann Intern Med 
2008; 148: 728-36. 
11. Levine A. HIV-associated Hodgkin’s disease. Hematol Oncol Clin North Am 1996; 10; 
1135-48. 
12. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 2002; 
99:4283-4297. 
13. Levine AM. Hodgkin lymphoma: to the HAART of the matter. Blood 2006; 108; 3630. 
14. Biggar RJ, Jaffe ES, Goedert JJ et al. Hodgkin lymphoma and immunodeficiency in persons 
with HIV/AIDS. Blood 2006; 108: 3786-91. 
15. Spina M, Carbone A, Gloghini A, Serraino D, Berretta M, Tirelli U. Hodgkin's Disease in 
Patients with HIV Infection. Adv Hematol. 2011;!doi:10.1155/2011/402682. 
16. 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 
1998; 19:1506-14. 
17. Ambinder RF. Epstein-Barr virus and Hodgkin lymphoma. Hematology Am Soc Hematol 
Educ Program. 2007:204-9. 
18. Keegan TH, Glaser SL, and Clarke CA et al. Epstein-Barr virus as a marker of survival after 
Hodgkin's lymphoma: a population-based study. J Clin Oncol. 2005; 23: 7604-1. 
19. Carbone A, Gloghini A, Larocca LM et al. Human immunodeficiency virus-associated 
Hodgkin's disease derives from post-germinal center B cells. Blood. 1999; 93: 2319-26. 


AMC-085 (Version 19.0) 15APR2019 
 
83 
NCI Version Date 15APR2019 
20. Powles T and Bower M. HIV-associated Hodgkin’s Disease. Int J STD AIDS 2000; 11, 492-
4. 
21. Gerard L, Galicier L, Boulanger E, et.al Improved survival in HIV-related Hodgkin's 
lymphoma since the introduction of highly active antiretroviral therapy. AIDS. 2003 Jan 
3; 17(1):81-7. 
22. Hentrich M, Maretta L, Chow KU et al. Highly active antiretroviral therapy (HAART) 
improves survival in HIV-associated Hodgkin's disease: results of a multicenter study. 
Ann Oncol. 2006; 17: 914-9. 
23. Spina M, Gabarre J, Rossi G et al. Stanford V regimen and concomitant HAART in 59 
patients with Hodgkin disease and HIV infection. Blood. 2002; 100:1984-8. 
24. Xicoy B, Ribera JM et al. Results of treatment with doxorubicin, bleomycin, vinblastine and 
dacarbazine and highly active antiretroviral therapy in advanced stage, human 
immunodeficiency virus- related Hodgkin’s Lymphoma. Haematologica 2007; 92: 191-
198. 
25. Spina M, Rossi G, Antinori A et al. VEBEP regimen and highly active antiretroviral therapy 
(HAART) in patients with HD and HIV Infection (HD-HIV). Blood 2005; 106:100a. 
26. Hartmann P, Rehwald U, Salzberger B et al. BEACOPP therapeutic regimen for patients with 
Hodgkin's disease and HIV infection. Ann Oncol. 2003; 14:1562-9. 
27. Levine A M, Li P, et al. Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, 
and dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with 
newly diagnosed Hodgkin's disease: a prospective, multi-institutional AIDS clinical trials 
group study (ACTG 149). J Acquir Immune Defic Syndr. 2000; 24(5): 444-50. 
28. Errante D, Gabarre J, Ridolfo AL et al. Hodgkin's disease in 35 patients with HIV infection: 
an experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in 
combination with antiretroviral therapy and primary use of G-CSF. Ann Oncol. 1999; 
10:189-95. 
29. Errante D, Tirelli U, Gastaldi R et al. Combined antineoplastic and antiretroviral therapy for 
patients with Hodgkin’s disease and human immunodeficiency virus infection: a 
prospective study of 17 patients. Cancer 1994; 73: 437-444. 
30. Gastaldi R, Martino P, Gentile G et al. Hodgkin's disease in HIV-infected patients: report of 
eight cases usefully treated with doxorubicin, bleomycin, vinblastine and dacarbazine 
(ABVD) plus granulocyte colony-stimulating factor. Ann. of Oncol 2002; 13: 1158-1160. 
31. Tirelli U. Errante D, Vaccher E et al. Hodgkin's disease in 92 patients with HIV infection: 
The Italian experience. Ann Oncol 1992; 3: S69-72. 
32. Andrieu JM, Roithmann S, Tourani JM et al. Hodgkin's disease during HIV-I infection: The 
French registry experience. Ann Oncol 1993; 4: 635-41. 
33. Berenguer J, Miralles P et al. Characteristics and outcome of AIDS-related Hodgkin 
lymphoma before and after the introduction of highly active antiretroviral therapy. J 
Acquir Immune Defic Syndr 2008; 47: 422-8. 
34. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30–monomethyl 
auristatin E conjugate with potent and selective antitumor activity. Blood 2003; 102: 
1458-1465. 
35. Wahl AF, Klussman K, Thompson JD, Chen JH, Francisco LV, Risdon G, Chace DF, Siegall 
CB and Francisco JA (2002). The anti-CD30 monoclonal antibody SGN-30 promotes 


AMC-085 (Version 19.0) 15APR2019 
 
84 
NCI Version Date 15APR2019 
growth arrest and DNA fragmentation in vitro and affects antitumor activity in models of 
Hodgkin's disease. Cancer Res 62: 3736-42. 
36. Younes A, Forero-Torres A, Bartlett NL, et al. Multiple complete responses in a phase 1 
dose-escalation study of the antibody-drug conjugate SGN-35 in patients with relapsed or 
refractory CD30-positive lymphomas. Blood (ASH Annual Meeting Abstracts) 2008. 
112:1006. 
37. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed 
CD30-positive lymphomas. N Engl J Med. 2010; 363: 1812-21 
38. Chen, Gopal A, Smith SE, Ansell SM, Rosenblatt JD, Klasa R, Connors JM, Engert A, 
Larsen EK, Kennedy D, Sievers E and Younes A. Results of a Pivotal Phase 2 Study of 
brentuximab Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin 
Lymphoma Blood (ASH Annual Meeting Abstracts) 2010 116: Abstract 283. 
39. Advani RH, Shustov AR, Brice P, et al. Brentuximab Vedotin (SGN-35) in Patients with 
Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study 
Update. American Society of Hematology 2011. Abstract 443. 
40. Forero-Torres A, Berryman RB, Advani RH et al. Prolonged Treatment with brentuximab 
Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or 
Systemic Anaplastic Large Cell Lymphoma (sALCL). American Society of Hematology 
2011. Abstract 3711. 
41. Younes A, Connors J, Park S, et al. Frontline Therapy with brentuximab Vedotin Combined 
with ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin 
Lymphoma. American Society of Hematology 2011. Abstract 955. 
42. Hoskin PJ, Lowry L, Horwich A, et al. Randomized Comparison of the Stanford V Regimen 
and ABVD in the Treatment of Advanced Hodgkin’s Lymphoma: United Kingdom 
National Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin 
Oncol. 2011 Nov 10; 29(32):4227-33. 
43. Ngeow J, Tan IB, Kanesvaran R, Tan HC, Tao M, Quek R, Lim ST. Prognostic impact of 
bleomycin-induced pneumonitis on the outcome of Hodgkin's lymphoma. Ann Hematol. 
2011 Jan; 90(1):67-72. 
44. Pizzolo G, Vinante F, Morosato L, Nadali G, Chilosi M, Gandini, G, Sinicco A, Raiteri R, 
Semenzato G, Stein H, and Perona G. High serum level of the soluble form of CD30 
molecule in the early phase of HIV-1 infection as an independent predictor of progression 
to AIDS. AIDS 1994. 8: 741–745. 
45. Rizzardi GP, Barcellini W, Tambussi G, Lillo F, Malnati M, Perrin L, and Lazzarin A. 
Plasma levels of soluble CD30, tumour necrosis factor (TNF)- § and TNF receptors 
during primary HIV-1 infection: correlation with HIV-1 RNA and the clinical outcome. 
AIDS 1996. 10:45-50. 
46. Pizzolo, G., Vinante, F., Nadali, G., Krampera, M., Morosato, L., Chilosi, M., Raiteri, R. and 
Sinicco, A., High serum level of soluble CD30 in acute primary HIV-1 infection. Clin. 
Exp. Immunol. 1997. 108: 251–253. 
47. Maggi E, Annunziato F, Biagiotti R, Giudizi MG, Ravina A, Almerigogna F, Boiani N, 
Alderson M, Romagnani S. Activation of HIV expression by CD30 triggering in CD4 + 
T cells from HIV infected individuals. Immunity 1995; 3:251–255. 


AMC-085 (Version 19.0) 15APR2019 
 
85 
NCI Version Date 15APR2019 
48. Brew BJ, Davies NW, Cinque P, Clifford DB and Nath A. Progressive multifocal 
leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010; 6: 667-
79. 
49. Koralnik IJ, Schellingerhout D, Frosch MP. Case records of the Massachusetts General 
Hospital. Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with 
progressive neurologic deficits. N Engl J Med. 2004; 350(18):1882. 
50. Cinque P, Koralnik IJ, Gerevini S, Miro JM, and Price RW. Progressive multifocal 
leukoencephalopathy in HIV-1 infection. Lancet Infect Dis. 2009 Oct; 9(10):625-36. 
51. Engsig FN, Hansen AB, Omland LH et al. Incidence, clinical presentation, and outcome of 
progressive multifocal leukoencephalopathy in HIV-infected patients during the highly 
active antiretroviral therapy era: a nationwide cohort study. J Infect Dis. 2009; 199(1):77. 
52. Khanna N, Elzi L, Mueller NJ et al. Incidence and outcome of progressive multifocal 
leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis. 2009 
May 15; 48(10):1459-66. 
53. Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 
therapies. Annu Rev Med. 2010; 61:35-47. 
54. FDA Drug Safety Communication, New Boxed Warning and Contraindication for Adcetris 
(brentuximab vedotin) 1/13/2012. 
http://www.fda.gov/Drugs/DrugSafety/ucm287668.htm. 
55. Antoniou T and Tseng AL. Interactions Between Antiretrovirals and Antineoplastic Drugs. 
Clin Pharmacokinet 2005; 44: 111-145. 
56. Rubinstein PG, Braik T, Jain S et al. Ritonavir Based Highly Active Antiretroviral Therapy 
(HAART) Correlates with Early Neurotoxicity When Combined with ABVD Treated 
HIV Associated Hodgkin Lymphoma but Not Non-Hodgkin Lymphoma. A Retrospective 
Study. American Society of Hematology 2010. Abstract # 2807. 
57. Sandu S, Gupta S, Itokazu G et al. Suspension of Ritonavir and Zidovudine Prevents Adverse 
Events During the Treatment of HIV Associated Hodgkin Lymphoma. ASCO 2012, 
abstract #8085. 
58. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose 
positron emission tomography is prognostically superior to international prognostic score 
in advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J. 
Clin. Oncol. 25:3746-52, 2007. 
59. Hutchings M, Loft A, Hansen M, et. al. FDG-PET after two cycles of chemotherapy predicts 
treatment failure and progression-free survival in Hodgkin lymphoma Blood, 1 January 
2006, Vol. 107, No. 1, pp. 52-59. 
60. Wedgwood A.R, Fanale A, Fayad L.E, et al. Rituximab + ABVD Improves Event-Free 
Survival (EFS) in Patients with Classical Hodgkin Lymphoma in All International 
Prognostic Score (IPS) Groups and in Patients Who Have PET Positive Disease after 2–3 
Cycles of Therapy. Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 215. 
61. Brust D, Polis M, Davey R, et al. Fluorodeoxyglucose imaging in healthy subjects with HIV 
infection: impact of disease stage and therapy on pattern of nodal activation. AIDS 2006, 
Vol 20 No 7. 
 
 


AMC-085 (Version 19.0) 15APR2019 
 
86 
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62. Kelley T, Pohlman B, Elson P, et al. The ratio of FOXP3+ regulatory T cells to granzyme B+ 
cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is 
independent of bcl-2 and MAL expression. Am J Clin Pathol 128:958-65, 2007. 
63. Epeldegui M, Lee JY, Martinez AC, Widney DP, Magpantay L, Regidor D, Mitsuyasu R, 
Sparano JA, Ambinder RF and Martίnez-Maza O. Serum levels of several molecules 
associated with B cell activation and inflammation are elevated in AIDS-NHL and 
predict response to treatment. In preparation. 
64. Epeldegui, M. D. P. Widney, A. C. Martínez, D. Regidor, L. Magpantay, R. Mitsuyasu, J. A. 
Sparano, J. Y. Lee, R. F. Ambinder, O. Martínez-Maza. 2011. Serum levels of several 
molecules that are associated with B cell activation and inflammation are elevated in 
AIDS-associated non-Hodgkin’s lymphoma (AIDS-NHL) and predict response to 
treatment. International Conference on Malignancies in AIDS and Opportunistic 
Infections (ICAMOI). Abstract. Bethesda, MD. 
65. Levin, L., E. C. Breen, B. Birmann, J. J. Kasperzyk, L. Magpantay, R. F. Ambinder, N. 
Mueller and O. Martίnez-Maza. Elevated serum levels of soluble CD30, IL-6 and IL-10 
precede the diagnosis of Hodgkin lymphoma. In preparation. 
66. Levin, L., E. C. Breen, C. Kitchen, D. Widney, B. Kim B, A. Marrogi, R. Krampf, L. 
Magpantay, and O. Martínez-Maza. 2010. Elevated Serum Levels of CXCL13 Precede 
the Diagnosis of B Cell Non Hodgkin Lymphoma (NHL). AACR Special Conference on 
The Future of Molecular Epidemiology: New Tools, Biomarkers, and Opportunities. 
Abstract. Miami, FL. 
67. Yeung ML, Bennasser Y, LE SY, Jeang KT. siRNA, miRNA and HIV: promises and 
challenges. Cell Res. 2005; 15(11-12):935-46. 
68. Qi P, Han JX, Lu YQ, Wang C, Bu FF. Virus-encoded microRNAs: future therapeutic 
targets? Cell Mol Immunol. 2006; 3(6):411-9. 
69. Visone R, Croce CM. MiRNAs and Cancer. Am J Pathol. 2009; 174(4):1131-8. 
70. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136 (2): 215–
33. 
71. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (2): 
281–97. 
72. Bentwich I, Avniel A, Karov Y et al. Identification of hundreds of conserved and 
nonconserved human microRNAs. Nat. Genet. 2005; 37 (7): 766–70. 
73. Homo sapiens miRNAs in the miRBase at Manchester University. 
74. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. 
Nature 2005; 435:834-838. 
75. Navarro A, Gaya A, and Martinez A et. al. MicroRNA expression profiling in classic 
Hodgkin lymphoma. Blood 2008; 111: 2825-2832 
76. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep; 50(3):1-36. 
77. 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. 
78. 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. 
 
 


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87 
NCI Version Date 15APR2019 
79. Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, Canellos GP and 
Peterson BA. Randomized comparison of ABVD and MOPP/ABV hybrid for the 
treatment of advanced Hodgkin's disease. Report of an intergroup trial. J Clin Oncol; 
2003 21: 607-14. 
80. Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE and Ansell SM. Bleomycin 
pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's 
lymphoma. J Clin Oncol; 2005 23: 7614-20. 
81. Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW, Smith P, Qian W, Patrick 
P, Popova B, Pettiti A, Cunningham D, Pettengell R, Sweetenham J, Linch D and 
Johnson PW. Randomized comparison of the Stanford V regimen and ABVD in the 
treatment of advanced Hodgkin’s Lymphoma: United Kingdom National Cancer 
Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol 2009; 27: 
5390-6. 
82. Glaser, S.L., et al., Population-based patterns of human immunodeficiency virus-related 
Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998. Cancer, 2003. 
98(2): p. 300-9. 
83. Keegan, T.H., et al., Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a 
population-based study. J Clin Oncol, 2005. 23(30): p. 7604-13. 
84. Hohaus, S., et al., The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood 
predicts for biological and clinical characteristics in Hodgkin lymphoma. Clinical Cancer 
Research: an official journal of the American Association for Cancer Research, 2011. 
17(9): p. 2885-92. 
85. Gandhi, M.K., et al., Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive 
Hodgkin's lymphoma. Clinical cancer research: an official journal of the American 
Association for Cancer Research, 2006. 12(2): p. 460-4. 
86. Kanakry, J.A., Plasma viral DNA as a marker of tumor response in EBV(+) Hodgkin 
lymphoma in a phase III study (E2496). Journal of clinical oncology, 2012. 30. 
87. Chan, K.C., et al., Molecular characterization of circulating EBV DNA in the plasma of 
nasopharyngeal carcinoma and lymphoma patients. Cancer research, 2003. 63(9): p. 
2028-32. 
88. Lin, L., et al., Effects of chemotherapy in AIDS-associated non-Hodgkin's lymphoma on 
Kaposi's sarcoma herpesvirus DNA in blood. J Clin Oncol, 2009. 27(15): p. 2496-502. 
89. Shamay, M., et al., CpG methylation as a tool to characterize cell-free Kaposi sarcoma 
herpesvirus DNA. J Infect Dis, 2012. 205(7): p. 1095-9. 
90. Kasamon, Y.L., et al., Multicenter phase II study of rituximab-ABVD in classic Hodgkin 
lymphoma (cHL). ASCO Meeting Abstracts, 2011. 29(15_suppl): p. 8039. 
91. Meignan M, Barrington S, Itti E, Gallamini A, Haioun C, Polliack A. Report on the 4th 
International Workshop on Positron Emission Tomography in Lymphoma held in 
Menton, France, 3-5 October 2012. Leuk Lymphoma. 2013 Jun 14. [Epub ahead of print] 
92. Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First 
International Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009 
Aug; 50(8):1257-60. 


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93. Heiser RA, Grogan BM, Manlove LS, Gardai SJ. Abstract 1789: CD30+T regulatory cells, 
but not CD30+CD8 T cells, are impaired following brentuximab vedotin treatment in 
vitro and in vivo. Cancer Res July 1 2018 (78) (13 Supplement) 1789. 
 


 
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APPENDIX I: SCHEDULE OF EVALUATIONS 
Evaluations 
Eligibility 
(Baseline)a 
Cycle 1-6 
Day 1 
Cycle 1-6 
Day 15 
Cycle 2 
Day 1 
Cycle 2 
Day 22-28 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
Cycle 5 
Day 1 
Post- 
Treatment 
Early Treatment 
Discontinuationj 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
ACSR consent and donation (optional) 
X 
 
 
 
 
 
 
 
 
 
Medical history and physical 
examination 
X 
Xg 
 
 
 
 
 
 
Xb 
X 
FDG-PET/CT or FDG-PET + CT 
Xo 
 
 
 
X 
 
 
 
Xr 
 
CT scan with oral/IV contrast 
Xn 
 
 
 
 
 
 
 
Xi 
 
MRI of brain with and without IV 
gadolinium contrast 
X 
 
 
 
 
 
 
 
 
 
MUGA or echocardiogram 
X 
 
 
 
 
 
 
 
 
 
FACT-GOG-neurotoxicity questionnaire 
 
Xg 
 
 
 
 
 
 
 
 
Bone marrow biopsy 
Xc 
 
 
 
 
 
 
 
Xd 
 
Central pathology review 
X 
 
 
 
 
 
 
 
 
 
Paraffin Cores for miRNA and Tissue 
Microarray Analysis 
X 
 
 
 
 
 
 
 
 
 
CBC with diff 
Xe 
Xh 
Xh 
 
 
 
 
 
Xb 
X 
Sedimentation rate 
Xe 
 
 
 
 
 
 
 
 
 
Serum chemistries: electrolytes (Na, K, 
Cl, bicarbonate, Ca, Mg, phosphorus), 
glucose, BUN, creatinine, total bilirubin, 
alkaline phosphatase (ALP), LDH, total 
protein, albumin, AST and ALT 
Xe 
Xg 
Xg 
 
 
 
 
 
Xb 
X 
CD4/CD8 cell count 
X 
 
 
Xg 
 
 
 
Xg 
Xq 
Xk 
HIV-1 RNA viral load 
Xp 
 
 
Xg 
 
 
 
Xg 
Xq 
Xk 
Hepatitis C antibody, Hepatitis B core 
antibody, Hepatitis B surface antigen 
(HBsAg), and Hepatitis B surface 
antibody 
X 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test 
Xf 
 
 
 
 
 
 
 
 
 


 
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Evaluations 
Eligibility 
(Baseline)a 
Cycle 1-6 
Day 1 
Cycle 1-6 
Day 15 
Cycle 2 
Day 1 
Cycle 2 
Day 22-28 
Cycle 3 
Day 1 
Cycle 4 
Day 1 
Cycle 5 
Day 1 
Post- 
Treatment 
Early Treatment 
Discontinuationj 
Pharmacokinetic studies (select Phase II 
participants only) 
 
Xl 
Xl 
 
 
 
 
 
Xl 
Xl 
EBV/Immunogenicity Studies (Phase II 
only) 
Xm 
Xm 
 
 
 
 
 
 
Xm 
Xm 
HIV Reservoir Studies 
Xs 
 
 
 
 
Xt 
 
 
Xu 
Xk 
Cytokine and T-cell Subset StudiesV 
X 
 
 
X 
 
 
X 
 
X 
X 
 
A. Screening to be completed within 6 weeks prior to participant registration unless otherwise specified. 
B.  Post-treatment evaluation to occur within 6-8 weeks of the last treatment dose and then every 3 months thereafter (+/- 7 days) for 2 years; every 6 (+/- 7 days) months 
for the third through fifth years unless otherwise specified. 
C.  Does not have to be repeated if bone marrow involvement by lymphoma already documented after bone marrow biopsy more than 6 weeks prior to registration. 
D.  Only need to perform to confirm CR is positive at baseline (only once, within 8 weeks of last treatment dose).  
E.  Must be completed within 2 weeks prior to participant registration. 
F.  To be performed within 7 days prior to Cycle 1, Day 1. 
G.  To be performed within 48 hours prior to or on first day of each cycle, where required for a given visit. 
H.  To be performed within 48 hours of day 1 and 15 of every cycle. Results must be known prior to treatment. 
I.  Every 6 months after end of treatment for 5 years, to begin 6 months from the post treatment FDG-PET/CT scan, obtained 6-8 weeks post the final chemotherapy 
dose 
J.  To be performed within 1 month after treatment discontinuation. 
K.  Do not repeat if done within 1 month from removal from treatment. 
L.  In select Phase II participants only. See Section 10.1 and Appendix IX for details on time points and sample processing. 
M.  In Phase II participants only. After study entry, samples will be collected at the end of Cycles 1 and 3, treatment discontinuation, and at 3, 6, and 12 months post 
treatment discontinuation. See Section 10.1 and Appendix XI for details on time points and sample processing. 
N.  To be done if the CT portion of the PET/CT is without contrast. 
O.  To be performed no more than 28 days before enrollment. 
P.  To be performed within 21 days prior to Cycle 1, Day 1. 
Q.  To be performed at 6-8 weeks following protocol therapy completion and every 3 months thereafter for one year. 
R.  To be done once at the completion of the study, at the 6-8 week follow up after the final treatment dose at Cycle 6 Day 15. 
S.  To be done, 1 week before cycle 1 day 1 (+/- 3 days) and again 24 hours prior or on the day of cycle 1 day 1. Only for participants who are found to have undetectable 
plasma HIV-1 RNA by the standard assay performed at the clinical site within 21 days of C1 Day 1. 
T.  To be done, 48 hours prior to or on the first day of Cycle 3 and /or at the Early Treatment Discontinuation Visit if indicated. 
U. To be done within 6-8 weeks following the last cycle and at the 12 months follow up visit. 
V. Cytokine studies required of all participants (Appendix X). T-cell subsets required for consented participants per Appendix XIV (no additional samples collected 
beyond those required for HIV viral reservoirs per Appendix XII). 
 


 
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APPENDIX II: COLLABORATIVE RESEARCH AGREEMENT 
The agent, brentuximab vedotin, supplied by CTEP, DCTD, NCI used in this protocol is/are 
provided to the NCI under a Collaborative Agreement (CRADA, CTA, CSA) between Seattle 
Genetics (hereinafter referred to as “Collaborator(s)”) and the NCI Division of Cancer Treatment 
and Diagnosis. Therefore, the following obligations/guidelines, in addition to the provisions in the 
“Intellectual Property Option to Collaborator” 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm) contained within the 
terms of award, apply to the use of the Agent(s) in this study: 
1. Agent(s) may not be used for any purpose outside the scope of this protocol, nor can Agent(s) 
be transferred or licensed to any party not participating in the clinical study. Collaborator(s) 
data for Agent(s) are confidential and proprietary to Collaborator(s) and shall be maintained 
as such by the investigators. The protocol documents for studies utilizing Agents contain 
confidential information and should not be shared or distributed without the permission of the 
NCI. If a copy of this protocol is requested by a participant or participant’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. 
2. For a clinical protocol where there is an investigational Agent used in combination with 
(an)other Agent(s), each the subject of different Collaborative Agreements, the access to and 
use of data by each Collaborator shall be as follows (data pertaining to such combination use 
shall hereinafter be referred to as "Multi-Party Data”): 
a. NCI will provide all Collaborators with prior written notice regarding the existence and 
nature of any agreements governing their collaboration with NCI, the design of the 
proposed combination protocol, and the existence of any obligations that would tend to 
restrict NCI's participation in the proposed combination protocol. 
b. Each Collaborator shall agree to permit use of the Multi-Party Data from the clinical trial 
by any other Collaborator solely to the extent necessary to allow said other Collaborator to 
develop, obtain regulatory approval or commercialize its own Agent. 
c. Any Collaborator having the right to use the Multi-Party Data from these trials must agree 
in writing prior to the commencement of the trials that it will use the Multi-Party Data 
solely for development, regulatory approval, and commercialization of its own Agent. 
3. Clinical Trial Data and Results and Raw Data developed under a Collaborative Agreement will 
be made available to Collaborator(s), the NCI, and the FDA, as appropriate and unless 
additional disclosure is required by law or court order as described in the IP Option to 
Collaborator 
(http://ctep.cancer.gov/industryCollaborations2/intellectual_property.htm). 
Additionally, all Clinical Data and Results and Raw Data will be collected, used and disclosed 
consistent with all applicable federal statutes and regulations for the protection of human 
subjects, including, if applicable, the Standards for Privacy of Individually Identifiable Health 
Information set forth in 45 C.F.R. Part 164. 
4. When a Collaborator wishes to initiate a data request, the request should first be sent to the 
NCI, who will then notify the appropriate investigators (Group Chair for Cooperative Group 
studies, or PI for other studies) of Collaborator's wish to contact them. 


 
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5. Any data provided to Collaborator(s) for Phase 3 studies must be in accordance with the 
guidelines and policies of the responsible Data Monitoring Committee (DMC), if there is a 
DMC for this clinical trial. 
6. Any manuscripts reporting the results of this clinical trial must be provided to CTEP by the 
Group office for Cooperative Group studies or by the principal investigator for non-
Cooperative Group studies for immediate delivery to Collaborator(s) for advisory review and 
comment prior to submission for publication. Collaborator(s) will have 30 days from the date 
of receipt for review. Collaborator shall have the right to request that publication be delayed 
for up to an additional 30 days in order to ensure that Collaborator’s confidential and 
proprietary data, in addition to Collaborator(s)’s intellectual property rights, are protected. 
Copies of abstracts must be provided to CTEP for forwarding to Collaborator(s) for courtesy 
review as soon as possible and preferably at least three (3) days prior to submission, but in any 
case, prior to presentation at the meeting or publication in the proceedings. Press releases and 
other media presentations must also be forwarded to CTEP prior to release. Copies of any 
manuscript, abstract and/or press release/ media presentation should be sent to: 
Email: ncicteppubs@mail.nih.gov 
The Regulatory Affairs Branch will then distribute them to Collaborator(s). No publication, 
manuscript or other form of public disclosure shall contain any of Collaborator’s confidential/ 
proprietary information. 


 
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APPENDIX III: PERFORMANCE STATUS SCALES 
 
Karnofsky Performance Scale 
 
 
ECOG Performance Status Scale 
Percent 
Description 
Grade 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary nature (e.g., light 
housework, office work). 
70 
Cares for self, unable to carry on 
normal activity or to do active 
work. 
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
2 
In bed <50% of the time. 
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities. Up and about more 
than 50% of waking hours. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special care and 
assistance. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
5 
Dead. 
 


 
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APPENDIX IV: FACT-GOG-NEUROTOXICITY QUESTIONNAIRE V4.0 
By circling one (1) number per line, please indicate 
how true each statement has been for you during the 
past 7 days. 
ADDITIONAL CONCERNS 
Not at 
all 
A little 
bit 
Some- 
what 
Quite a 
bit 
Very 
much 
I have numbness or tingling in my hands………  
0 
1 
2 
3 
4 
I have numbness or tingling in my feet…………  
0 
1 
2 
3 
4 
I feel discomfort in my hands………………….  
0 
1 
2 
3 
4 
I feel discomfort in my feet……………………  
0 
1 
2 
3 
4 
I have joint pain or muscle cramps……………  
0 
1 
2 
3 
4 
I feel weak all over……………………………  
0 
1 
2 
3 
4 
I have trouble hearing…………………………  
0 
1 
2 
3 
4 
I get a ringing or buzzing in my ears…………  
0 
1 
2 
3 
4 
I have trouble buttoning buttons………………  
0 
1 
2 
3 
4 
I have trouble feeling the shape of small objects 
when they are in my hand………………………  
0 
1 
2 
3 
4 
I have trouble walking…………………………  
0 
1 
2 
3 
4 
 
 


 
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APPENDIX V: AIDS AND CANCER SPECIMEN RESOURCE (ACSR) DONATION 
SPECIMEN PREPARATION AND SHIPPING INSTRUCTIONS 
A. 
GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an OVERNIGHT 
PRIORITY shipment. Specimens are NOT ACCEPTED ON SATURDAYS, OR 
SUNDAYS in the GWU/ACSR Lab. When sending to the ACSR, please be certain to 
create a shipment, assign specimens, and send the shipment in Global Trace prior to 
shipping the specimens to the ACSR. Include the FedEx Tracking number in Global Trace 
shipment information. 
B. 
SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
Blood Specimens 
Draw two 8.5 cc (mL) yellow top [acid citrate dextrose (ACD) solution A] tubes from 
study participant. With a black, water resistant, sharpie pen, label each specimen with the 
following information: 
• AMC Protocol #  
• AMC Participant ID#  
• Date and time of collection  
• Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum, or Tissue 
• Specimen purpose: Donation 
Specimen Shipment 
1. Seal the tops of the two 8.5 cc yellow tops with parafilm. 
2. Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
3. Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. 
4. Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal.” 
5. Place poly-bag containing tubes into the white TYVEK bag and seal. 
6. Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Include a 
shipment manifest form Global Trace. Then seal the cardboard shipper with clear 
packing/shipping tape. 
7. Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT.” 


 
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8. Mark “OTHER” in the airbill under “Packaging.” Please use the FedEx number 
provided on the AMC members’ only website. 
9. Under airbill section “Special Handling,” indicate “YES-SHIPPERS 
DECLARATION NOT REQUIRED.” 
10. Place “From/To” information onto areas provided on the shipper. 
Blood specimens should be shipped by overnight express at room temperature to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
11. Make certain that shipper is already either pre-labeled with the “UN#3373” stamp, or 
make a paper label with “UN#3373” and affix it to the shipper. 
12. Make certain that the net volume of the specimen being shipped is written in the 
space provided on the shipper or make a separate label with the volume in mL and 
affix to the shipper. 
13. Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
14. RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
15. Place the box in the FedEx pickup area at your site or call to request a package 
pickup. 
Please Note: The shippers will be mailed back to each AMC site. 
INSTRUCTIONS FOR BLOOD SPECIMENS COLLECTED ON THURSDAY OR 
FRIDAY: 
Preparation of Plasma and Mononuclear Cells 
It is preferable that separation occurs as soon as possible. If necessary, whole blood in 
ACD (yellow top tubes) can be held at room temperature for no more than 24 hours. 
Plasma and PBMC should be separated according to the AMC Biorepository’s SOP on 
Separation of Plasma and Mononuclear Cells, available on the AMC Operations web site. 
Freeze the cell suspension in 0.5 mL aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store in 
the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long-term storage the next working day. 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires the 
use of packaging acceptable for dry ice and Class 9 label with weight of dry ice written 
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Preparation of Tissue Samples 
Tissue specimens to be fresh frozen should be placed in OCT and then on dry ice 
immediately. The specimens may stay on dry ice until being transferred to a -80ºC 
freezer. 
Tissue specimens for donation may be batched for shipping after storage in -80ºC freezer. 
Allowable shipment days are Monday through Thursday. Shipping frozen tissue requires 
the use of packaging acceptable for dry ice and Class 9 label with weight of dry ice 
written on package. 
TISSUE specimens should be shipped by overnight express to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
C. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimen shipments. 


 
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APPENDIX VI: ACSR INFORMED CONSENT 
INFORMED CONSENT FORM 
RESEARCH STUDY 
AIDS AND CANCER SPECIMEN RESOURCE (ACSR) 
 
A. 
INTRODUCTION 
You are being asked to donate blood and/or tissue for research. Before you decide to donate 
to this research project you need to understand the risks and benefits. This consent form 
provides information about the research project. The medical team will explain it to you 
and answer questions. If you agree to donate samples you will be asked to sign this consent 
form. This is known as informed consent. 
Your decision is entirely voluntary. You are free to choose if you want to donate or not. 
B. 
PURPOSE AND BACKGROUND 
The National Cancer Institute (NCI) has set up the AIDS and Cancer Specimen Resource 
(ACSR). The ACSR collects, stores, and gives out human biological specimens 
(biospecimens) from persons who have HIV-related medical conditions, including HIV-
related cancers. Scientists use these biospecimens for research purposes only. Scientists 
use the biospecimens to study cancers and other diseases associated with HIV disease. 
They hope to better understand the causes of these diseases and to develop better 
treatments. If you agree to take part, we will ask you to provide a blood sample and to 
donate some leftover tissue biopsy material to the ACSR. 
Why is this being done? 
The ACSR collects and stores biospecimens from people with and without HIV-related 
diseases and cancers. The ACSR makes the specimens available to researchers for use in 
research studies. These studies aim to increase our understanding of biological, molecular, 
and genetic factors that cause or increase risk for HIV-related diseases and cancers. The 
information may help to identify those who are at increased risk and those who may benefit 
from targeted treatment and screening. In turn, this could reduce the development of these 
diseases or improve the outcomes for patients with HIV diseases. 
Currently, scientists are working to identify where cancer-causing genetic changes occur, 
if you agree we would like to make available for future studies the genetic material from 
your cancer tissue and compare it to the material from your normal tissue (blood) to try to 
find the differences that exist. From these results, it may be possible to identify many of 
the changes that are associated with diseases such as cancers. It may also help us to 
understand how patients respond to treatment. With such knowledge, treatments could 
potentially become more tailored to a patient's unique genetic make-up and/or to the genetic 
markers of the tumors. 
C. 
PROCEDURES 
If you agree to donate biospecimens to the ACSR, the following will happen: 
1. The medical team will draw about 2 tablespoons of blood to give to the ACSR (this 
takes about 10 minutes). These samples may be studied to explore how genetic factors 
may be related to HIV-infection, AIDS and cancer. Please see the “Biologic studies” 
section of this consent form for more information. 


 
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2. If you agree, leftover tissue biopsy material will be donated to and stored by the ACSR. 
Your specimens may be used for a wide variety of tests. Scientists may study how 
genetic factors are related to HIV-infection, AIDS and cancer. However, we cannot tell 
you at this time what those tests will be. Please see the “Biologic studies” section of 
this consent form for more information. 
3. Some of your clinical information will be released to the ACSR and entered into their 
database. The information given to the ACSR will not have any information which 
could personally identify you. We may give your specimens and certain clinical 
information to scientists or researchers who have approved research projects. The 
ACSR’s independent research panel has approved these scientists/researchers to do 
research studies using specimens collected and stored by the ACSR. 
4. Biologic Studies: A sample of your blood or tissue biopsy that is collected and is not 
required for routine diagnosis or treatment may be provided by the ACSR in the future 
for research studies. The samples may be studied in combination with hundreds or 
thousands of other samples to explore how genetic factors may be related to HIV-
related diseases and cancer. The information might help doctors in the future to identify 
who will or will not benefit from treatment. The sample may be used to learn more 
about how HIV-related diseases and cancers develop. The sample may also lead to new 
tests or discoveries. 
5. You will not need any extra study procedures to donate your samples to the ACSR. 
You are free to decide if you want to donate your samples to the ACSR. You are not 
required to donate your samples to take part in any AMC clinical trial. If you donate 
your samples to the ACSR, your blood or tissue sample may be used for future research 
that includes genetic testing. If genetic tests are done, the results will not be put in your 
health records or provided to your doctor. The information will be combined with the 
results of others to help determine the causes of HIV-related diseases and cancers. The 
research will not change the care you receive. You will not receive the results of genetic 
tests because the tests are done for research and not for diagnostic purposes. 
6. Your sample will be labeled with a unique number. Your clinical information (for 
example your diagnosis, sex) may be given with your sample to researchers and added 
to a government health research database. Your name, address or other information that 
could identify you will not be given out. The ACSR will not be able to link your 
samples to you. Your blood or tissue sample will be stored until it is used up or 
destroyed. If you later decide you do not want your specimens and information to be 
used for future research, you may contact your AMC study coordinator. The 
coordinator can ask in writing that your sample be removed from research use and that 
any identifiable sample and information still in their possession be destroyed. However, 
if any research has already been done using some of your biospecimens, the data will 
be kept and analyzed as part of those studies. Please tell us whether we may use your 
samples for future research by initialing one of the lines at the end of this consent form. 
 
 


 
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D. 
RISKS/DISCOMFORTS 
If you choose to participate:  
• Blood Draw: The risks of drawing blood include temporary discomfort from the 
needle stick, bruising, and, rarely, infection. 
• Biopsy: The risks of biopsy include possible need for stitches depending on the size 
of the biopsy. There may be swelling, slight pain and a small amount of blood loss. 
There is also a chance of infection at the site of the biopsy. 
• Confidentiality: The ACSR will receive study samples with code numbers. There will 
be no personal identifiers on the samples. Then the samples will be relabeled with a 
bar-code scan. Samples will be stored in groups of samples for future testing. 
E. 
ALTERNATIVES 
If you decide not to donate, it will not affect your participation in the AMC clinical study. 
You may decide not to join or withdraw your biospecimens from the ACSR at any time. 
However, if any research has already been done using portions of the biospecimens, the 
data will be kept and analyzed as part of those research studies. 
F. 
POSSIBLE BENEFITS 
There may be no direct benefit to you by allowing the ACSR to have portions of your 
biopsies and biological fluids. However, this research may help us learn more about how 
to prevent and treat HIV-associated cancers and diseases in the future. 
G. 
COSTS 
There will be no cost to you for donating your biospecimens to the ACSR.  
H. 
PAYMENT FOR INJURY OR HARM 
If you agree to donate specimens to the ACSR, there is a chance of injury or harm to you. 
If you require immediate medical care, you should go to an emergency room. Otherwise, 
the doctor in charge of the study will take care of you or help you get the care you need. 
No funds have been set aside to compensate you in the event of injury. You or your 
insurance company will be charged for continuing medical care and/or hospitalization. 
However, you are not giving up your right to seek to collect compensation for injury related 
to malpractice, fault, or blame on the part of those involved in the research. 
I. 
PRIVACY 
To protect your privacy, the AMC does not keep identifying information that links study 
participants to specific samples. As a result, the AMC and ACSR will not be able to link 
the results from studies that use your samples back to you. Further, the ACSR has obtained 
a Certificate of Confidentiality from the National Institutes of Health. With this Certificate, 
the researchers cannot be forced to disclose information that may identify the participant, 
even by a court subpoena, in any federal, state, or local civil, criminal, administrative, 
legislative, or other proceedings. 
Thus, information including genetic information, that may be obtained by studies that use 
your biospecimens cannot be linked to you, placed in, or linked to your medical record. 
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be attached with these data. It is possible that findings may one day help, for example, 
people of the same race or sex as you. It also is possible that genetic factors might come to 
be associated with people who have HIV and cancer through these kinds of studies. 
There is a new federal law called the Genetic Information Nondiscrimination Act (GINA). 
It makes it illegal for health insurance companies, group health plans, and most employers 
to discriminate against you based on your genetic information. This means that: 
• 
Health insurance companies and group health plans may not request the genetic 
information that we get from this research. 
• 
Health insurance companies and group health plans may not use your genetic 
information when making decisions regarding your eligibility or premiums.  
• 
Employers with 15 or more employees may not use the genetic information that we 
get from this research when making a decision to hire, promote, or fire you or when 
setting the terms of your employment. 
This new federal law does not protect you against genetic discrimination by companies that 
sell life insurance, disability insurance, or long-term care insurance. 
J. 
PAYMENT 
You will not receive any payment for donating your samples to the ACSR. If any discovery 
or new treatment results from studies that use your specimens you will not receive any 
payment. 
K. 
QUESTIONS 
If you have any questions about this research study, you should contact the AMC 
Investigators, Dr. (_____________) at (Phone Number) or, (_____________), the study 
coordinator, at (Phone Number). If you have any questions about your rights as a as a 
donor and volunteer in a research project, you should call or write (IRB Representative), in 
(Institution) Office of Human Research at (______________). (IRB Representative) is your 
representative and is not employed by the individuals conducting the study. 
L. 
CONSENT 
You have been given copies of this consent form and the Research Participant’s Bill of 
Rights to keep.  
Participation in research is voluntary. You have the right to decline to donate your 
biospecimens or to withdraw your biospecimens at any time without affecting your medical 
care. Your participation or nonparticipation will in no way affect the treatment you receive 
from any medical center now or in the future. You may choose to donate blood, biopsy 
tissue or both. 
Please read each sentence below and indicate your choice by putting your initials next to 
“Yes” or “No.” 
1. 
I agree to donate my blood to the ACSR for future research that may be used to 
learn about, prevent, diagnose or treat HIV-related diseases and cancer. 
YES 
 
 
NO 


 
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2. 
I agree to donate my blood to the ACSR for future research that may include 
genetic testing to learn about, prevent, diagnose or treat HIV-related diseases 
and cancer.  
YES 
 
 
NO 
3. 
I agree to donate some of my tissue biopsy material that is not required for my 
treatment or diagnosis to the ACSR for future research that may be used to 
learn about, prevent, diagnose or treat HIV-related diseases and cancer. 
YES 
 
 
NO 
4. 
I agree to donate some of my tissue biopsy material that is not required for my 
treatment or diagnosis to the ACSR for future research that my include genetic 
testing to learn about, prevent, diagnose or treat HIV-related diseases and 
cancer. 
YES 
 
 
NO 
M. 
SIGNATURES  
I understand that, where appropriate, the NCI may inspect the records held by the ACSR. 
I understand that my donation will remain confidential. 
I am free to withdraw my consent and donation at any time after written notification to the 
AMC collecting site. The AMC site will immediately notify the ACSR to destroy any 
remaining identifiable specimens and information. However, if any research has already 
been done using my specimens, the data will be kept and analyzed as part of those research 
studies without prejudicing any involvement with the AMC.  
I understand that signing this form, beyond giving consent, I am not waiving any legal 
rights that I might otherwise have, and I am releasing the investigator, the sponsor, the 
institution, or its agents from any legal liability for damages that they might otherwise have.  
 
_________________________________ 
 
______________________________ 
Donor  
 
 
 
 
 
Date 
 
 
 
 
 
 
_________________________________ 
 
_____________________________ 
Professional Obtaining Consent 
 
 
Date 
 
_______________________________ 
 
______________________________ 
Witness 
 
 
 
 
 
Date 
 


 
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APPENDIX VII: AMC DATA AND SAFETY MONITORING PLAN 
(Version 6.0  March 21, 2017) 
 
Monitoring the Progress of Trials and the Safety of Participants 
All AMC protocols that collect safety data follow the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(http://ctep.cancer.gov/guidelines/index.html). All adverse events that meet the NCI’s expedited 
reporting requirements are reported to the Investigational Drug Branch (IDB) of the NCI via the 
CTEP Adverse Event Reporting System (CTEP-AERS) web application. All expedited adverse 
event reports are also required to be submitted to the local Institutional Review Board (IRB) of the 
reporting institution. If NCI holds the IND or no IND is required for a study, the AMC site reports 
serious adverse events directly to the AMC Operations and Data Management Center (ODMC) via 
CTEP-AERS; expedited reporting via AdvantageEDC/Advantage eClinical may be permitted for 
select commercial agent studies per protocol requirements. In some instances, the AMC sites may 
report serious adverse events directly to a commercial sponsor holding the IND, who will then 
report the event to the AMC ODMC. Most AMC protocols require sites to report all serious 
adverse events via CTEP-AERS and the AMC ODMC to forward a copy of the report to the 
sponsor. The AMC ODMC also distributes all IND safety reports to all investigators upon receipt, 
and makes these reports available on the password-protected section of the AMC Operations web 
site. Unless an AMC protocol specifies an alternate plan for the review and submission of serious 
adverse events, all serious adverse events received by the AMC ODMC will be reviewed by the 
AMC Medical Monitor at the AMC ODMC. For protocols for which the IDB does not have an 
assigned drug monitor to review serious adverse event reports, in the event of disagreement 
between the reporting physician and the AMC Medical Monitor regarding the attribution of the 
event to the investigational agent(s) (i.e., determination of whether the relationship is unrelated, 
unlikely, possible, probable, or definite), the AMC Medical Monitor will provide the final 
determination of the relationship. 
The AMC ODMC provides listings of all reported adverse events and serious adverse events to 
the Protocol Chair and Co-chair(s) for review on a regular basis. The AMC ODMC compiles these 
events in a tabular format and posts them on the password-protected section of the AMC web site 
where these reports are updated nightly. The AMC web site is accessible to all AMC investigators, 
co-investigators, and their staff. Email notification that this information is available on the web 
site will be sent to all site PIs. It is the responsibility of each site to provide this information to 
their respective IRBs, if required by their IRB. For blinded studies, the serious adverse events are 
reviewed and tabulated without treatment assignment. The AMC Medical Monitor will review 
listings of all reported adverse events on a quarterly basis for safety concerns. 
Accrual summaries for each AMC trial are updated nightly on the password-protected section of 
the AMC web site. The progress of each AMC trial is reviewed regularly by the Protocol Chair 
and also by the appropriate disease-oriented Working Group during scheduled conference calls. 
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the Protocol Chair, AMC Medical Monitor, and Group Statistician determine 
whether these criteria have been met. For phase II trials, stopping the trial for toxicity or efficacy, 
or suspending enrollment pending observation of responses in a multi-stage phase II trial, is based 
on meeting criteria stated in the protocol, and the Protocol Chair, AMC Medical Monitor, and 
Group Statistician determine whether these criteria have been met. 


 
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For phase III trials and other select studies requiring additional oversight, the AMC has formed an 
independent Data and Safety Monitoring Board (DSMB). Voting members of the DSMB are 
physicians, a statistician, and a patient advocate. All voting members are from outside the AMC. 
Nonvoting members are the AMC Group Statistician, the protocol statistician, an AMC Operations 
Center staff member, two representatives (normally a clinician or statistician) from the Office of 
HIV AIDS Malignancy (OHAM) or from the Cancer Therapy Evaluation Program, Division of 
Cancer Treatment and Diagnosis, of the National Cancer Institute (NCI). The DSMB reviews 
AMC phase III studies in accordance with the National Cancer Institute’s Policy for Data and 
Safety Monitoring. Confidential reports of all phase III trials are prepared by the AMC Group 
Statistician with support from the AMC ODMC. A written report containing the current status of 
each trial monitored, and when appropriate, any toxicity and outcome data, are sent to DSMB 
members by the AMC ODMC within the timelines specified by the DSMB Charter. This report 
addresses specific toxicity concerns as well as concerns about the conduct of the trial. The report 
may contain recommendations for consideration by the DSMB concerning whether to close the 
trial, report the results, or continue accrual or follow-up. 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB Chair to 
the Group Chair and AMC ODMC. The DSMB report contains recommendations on whether to 
close each study reviewed, whether to report the results, and whether to continue accrual or follow-
up. A primary recommendation (e.g., continue with no change; recommended or required 
modification; stop) must be included in the document. The Group Chair is then responsible for 
notifying the Protocol Chair and relevant Disease-oriented Working Group Chair before the 
recommendations of the DSMB are carried out. In the unlikely event that the Protocol Chair does 
not concur with the DSMB, then the NCI Division Director or designee must be informed of the 
reason for the disagreement. The Study Chair, relevant Disease-oriented Working Group Chair, 
Group Chair, DSMB Chair, and NCI Division Director or designee will be responsible for reaching 
a mutually acceptable decision about the study. CTEP approval of a formal amendment will be 
required prior to any implementation of a change to the study. 
Following a DSMB meeting, a summary of the serious adverse events reported to the DSMB is 
posted to the AMC web site. It is each site’s responsibility for conveying this information to its 
IRB. 
Plans for Assuring Compliance with Requirements Regarding the Reporting of Adverse 
Events (AE) 
For trials monitored by the NCI’s Clinical Data Update System (CDUS), adverse event 
information is transmitted electronically to NCI on a quarterly basis. For trials monitored by NCI’s 
Clinical Trials Monitoring Service (CTMS), adverse event information is transmitted 
electronically to NCI every two weeks. 
The Protocol Chair, AMC Group Chair, and the AMC ODMC share responsibility in assuring that 
participating investigators comply with the protocol requirements for adverse event reporting. All 
AMC investigators certify compliance with NCI and FDA requirements for adverse event 
reporting by signing the AMC Adherence Statement for site membership, the protocol signature 
page for each protocol active at the site, and Form FDA-1572 for CTEP investigator registration 
and IND studies sponsored by AMC investigators. Investigators are responsible for identifying 
and reporting all adverse events to the AMC ODMC, CTEP-AERS, and/or sponsors according to 
the protocol requirements, and assuring compliance with reporting to the local IRB. Protocol 


 
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compliance with adverse event reporting requirements is assessed by the AMC ODMC during 
routine site audits by reviewing the site’s source documentation.  
The data entry system used for AMC studies, AdvantageEDC/Advantage eClinical  (a web-based 
data entry and enrollment system), is programmed to notify the site investigator, protocol chair, 
AMC Medical Monitor, and AMC ODMC via email in the event that a site reports an adverse 
event that meets expedited reporting criteria to NCI and/or FDA. If the site does not follow with 
an expedited  report, the AMC ODMC contacts sites to request compliance with reporting 
requirements. Additionally, the protocol chair, AMC ODMC, and the AMC Medical Monitor 
review reported adverse events on a routine basis to identify adverse events reported by sites that 
require expedited reporting. The Protocol Chair, AMC Group Chair, and IND sponsors have 
general oversight for assuring that routine and expedited adverse reporting requirements are met 
by the responsible parties. 
Plans for Assuring that any Action Resulting in a Temporary or Permanent Suspension of 
an NCI-Funded Clinical Trial is Reported to the NCI Grant Program Director Responsible 
for the Grant 
In the event that termination of the trial or major modification to the protocol is under 
consideration, the Protocol Chair will convene the AMC Data Coordinator and Disease-oriented 
Working Group Chair by conference call to discuss the options. For phase I and II trials, the 
Protocol Chair also has the option of asking the DSMB to review the study. The AMC ODMC will 
inform the CTEP Protocol Information Office (PIO) when studies are temporarily or permanently 
closed. The Cancer Treatment and Evaluation Program (CTEP) of the National Cancer Institute 
(NCI) must approve all protocol amendments prior to distributing to the AMC sites. 
Plans for Assuring Data Accuracy and Protocol Compliance 
All study data for AMC clinical trials are entered directly by AMC clinical site staff into 
AdvantageEDC/Advantage eClinical. During data entry, the system performs validation checks on 
many fields and performs consistency checks between select fields. Range checks are placed on 
each field to eliminate entry of out-of-range values. Edit check programs are run on the database 
on a set schedule to identify and resolve inconsistencies between forms or data collected at 
different points in time. AMC ODMC staff routinely interacts with site staff to resolve any data 
problems. 
In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to evaluate 
compliance with regulatory issues, and to review data for specific cases by checking source 
documents. These reports are sent to the site Principal Investigator and to the NCI. In the event 
that major violations are identified, sites are asked to provide a written corrective and preventative 
action plan. If needed, a repeat site audit is conducted. In the event that a site does not correct 
deficiencies in a pre-determined time frame, the AMC Executive Committee has the option of 
taking action against the site. Possible actions include, but are not limited to, suspending 
enrollment of new patients to AMC trials until deficiencies are corrected; recommending a 
decrease in funding to the site; and requiring specific training for site investigators or staff 
members. 


 
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APPENDIX VIII: CENTRAL PATHOLOGY REVIEW 
Handling of Tissues: 
Institutions should submit: 
• A paraffin block 
OR 
• 1 hematoxylin and eosin stained slide and 10 blank tissue sections at 5 microns for 
pathology review; 
• 10 blank tissue sections at 20um for miRNA analysis; and 
• 3 cores of the paraffin tissue block for TMA production and analysis. 
The block or the sections and cores involved by lymphoma should be sent to the AMC 
Biorepository housed at George Washington University 
(www.ncbi.nlm.nih.gov/pubmed/20949389). 
AMC Biorepository: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
Specimen Labeling 
Each sample should be labeled using a fine-tipped Sharpie pen with the following 
information: 
• Protocol #: AMC-085 
• 9-digit Participant ID # 
• Visit # 
• Date and time of specimen collection 
• Specimen Type: “Tissue (tissue block),” “Tissue (unstained slide/section),” “H&E stained 
slide” 
• Purpose: “Central Pathology Review” 
The AMC Biorepository will send the following specimens in batch to the following address: 
For Central Pathology Review 
Each tissue block or 1 hematoxylin and eosin stained slide and 10 blank tissue sections 
at 5 microns per participant will be sent to Dr. Cesarman for pathology confirmation to 
the following address: 


 
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Julio Cordero 
Research Coordinator 
Laboratory of Hematopathology 
Department of Pathology and Laboratory Medicine 
Weill Cornell Medical College/The New York Presbyterian Hospital 
Starr-702 
525 East 68th Street  
New York, New York 10065 
Tel (212) 746-6357 
Fax (212) 746-2009 
juc9045@med.cornell.edu 
For HIV-HL miRNA Analysis 
3 cores/participant or 10 unstained sections at 20 μm each for miRNA analysis 
Dirk P. Dittmer, Ph.D. 
University of North Carolina at Chapel Hill 
CB# 7290, 715 Mary Ellen Jones Bldg 
Chapel Hill, NC 27599-7290 
Phone (lab): (919) 966-7962 
Fax: (919) 966-6153 
Email: dirkdittmer@me.com 
For TMA for HIV-HL Construction and Analysis 
3 cores/participant on study for TMA construction and analysis. 
Amy Chadburn, MD 
Feinberg Pavilion 7-210 
Northwestern Memorial Hospital 
251 E. Huron 
Chicago, IL 60611 
Handling of Tissues: 
The submitting Pathology Laboratory is also asked to provide the tissue block from 
representatively involved tissues; a total of 5-7 1.0 mm tissue cores from the block will be taken 
by the Immunopathology Laboratory for the miRNA studies and for inclusion in a tissue 
microarray, in addition to sections for diagnosis confirmation. The tissue block will be returned 
to the submitting laboratory one month after pathology review. If the submitting Pathology 
Department does not agree to submission of the block, we will accept, instead, 1 hematoxylin 
and eosin stained slide and 10 blank tissue sections at 5 microns for immunohistochemistry 
studies and diagnosis confirmation, ten unstained sections at 20 microns for the miRNA studies 
and three, 4mm punches for tissue micro array. 
Specimens should be sent to Dr. Sylvia Silver (see above) within 30 days of enrollment. The 
handling procedures and shipping requirements are described below.  
Specimen Accessioning: 
Upon receipt from the AMC Biorepository, each specimen from an AMC participant will be 
identified by an Immunopathology Laboratory accession number which will be sequential with 


 
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the other the specimens, including clinical specimens, received in the laboratory. This will avoid 
delays in processing specimens belonging to the AMC. AMC will be stated under “Clinical 
Information,” and therefore, can be easily identified and tracked by Dr. Cesarman and her team. 
A report will be issued by Dr. Cesarman or a member of her team within two weeks of receipt, 
with a description and preliminary diagnosis based on the microscopic review of H&E-stained 
sections, results of immunohistochemistry, and in situ hybridization for EBV (EBER). All the 
reports will be sent by FAX to the Operations Center as well as to the submitting physician if the 
information is provided, and hard copies to both will follow. 
Tissue Microarrays and MiRNA Analysis: 
Tissue microarrays will be constructed from formalin-fixed paraffin-embedded tissues from all 
the cases for which blocks are received. A Beecher tissue microarray instrument (Beecher 
instruments Inc., Sun Prairie, WI) will be used. Six 1.0 mm tissue cores will be obtained from 
representative lesional areas from each block. Controls will include a variety of benign and 
malignant lymphoid tissue appropriate for the studies to be done and will be provided from 
patients outside the trial. Once all the patients are recruited and all trial specimens are received, 3 
cores will be made available for complete miRNA analysis and 3 for tissue microarray 
construction and analysis.  
Pathology Review: 
Specimens received from AMC will undergo histopathologic diagnosis and classification, 
immunostaining and in situ hybridization for EBV EBER. Pathologic evaluation will be 
performed by Dr. Cesarman’s team; all interesting, atypical and unusual cases will also be 
reviewed by Dr. Knowles. Specifically, cases will be processed as follows: 
1. Histopathology- Pathologist review of H&E stained slide with tumor classification.  
2.  Immunohistochemistry for HL will include the following antibodies as necessary for HL 
diagnosis CD45, CD20, CD3, CD30, CD15, and in situ hybridization for EBER. 
3. If funding is available, Dr. Cesarman will immunostain for CD68, for the number of 
macrophages, as well as for Granzyme B and FoxP3, to determine the Granzyme B to FoxP3 
ratio to determine if these values, which have been reported to be prognostic indicators in 
non-HIV associated cHL, also correlate with outcome in HIV-HL. 
Record of Specimens: 
The specimens will be tracked via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
AMC BIOREPOSITORY DISTRIBUTION OF SAMPLES 
Upon receipt from a site, slides for central pathology review will be sent to Dr. Cesarman. The 
AMC Biorepository will cut slides from the tissue block as required. 
Upon a final decision on the participant’s eligibility from the central pathology review, the AMC 
Biorepository will cut cores and slides as needed for tissue microarray and miRNA analysis for 
batch shipment at the end of the study. Materials for ineligible cases will be returned to the 
submitting site. 
 
 


 
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APPENDIX IX: PHARMACOKINETIC/IMMUNOGENICITY STUDIES 
BACKGROUND AND PROCEDURES 
Since pharmacokinetic interactions between HAART and brentuximab vedotin are unknown, these 
interactions will be carefully monitored. Drug levels will be determined by assaying brentuximab 
vedotin, total antibody, and the free drug MMAE concentration over time. The formation of anti-
brentuximab vedotin antibodies will be also assessed at the time points summarized below in Table 
App IX-A. The pharmacokinetic data of  participants from both groups (efavirenz and non-
efavirenz- based HAART) for a total of 12 participants will be assessed in the phase II portion of 
the clinical trial once the maximum tolerated dose has been determined. Equal group sizes may 
not be analyzed given infrequent use of efavirenz-based HAART in the U.S. Participants taking 
any azole-based therapy should not be approached for participation in the pharmacokinetic 
studies. However, participants with protocol deviations for concurrent medications with sufficient 
samples for the PK analysis may be analyzed with the protocol chair’s approval. 
The study coordinator will be informed of which arm the participant enrolled will be 
assigned to. 
Sensitive, validated assays will be used to measure concentrations of brentuximab vedotin, total 
antibody, ATA in serum, and free MMAE in plasma. These assays will include enzyme-linked 
immunosorbent assays (ELISA) and LC/MS/MS assays. Other assays may be utilized if required 
to further characterize pharmacokinetics. These assays will be performed at Covance, Inc. Each 
assay will have a positive control and a pre-infusion serum sample will serve as the negative 
control. These data will provide unique insight in how we use this drug in participants receiving 
anti-HIV therapy.  
RELEVANT PRECLINICAL DATA 
Little to no data exists on the dosing of 1.3mg/kg of brentuximab vedotin to be used in this study, 
and no information exists on its interactions with anti-HIV medications. The data summarized 
below were obtained using 1.8mg/kg.  
Pharmacokinetic parameters for individual patients were determined using concentrations of 
serum brentuximab vedotin ADC, plasma MMAE, serum TAb, and actual sampling times relative 
to the start of the infusion. The maximum concentrations for the serum PK of brentuximab vedotin 
ADC following an IV dose of 1.8 mg/kg were typically observed at the end of infusion. A multi-
exponential decline in ADC serum concentrations was observed with a terminal half-life (t1/2) of 
approximately 4 to 6 days. Exposures were approximately dose proportional. After administration 
of multiple doses of brentuximab vedotin, steady-state was achieved by 21 days, consistent with 
the t1/2 estimate. Minimal to no accumulation was observed with multiple doses with the q3wk 
regimen, and ADC exposure did not decrease with subsequent doses. 
The plasma PK profile of MMAE following an IV dose of 1.8 mg/kg brentuximab vedotin 
appeared to follow metabolite kinetics, with the elimination of MMAE appearing to be limited by 
its rate of release from ADC. Tmax ranged from approximately 1 to 3 days. Exposures were linear 
and approximately dose proportional with MMAE exposures decreasing after multiple doses with 
approximately 50% to 80% of the exposure of the first dose observed at subsequent doses. After 
administration of multiple doses of brentuximab vedotin, MMAE steady-state was achieved by 21 
days, similar to ADC. Total antibody exposures were approximately dose proportional and higher 
than brentuximab vedotin ADC exposures while Tmax was similar. 


 
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TIME POINT OF SPECIMEN COLLECTION 
Table App IX-A: Pharmacokinetic Time Point and Immunogenicity Sampling Time Points 
Cycle 
Study Day 
Time 
Window 
Relative 
Time 
PK  
(ADC & 
fMMAE) 
ATA 
1 
Day 1 
Pre-dose 
within 2 hrs of 
BV infusion 
start of BV 
infusion 
X 
X 
 
 
0 min 
within 5 min post 
end of infusion 
End of BV 
infusion 
X 
 
 
Day 3 
At Clinic Visit 
 
 
X 
 
 
Day 15 
Pre-Dose 
within 2 hrs of 
BV infusion 
start of BV 
infusion 
X 
 
2nd and 
Subsequent 
Cycles 
Day 1 
Pre-dose 
within 2 hrs of 
BV infusion 
start of BV 
infusion 
X 
X 
Post-Treatment 
Evaluation 
6-8 weeks after 
Cycle 6 Day 15 
At Clinic Visit 
 
 
X 
X 
Early 
Discontinuation 
Within 1 month 
after treatment 
discontinuation 
At Clinic Visit 
 
 
X 
X 
PK (Includes assay for Brentuximab vedotin and Free MMAE) ATA (Anti-Therapeutic 
Antibody) 
SPECIMEN COLLECTION AND PROCESSING INSTRUCTIONS 
Antibody Drug Conjugate (ADC) - Serum PK Specimen Collection & Processing: 
 5.0 mL of whole blood will be collected in a gold-top serum separator tube. 
 Sample will be allowed to clot for 30 minutes at room temperature. 
 Centrifuge sample for 15 minutes at approximately 1500 x g at room temperature. 
 Serum will be aliquotted into two 3 mL cryovials, and frozen at -20ºC or -80ºC preferably as 
soon as possible. Do not use liquid nitrogen to flash freeze the specimen. 
For Free MMAE (fMMAE) Specimen Collection and Processing: 
 2.5 mL of whole blood will be collected in a 2.7 mL Na Citrate tube (blue top) tube. 
 Immediately after the blood draw, carefully mix the blood with the anticoagulant by gently 
inverting the tube 8-10 times. DO NOT SHAKE. 
 Immediately after mixing the specimen, place the vacutainer tube into a container with cold 
water and ice for 1-2 minutes. If your site does not a have a refrigerated centrifuge, leave the 
specimen in the ice mixture for 5-6 minutes before processing. The samples should be 
processed within 1 hour of collection. 
 Centrifuge blood at 800-1000 g for 15 minutes to separate the plasma from blood cells. 
 Transfer the plasma into one appropriately labeled 2 mL cryogenic vial. Be careful not to 
include any of the separated cells. 


 
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 Samples must be frozen and stored immediately at -20ºC or -80ºC preferably. Do not use 
liquid nitrogen to flash freeze the specimen. If it is impossible to place the specimen 
immediately at >-20ºC, it may be refrigerated up to 8 hours prior to storage at > -20ºC. 
Antitherapeutic Antibody (ATA) Specimen Collection & Processing: 
 2.5 mL of whole blood will be collected in a gold-top serum separator tube. 
 Sample will be allowed to clot for 30 minutes at room temperature. 
 Centrifuge sample for 15 minutes at approximately 1500 x g at room temperature. 
 Serum will be aliquotted into one 3 mL cryovial, and frozen at -20ºC or -80ºC preferably as 
soon as possible. Do not use liquid nitrogen to flash freeze the specimen. 
Store all serum and plasma samples at -80°C if not able to ship within the month to the AMC 
Biorepository. 
Each sample tube should be labeled using a fine-tipped Sharpie pen with the following 
information: 
• Protocol #: AMC-085 
• 9-digit Participant # 
• Date and time of collection 
• Specimen type: “Plasma,” “Serum” 
• Sample Volume 
• Specimen purpose: Indicate which analyses should be performed on each tube (i.e., 
“Antibody Drug Conjugate (ADC) - PK/Immuno Studies,” “free MMAE (fMMAE) - 
PK/Immuno Studies,” or “Antitherapeutic Antibody (ATA) - PK/Immuno Studies”). 
• Nominal Timepoint 
SPECIMEN SHIPMENT  
Specimens are accepted MONDAY through FRIDAY. All specimens should be shipped to the 
AMC Biorepository housed at George Washington University  
(www.ncbi.nlm.nih.gov/pubmed/20949389) within one month of collection. 
AMC Biorepository: 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
The AMC Biorepository will send the following specimens in batch to the following addresses 
upon direction from the AMC ODMC: 


 
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ADC and ATA serum samples should be sent to: 
Covance Chantilly: 
Attn: Reena Pappachen 
3635 Concorde Pkwy, Suite100 
Chantilly, VA, 20151 
MMAE Plasma samples should be sent to: 
Covance Madison: 
Attn: Sample Management – Bioanalytical (Rm 131D 1S) 
3301 Kinsman Blvd 
Madison, WI 53704-2523 
SHIPPING INSTRUCTIONS 
To ship to Covance, remember to include the following information for samples: 
• Sample matrix (plasma, serum, etc.) 
• Analyte (which analyses should be performed on each tube) 
• Sample volume 
• Sample draw date 
• Sample draw time 
• Participant identifier 
• Nominal time point 
1) Put the serum or plasma tube in the inner biohazard bag with absorbent material and seal  
2) Put the biohazard bag in the outer therapak envelope and seal well per instructions on the 
packaging 
3) Envelope goes in the provided dry ice shipper, surround with dry ice 
4) Close foam inner box, and place the requisite and any other relevant sample documentation in 
a ziplock bag on top of the foam inner box.  
5) Seal the outer cardboard, add appropriate hazard stickers for the blood product and dry ice (not 
provided). 
6) Ship to Covance following the instructions below 


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To order the shippers:
Biohazard bags from Fisher: 95kpa catalog #22-130-020
Shipping boxes from VWR: thermosafe 11x14.5x9, catalog #14100-414
Contact Covance’s contacts for technical questions (below) prior to using alternate shippers.
•
It is the responsibility of the Primary Investigator to ensure that all staff personnel who will be 
handling, packaging, and/or shipping clinical specimens act in conformance with International 
Air Transport Association (IATA) regulations (IATA Packing Instruction 650) relating to the 


 
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handling and shipping of hazardous goods. (IATA Packing Instruction 650 is located on the 
AMC web site.) 
• Use a federally approved shipper for biological substance shipment (Category B). Label the 
shipper with the "Infectious substance" diamond shaped label. On one side, in black marker 
write “Biological Substance, Category B, UN 3373”, your name or name of responsible person, 
date of collection and phone number of the person responsible for the package. Package and 
label the shipment in accordance with the instructions provided for that specific shipper. 
• A Shipper’s Declaration for Dangerous Goods is not required. However, for all dry ice 
shipments, the following information must be shown in sequence on the airway bill in the 
“Nature and Quality of Goods” box: Dry Ice, 9, UN1845, number of boxes being shipped, net 
weight of dry ice per box. 
Please Note: The shipper will be mailed back to the AMC site. The STP-100 SAF-T-PAK shipper 
(VWR Cat # 11217-163) is a complete kit (bubble wrap, absorbent paper, labels, etc.) for specimen 
shipment. To reuse the shipper, you will need new labels, wrap, etc. There is a refurbishment kit 
with extra bubble wrap and absorbent material (STP102) (VWR Cat # 11217-166) sufficient for 
15 mailings. 
Billing 
Bill the FedEx number provided on the AMC members’ only website. This number is supplied by 
the AMC Operations and Data Management Center. It is only to be used for billing shipment of 
specimens to the lab where the sample is processed and/or stored.  
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDCSM 
system. The GlobalTraceSM shipment manifest must accompany all specimen shipments. 
Technical Questions 
For Free MMAE: 
Glenn Hanson  
Senior Principal Investigator 
Bioanalytical Chemistry 
Covance Laboratories, Inc. 
3301 Kinsman Boulevard 
Madison, WI 53704-2523 
E-mail: glenn.hanson@covance.com 
Tel: 608-242-2640 
Fax: 608-242-2735 
Available hours: Monday-Friday (9AM-5PM 
EST) 
For ADC, and ATA: 
Reena Pappachen 
Principal Investigator 
Immunochemistry Services 
Covance Laboratories, Inc. 
Chantilly, VA 
E-mail: reena.pappachen@covance.com 
Tel: 703-889-9482 


 
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APPENDIX X: ASSESSMENT OF CIRCULATING LEVELS OF PRO-
INFLAMMATORY AND ANGIOGENESIS-ASSOCIATED 
MOLECULES STUDY PLAN 
1.0 
OBJECTIVES 
The aims of this proposed pilot study are: 
1.1 
To determine if pre-treatment plasma levels of cytokines and/or biomarkers 
associated with inflammation and immune activation are elevated in persons with 
HL; 
1.2 
To evaluate the effect of brentuximab-containing AVD therapy on plasma levels 
of these biomarkers following 1 cycle of therapy, following 3 cycles of therapy, at 
the conclusion of therapy, and at 3, 6 and 12 months after the conclusion of 
therapy, to identify the clinical correlates with regard to tumor response and 
disease-free survival. 
2.0 
BACKGROUND 
We have seen that elevated serum/plasma levels of several molecules associated with 
immune activation and inflammation, including sCD30, CXCL13, IL-6 and IL-10, occur 
preceding the diagnosis of AIDS-associated NHL, as well NHL, and HL in presumably 
immunocompetent persons63-66. These studies were all done using specimens obtained 
from several prospective longitudinal cohort studies. In a prior study in the AMC, we also 
assessed the effect of treatment for AIDS-associated NHL on plasma levels of these 
biomarkers, finding that treatment resulted in a marked decrease in many of these 
molecules, and that pre-treatment initiation plasma levels of CXCL13, IL-6 and IL-10 were 
predictive of subsequent CR to treatment63-66. In fact, in multivariate analysis, CXCL13 
levels proved to be better predictors of subsequent clinical response that IPI or other 
established prognostic markers (8, 9). Therefore, biomarkers, including sCD30, IL-6 and 
IL-10 are known to be elevated preceding HL and NHL, and levels of these molecules may 
be associated with subsequent response to treatment in AIDS-NHL. However, little is 
known about these biomarkers in HIV infection-associated HL. 
3.0 
RATIONALE 
HIV-driven inflammatory cytokine production has the potential to contribute to the growth 
of AIDS-associated cancers, including HL, and enhanced production of these and other B 
cell-stimulatory molecules may contribute to the genesis and/or growth of HL. 
Additionally, dysregulated infection with EBV may contribute to immune activation and 
inflammation. However, there is little information available on the effect of treatment of 
AIDS-associated HL with brentuximab on serum levels of these biomarkers, nor on the 
prognostic significance of such biomarkers. 
The recent availability of multiplexed immunometric assays has made possible the 
simultaneous assessment of several of these immune activation and inflammation-
associated factors, using small volumes (<500 µl) of serum or plasma. 
The results of this study will provide information on immune activation/inflammation-
associated biomarker plasma levels in HIV-associated HL, and on effects of AVD-BV 


 
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therapy for HL on these biomarkers, as well as on the prognostic value of such biomarkers 
in those receiving AVD-BV treatment. 
4.0 
EVALUATIONS 
Plasma levels of cytokines and inflammation-associated molecules will be determined at 
the following study visits: pre-treatment (entry), and following 1 cycle of therapy, 
following 3 cycles of therapy, at the conclusion of therapy (6-8 weeks post treatment 
discontinuation), and at 3, 6 and 12 months after the treatment discontinuation visit. 
5.0 
ANALYSES 
The working hypothesis that will be tested is that participants who will achieve clinical CR 
will have plasma levels of sCD30, IL-6 and IL-10 that fall within the normal range, 
following the conclusion of therapy. 
Levels of cytokines and inflammation-associated biomarkers will be determined using two 
Luminex-based panels. The first is a high-sensitivity cytokine panel that can detect human 
IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, IL-12, TNFα, VEGF, GM-CSF, IFNγ. The 
second is a soluble receptor/inflammatory cytokine panel: BAFF/BLyS, sCD14, sIL-6R, 
sgp130, sIL-2R, sTNF-R2, CXCL13, sCD30 (or sCD27). Both of these panels are 
produced by R&D Systems, and have been used by us extensively in prior epidemiologic 
studies. The cytokine panel has yielded results that compare well to ELISA results for IL-
6 and IL-10. The soluble receptor/inflammation panel yields detectable results for these 
biomarkers in the majority of persons tested. 
2 mL of plasma in 1 mL aliquots should be sent in batch at the end of the study to the 
Martinez-Maza laboratory. 
6.0 
SHIPPING INSTRUCTIONS AND SAMPLE PROCESSING 
A. General 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an OVERNIGHT 
PRIORITY shipment. Specimens are NOT ACCEPTED ON SATURDAYS or SUNDAYS 
in the AMC BIOREPOSITORY. 
Should the site collect specimens on Friday and Saturday, samples should be processed for 
plasma according to the AMC Biorepository’s SOP on Separation of Plasma and 
Mononuclear Cells, available on the AMC Operations web site. At least four 0.5 mL 
aliquots of plasma are required. Aliquots should be frozen at specimens at -80°C and 
shipped on dry ice to the AMC Biorepository the following week. 
B. Specimen preparation, packaging, and shipment 
Draw two 6 cc (mL) lavender top [EDTA] tubes from study participant. Seal the tops of 
the tubes with parafilm. Place the two sealed tubes into bubble wrap (provided in STP-210 


 
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kit). Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. Place absorbent material sheet around the bubble wrapped tubes and slip into 
a biohazard poly-bag and “self-seal.” Place poly-bag containing tubes into the white 
TYVEK bag and seal. Place the TYVEK bag into the STP-210 diagnostic cardboard 
shipper. Seal the cardboard shipper with clear packing/shipping tape. 
Affix the FED-EX airbill on blank side of the shipper making sure that it is marked “FED-
EX PRIORITY OVERNIGHT.” Mark “OTHER” in the airbill under “Packaging.” Under 
airbill section “Special Handling,” indicate “YES-SHIPPERS DECLARATION NOT 
REQUIRED.” Place “From/To” information onto areas provided on the shipper. 
Blood specimens should be shipped by overnight express at room temperature to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
Specimen Labeling 
Each sample tube should be labeled using a fine-tipped Sharpie pen with the following 
information: 
• Protocol #: AMC-085 
• 9-digit Participant ID # 
• Visit # 
• Date and time of specimen collection 
• Specimen Type: “Plasma” 
• Purpose: “Cytokine Assays” 
Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp. Make 
certain that the net volume of the specimen being shipped is written in the space provided 
on the shipper or make a separate label with the volume in mL and affix to the shipper. 
Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. RETAIN THE 
TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. Place the box in the FedEx 
pickup area at your site or call to request a package pickup. 
Billing 
Bill the FedEx number provided on the AMC members’ only website. This number is 
supplied by the AMC Operations and Data Management Center. It is only to be used for 
billing shipment of specimens to the lab where the sample is processed and/or stored. 
Contact for Site Questions (9AM-5PM Pacific Time) 
Lab Manager: Larry Magpantay (lmagpantay@mednet.ucla.edu) 
Lab phone: 310-206-6846 


 
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Otto Martinez-Maza’s office phone: 310-825-2542 
7.0 
AMC BIOREPOSITORY INSTRUCTIONS ONLY 
The AMC Biorepository will separate plasma, aliquot the plasma into as many 1.0 mL 
aliquots until the sample is used as per AMC Biorepository SOPs, and store at -80°C. 
Specimens should be sent in batch at the end of the study to: 
Larry Magpantay 
BSRB 173 
UCLA AIDS Institute 
615 Charles Young Drive 
Los Angeles, CA 90095-7363 
Tel: 310-206-6846 
Fax: 310-206-5387 
Email: lmagpantay@mednet.ucla.edu 


 
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APPENDIX XI: ASSESSMENT OF EBV DNA IN PLASMA 
1.0 
OBJECTIVES 
The aims of this proposed pilot study are: 
1.1 
To determine if pre-treatment levels of EBV DNA in plasma from HL participants 
prior to treatment are prognostic indicators 
1.2 
To determine if following the initiation of treatment EBV DNA in plasma serves 
as a tumor marker 
1.3 
to determine whether measurement of methyl CpG EBV DNA in plasma is a 
prognostic indicator at baseline or a tumor marker at follow up. 
2.0 
BACKGROUND 
Approximately 90% of HL in HIV patients is associated with the presence of EBV in the 
malignant cells as assessed by in situ hybridization or immunohistochemistry of diagnostic 
biopsies82. In other populations the association is less common83. Several groups have 
reported that detection of EBV DNA in plasma or serum correlates with the presence of 
EBV in tumor cells in HL84,85. In a recent study we have seen that in non-HIV patients in 
North America with HL, pretreatment plasma copy number had an excellent concordance 
rate with in situ hybridization (95%) and was a prognostic factor in multivariate analysis 
for failure-free survival that superseded the international prognostic score (IPS)86. 
Furthermore, failure to clear EBV DNA from plasma after the initiation of therapy was 
associated with a very poor failure-free survival (44% at 3 years, p=0.0001). In 
immunocompetent patients without HIV infection, detection of EBV DNA in plasma of 
patients with EBV-associated tumors reflects mainly release of viral DNA from latently 
infected tumor cells87. 
In contrast, in HIV patients, plasma copy number for EBV and KSHV are often elevated. 
Copy number measurements often fail to distinguish between patients with virus associated 
malignancy and patients without virus-associated malignancy88. The explanation is that 
HIV patients are often viremic i.e., whereas viral DNA in other settings is mainly that 
released from tumor cells, in HIV patients EBV and KSHV virions are also present in 
plasma. Because the virion coat provides protection from DNase digestion, resistance to 
such digestion has been used to distinguish virion DNA from viral DNA released from 
tumor or other cells that was not encapsidated. However, the approach is difficult to 
standardize and not readily applied to clinical trials specimens. We have developed a 
technique to distinguish virion DNA from cell viral DNA which is straightforward and 
quantitative. The technique involves measurement of copies of methylCpG KSHV or EBV 
DNA89. Virion DNA is never CpG methylated, whereas cellular EBV DNA is usually CpG 
methylated. 
3.0 
RATIONALE 
Detection of EBV DNA in plasma is very useful in EBV-associated malignancies in non-
immunocompromised patients including nasopharyngeal carcinoma and Hodgkin 
lymphoma. It has not been carefully studied in HIV HL before, but we suspect that as in 
other HIV settings, tumor-derived DNA will be obscured by virion DNA. By comparing 
measurements of viral DNA and methylCpG viral DNA, we expect to test our hypothesis, 
that methylCpG DNA will be much more useful as a tumor marker. 


 
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4.0 
EVALUATIONS 
Plasma levels of EBV DNA and methyl CpG EBV DNA will be determined at the 
following study visits: pre-treatment (entry), and following 1 cycle of therapy, following 3 
cycles of therapy, at the treatment discontinuation visit, and at 3, 6 and 12 months after the 
post treatment evaluation. At each required time point, participants will have two 6 cc (mL) 
lavender top [EDTA] tubes of blood drawn at ambient temperature. 
5.0 
ANALYSES 
We will analyze baseline EBV DNA and methylCpG EBV DNA for prognostic value. We 
will also measure serial changes in these values with therapy. 
For detection of EBV DNA in plasma we used standard PCR-based real time techniques90. 
For detect of methyl CpG EBV DNA, we fractionate DNA extracted from plasma using 
DNA methylbinding protein 2 magnetic beads as described90. Methyl CpG DNA is eluted 
from the beads in high salt and then assayed by standard PCR as above. 
6.0 
SHIPPING AND SAMPLE PROCESSING 
Preparation and Shipping Instructions 
A. General 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 
cc. The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. 
These shippers may be ordered at the SAF-T-PAK website www.saftpak.com. The 
following instructions below are for use with the recommended STP-210 shipper. If 
using another federally approved diagnostic shipper, please follow instructions provided 
for that specific shipper. 
NOTE: Specimens MUST BE SHIPPED Monday through Thursday as an 
OVERNIGHT PRIORITY shipment. Specimens are NOT ACCEPTED ON 
SATURDAYS or SUNDAYS in the AMC BIOREPOSITORY.  
Should the site collect specimens on Friday and Saturday, samples should be processed 
for plasma according to the AMC Biorepository’s SOP on Separation of Plasma and 
Mononuclear Cells, available on the AMC Operations web site. At least four 0.5 mL 
aliquots of plasma are required. Aliquots should be frozen at specimens at -80°C and 
shipped on dry ice to the AMC Biorepository the following week. 
B. Specimen Preparation, Packaging, and Shipment 
Draw two 6 cc (mL) lavender top [EDTA] tubes from study participant. Seal the tops of 
the two 6 cc lavender tops with parafilm. Place the two sealed tubes into bubble wrap 
(provided in STP-210 kit). Tape around the bubble wrap so that the roll stays together 
and the tubes cannot fall out or break. Place absorbent material sheet around the bubble 
wrapped tubes and slip into a biohazard poly-bag and “self-seal.” Place poly-bag 
containing tubes into the white TYVEK bag and seal. Place the TYVEK bag into the 
STP-210 diagnostic cardboard shipper. Seal the cardboard shipper with clear 
packing/shipping tape.  
Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT.” Mark “OTHER” in the airbill under 
“Packaging.” Under airbill section “Special Handling,” indicate “YES-SHIPPERS 


 
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DECLARATION NOT REQUIRED.” Place “From/To” information onto areas 
provided on the shipper.  
Blood specimens should be shipped by overnight express at room temperature to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
Specimen Labeling 
Each sample tube should be labeled using a fine-tipped Sharpie pen with the following 
information: 
• Protocol #: AMC-085 
• 9-digit Participant ID # 
• Visit # 
• Date and time of specimen collection 
• Specimen Type: “Plasma” 
• Purpose: “EBV Load” 
Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp. Make 
certain that the net volume of the specimen being shipped is written in the space 
provided on the shipper or make a separate label with the volume in mL and affix to the 
shipper. Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. Place 
the box in the FedEx pickup area at your site or call to request a package pickup. 
Billing 
Bill the FedEx number provided on the AMC members’ only website. This number is 
supplied by the AMC Operations and Data Management Center. It is only to be used for 
billing shipment of specimens to the lab where the sample is processed and/or stored. 
7.0 
AMC BIOREPOSITORY INSTRUCTIONS ONLY 
The AMC Biorepository will separate cells in blood sample, aliquot the plasma into as 
many 0.5 mL aliquots until the sample is used as per AMC biorepository SOPs, and store 
at -80°C. At least four 0.5 mL plasma aliquots are required per collection time point. 
Specimens should be sent in batch at the end of the study to Dr. Ambinder’s laboratory at 
Johns Hopkins University. 
 


 
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APPENDIX XII: ASSESSEMENT OF HIV LATENT AND EXPRESSED HIV 
RESERVOIRS 
1.0 
BACKGROUND AND RATIONALE 
The effect of intensive chemotherapy on the HIV reservoirs is not well understood. The 
model of AIDS-related malignancies provides an opportunity to define alterations in HIV 
reservoirs resulting from cytoreductive cancer chemotherapy. In the current study, we 
propose to better characterize HIV reservoirs (HIV-1 DNA and RNA) prior to, during, and 
after treatment of HIV-related Hodgkin lymphoma by sensitive measurement of HIV-1 
DNA and RNA in plasma and peripheral blood mononuclear cells using quantitative PCR 
assays (qPCR). In patients with plasma HIV-1 RNA level below the limit of detection by 
standard commercial assays (typically <50 copies/mL), qPCR assays with single copy 
sensitivity (SCA) can detect HIV-1 RNA in plasma and in PBMC from most patients. The 
origin of this viremia has not been identified, but may be either from latently-infected that 
are triggered to produce virus, from virus-producing cells that are long-lived, from ongoing 
low-level virus replication and spread, or some combination of these possibilities. 
Cytoreductive chemotherapy may impact HIV reservoirs by killing latently-infected cells 
or those expressing HIV-1 RNA or producing virus, at least temporarily. Such an impact 
can be readily detected by qPCR assays of HIV-1 RNA in plasma and HIV-1 DNA and 
RNA blood mononuclear cells. The magnitude of the effect of chemotherapy on reservoirs 
and whether it is temporary or sustained are important questions that can be answered in 
this study. 
2.0  
HYPOTHESIS 
We hypothesize that treatment of AIDS-related malignancies using cytotoxic 
chemotherapy in participants will result in a substantial reduction in the size of the HIV 
reservoirs and thereby reduce low-level viremia and the number of HIV-infected cells 
expressing HIV-1 RNA. This study will apply the use of qPCR to assess viremia and 
cellular reservoirs in participants receiving three de-escalating doses of brentuximab 
vedotin in conjunction with standard, fixed doses of doxorubicin 25 mg/m2, vinblastine 6 
mg/m2, and dacarbazine 375 mg/m2 (AVD). Blood samples will be obtained at two time 
points prior to Cycle 1, Day 1 (baseline samples), at one time point during treatment, and 
then at completion of therapy and at one year post treatment. 
3.0 
SAMPLE REQUIREMENTS 
Single Copy HIV Assays (Plasma and Peripheral Blood Mononuclear Cells (PBMCs)) 
As stated below, as a requirement, the samples MUST be processed within 4 hours of 
blood collection. Only sites able to comply with this requirement will be permitted to 
participate in this correlative. 
Time points for sample collection: 
• Pre-Treatment: at 1 week (+/- 3 days) prior to Cycle 1 Day 1 and again 24 hours prior 
or on the day of Cycle 1 Day 1. Only for participants who are found to have 
undetectable plasma HIV-1 RNA by the standard assay performed at the clinical site 
within 21 days of C1 Day 1. 


 
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• Treatment Phase: Within 48 hours prior to or on the first day of Cycle 3 and/or at the 
Early Treatment Discontinuation Visit if indicated. 
Post-Treatment: 6-8 weeks following the last treatment dose only for those participants 
who are found to have undetectable plasma HIV-1 RNA by the standard assay performed 
at the clinical site on the Cycle 3 Day 1 sample. 
A subsequent 30 mL sample will be obtained 12 months (+/- 14 days) following the 
treatment discontinuation visit for participants who are found to have undetectable plasma 
HIV-1 RNA by standard assay performed at the clinical site. 
Sample preparation: 
A 30 mL peripheral blood sample will be collected in three (3) 10 mL EDTA-containing 
tubes. Gently mix the blood with EDTA by inverting the tubes 8-10 times. Store the tubes 
at room temperature for up to four hours prior to on-site processing to plasma and PBMCs 
at a local laboratory. 
4.0 
SPECIMEN PROCESSING 
Plasma 
Blood samples MUST be processed within 4 hours of collection. If samples cannot be 
processed within the 4 hours, sites will be able to opt out of this correlative study. 
Centrifuge blood at 400 x g for 10 minutes in a table top centrifuge. Remove plasma very 
carefully without disturbing the buffy coat and/or mixing cells into the plasma. To prevent 
contamination of the plasma with cells, leave about 0.5 mL of plasma behind above the 
cell layer. This is very important. Re-centrifuge plasma at 1350 x g for 15 min. Again, 
leave about 0.5 mL of plasma behind to prevent potential cell contamination. Save all cells 
for processing to cryopreserved PBMC as described below. 
Freeze at least 5 x1.5 mL aliquots and as many additional 1.5 mL aliquots as possible at -
70°C or colder and ship on dry ice to the AMC Biorepository. 
Peripheral Blood Mononuclear Cells (PMBCs) 
Blood samples MUST be processed within 4 hours of collection. If samples cannot be 
processed within the 4 hours, sites will be able to opt out of this correlative study. 
Dilute the cells and plasma left behind from above to the original blood volume with 
Dulbecco’s phosphate buffered saline. Isolate and cryopreserve PBMC as described in 
HANC Cross-Network PBMC processing SOP  
(https://www.hanc.info/labs/labresources/procedures/Pages/pbmcSop.aspx). Store at least 
5 aliquots of 5 million PBMC per vial at -70°C or colder and ship on dry ice to the AMC 
Biorepository. 
5.0 
SPECIMEN SHIPMENT 
To ship frozen specimens to the AMC Biorepository, please follow the instructions in 
Appendix V. Shipping will require the use of packaging acceptable for dry ice and Class 9 
label with the weight of dry ice indicated on the package. 
Available aliquots will be periodically shipped from the AMC Biorepository to the 
designated project laboratory at the University of Pittsburgh for testing. IF SPECIMENS 


 
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CAN NOT BE SHIPPED ON MONDAY THROUGH THURSDAY, STORE 
SAMPLES AT -70°C UNTIL THE FOLLOWING MONDAY. 
Specimens should be shipped by overnight express to: 
Dr. Sylvia Silver 
George Washington University Medical Center 
2300 I St, NW 
Room 118 
Washington, DC 20037 
Tel: (202) 994-2945 
Fax: (202) 994-5056 
Email: ssilver@gwu.edu 
amc-bio@emmes.com 
Specimen Labeling 
Each sample tube should be labeled using a fine-tipped Sharpie pen with the following 
information: 
• Protocol #: AMC-085 
• 9-digit Participant ID # 
• Visit # 
• Date and time of specimen collection 
• Specimen Type: “Plasma,” “PBMC” 
• Purpose: “HIV latent reservoir” 
6.0 
BILLING 
Bill the FedEx number provided on the AMC members’ only website. This number is 
supplied by the AMC Operations and Data Management Center. It is only to be used for 
billing shipment of specimens to the lab where the sample is processed and/or stored. 
7.0 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDCSM system. The GlobalTraceSM shipment manifest must accompany all 
specimen shipments. 
8.0 
AMC BIOREPOSITORY INSTRUCTIONS ONLY 
Batches of specimens will be sent from the AMC Biorepository to the Mellors Laboratory 
by overnight express on dry ice: 
The first shipment should be sent when the first 5 participants have completed the study 
and all the samples are received at the AMC Biorepository. Subsequent shipments will be 
batched when an additional 5 participants’ complete the study and their samples are 
available at the AMC Biorepository. 
Dianna Koontz/Virology Support Laboratory (Mellors) 
University of Pittsburgh 
3550 Terrace Street 
S816 Scaife Hall 


 
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Pittsburgh, PA 15261 
Tel: (412) 624-8509 
Email: zonarich@pitt.edu 


 
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APPENDIX XIII: PROHIBITED AND USE WITH CAUTION MEDICATIONS THAT 
ARE P-GLYCOPROTEIN AND CYP3A4 INHIBITORS 
Strong CYP3A inhibitors and P-glycoprotein inhibitors must be discontinued 7 days prior to 
therapy. Moderate CYP3A4 inhibitors should be Used with Caution but are not excluded. If 2 
moderate CYP3A4 inhibitors are used concurrently, one must be discontinued at least 7 days 
prior to chemotherapy. 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference for a list of drugs to avoid or minimize use of. 
 
P-Glycoprotein Inhibitors 
Strong CYP 3A4 Inhibitors 
Moderate CYP 3A4 
Inhibitors 
Antiretrovirals 
Lopinavir and ritonavir 
 
Other Agents 
Amiodarone 
Azithromycin* 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporine 
Diltiazem 
Dronedarone 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Quercetin 
Quinidine 
Ranolazine 
Tacrolimus 
Verapamil 
Antiretrovirals 
Cobicistat 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
 
Other Agents 
Boceprevir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Mibefradil 
Nefazodone 
Posaconazole  
Suboxone 
Telithromycin 
Telaprevir 
Troleandomycin 
 
Antiretrovirals 
Atazanavir 
 
Other Agents 
Aprepitant 
Amprenavir 
Amiodarone 
Ciprofloxacin 
Dronedarone 
Erythromycin 
Diltiazem 
Fluconazole 
Fosamprenavir 
Grapefruit juice 
Seville orange juice 
Verapamil 
Voriconazole 
* See Section 4.4.4 for guidance on azithromycin use in MAC prophylaxis. 
 
 


 
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APPENDIX XIV: ANALYSIS OF T-CELL SUBSETS AND CYTOKINES OVER TIME 
IN SUBJECTS TREATED WITH AVD-BV 
 
1.0 
OBJECTIVES 
The aims of this exploratory correlative study are to study the T-cell subsets and cytokine 
levels over time to understand CD4+ and CD8+ T-cell elevations identified in AMC-085: 
1.1 
To determine what changes from pre-treatment plasma levels of cytokines are 
associated with CD8 and CD4 + T-cell function. The cytokine analysis will be 
performed pretreatment, following cycle 1, cycle 3, and at the conclusion of 
therapy. Analysis will also be performed at 3, 6, and 12 months post therapy 
1.2 
We will also evaluate and attempt to identify changes in pretreatment T-cell subsets 
and cytokines in up to 10 participants via cytometry by time of flight (Cy-TOF) on 
subjects pre-treatment, following cycle 3, and at the conclusion of therapy. 
2.0 
BACKGROUND 
Brentuximab vedotin has the potential to destroy all cells that are CD30 positive, as seen 
in the HRS cell. Heiser et al. attempted to understand the distribution of CD30 expression 
across all T-cell subets.93 There data demonstrated that CD30 expression was identified 
mostly in the T-regulatory cells. While these cells have many roles, one of their main 
functions is to suppress CD8+ and CD4+ T-cell proliferation. In co-incubation experiments 
in vitro, it was demonstrated that when CD8+ and FOX-P3+ T-regulatory cells were co-
incubated, as T-regulatory T-cells decreased in number CD8+ T-cells also increased in 
number when challenged with brentuximab vedotin.93 
Preliminary data from this study realized in an interim analysis identified that CD4+ T-
cells as well as CD8+ T-cells increased in just about 1 month after AVD-BV treatment in 
essentially all subjects enrolled to date (unpublished data). To see if this was an effect of 
brentuximab vedotin, 54 patients with HIV-associated Hodgkin Lymphoma were identified 
at County Hospital in Chicago. To exclude the possibility that uncontrolled HIV was a 
cause for a drop in the CD4+ T-cell counts in subjects, patients with undetectable viral 
loads were identified. Of the patients with undetectable viral loads treated with ABVD, 
80% of the subjects had drops in CD4+ T-cell counts about 1-2 months post chemotherapy. 
Additionally, when CD8+ T-cell counts were analyzed in subjects treated with ABVD, 
100% had drops in CD8+ T-cell counts (unpublished data). Based on the interim analysis 
of AMC-085, the increase in CD4 T cell counts was observed only in patients that were 
treated with AVD-BV but not with ABVD. 
The fact the in subjects with ABVD had drops in CD8 and CD4+ T-cell counts while 
subjects with AVD-BV had elevations, points to brentuximab vedotin as the causative 
agent of the elevation. Combining this data with the data presented by Heiser and 
colleagues, points to the cause of the elevation as T-regulatory T-cell destruction. We 
hypothesize that brentuximab vedotin achieved T-regulatory T-cells destruction, 
thereby causing total CD8+ and total CD4+ T-cell count elevation. The purpose of 
this correlative study is to prove that this is the mechanism seen in vivo in subjects 
with HIV-associated cHL. 


 
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3.0 
RATIONALE 
The results of this study will provide information on immune activation/inflammation-
associated biomarker plasma levels in HIV-associated HL, and on effects of AVD-BV 
therapy for HL on these biomarkers, as well as on the prognostic value of such biomarkers 
in those receiving AVD-BV treatment. 
4.0 
EVALUATIONS 
Plasma levels of cytokines will be determined as described in Appendix X at the AMC 
Biomarkers Core Laboratory (Otto Martinez-Maza). The cytokine analysis will be 
performed pre-treatment, following cycle 1, cycle 3, and at the conclusion of therapy. 
Analysis will also be performed at 3, 6, and 12 months post therapy. T-cell subsets and 
further cytokine analysis will be examined pre-treatment, following cycle 3, and at the 
conclusion of therapy (6-8 weeks post-treatment discontinuation). The PBMC utilized for 
the CyTOF portion of this study will rely on aliquots of cells received for the HIV viral 
reservoirs correlative study utilized in Appendix XII, provided that the participant has 
consented to the additional use of his/her specimens in future research by the ACSR. The 
T-cell subset and cytokine assays performed by CyTOF and flow cytometry will be 
performed by Dr. Robert Baiocchi’s laboratory (Ohio State University AMC site). No 
additional blood draws will be required for this correlative study. 
5.0 
ANALYSES 
The working hypothesis that will be tested is that participants who will achieve clinical CR 
will have plasma levels of sCD30, IL-6 and IL-10 that fall within the normal range, 
following the conclusion of therapy. 
Levels of cytokines and inflammation-associated biomarkers will be determined using two 
Luminex-based multiplex assay panels. The first is a high-sensitivity cytokine panel that 
can detect human Granzyme B, IFN-alpha, IFN-beta, IFN-gamma, IL-1 beta, IL-2, IL-4, 
IL-5, IL-7, IL-12 p70, IL-13, IL-15, IL-17A. The second is a soluble receptor/inflammatory 
cytokine panel: CCL17/TARC, CCL22/MDC, CCL24/Eotaxin-2/MPIF-2, CD163, SDF-1 
alpha/CXCL12, IL-6 R alpha, IL-18. 
Both of these panels are produced by R&D Systems, and have been used by the Martinez-
Maza laboratory extensively in prior epidemiologic studies. Both of these cytokine assays 
will be added on to the assay already described in Appendix X, prospectively and for all 
other U.S. participants previously enrolled on AMC-085. 
The T-cell subset and cytokine assays performed by CyTOF and flow cytometry will be 
performed by Dr. Robert Baiocchi’s laboratory (Ohio State University AMC site) for up to 
10 participants. The cells required will be aliquots from blood samples already collected 
from participants in the optional HIV viral reservoir studies in Appendix XII, who have 
also consented for the additional use of his/her specimens in future research by the ACSR. 
Cy-TOF will be used to identify changes in T-cell subsets as described above looking at 
Live/dead dye, CD3, CD4, CD8, CCR7, CD45RA, CCR6, CXCR3, CD30, CD25, CD127, 
HLA-DR, CD38, and CCR4. We will also assay, KI 67, FoxP3, GATA3, and TBET 
(markers for TH1, TH2, and T-regulatory T cells). We will use CyTOF to also validate the 
cytokine portion of the correlative study, assaying pre, during, and post therapy levels. 


 
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6.0 
SHIPPING INSTRUCTIONS AND SAMPLE PROCESSING 
No additional samples will be collected for these correlative studies. Samples will be 
designated for this study as noted above under item 4 (Evaluations). 
7.0 
AMC BIOREPOSITORY INSTRUCTIONS ONLY 
The AMC Biorepository will send all plasma aliquots available for cytokine analysis in 
batch at the end of the study to as stated in Appendix X, for performance of these assays. 
For the T-cell subset analysis, cytokine, and CyTOF of PBMCs collected not utilized for 
the viral reservoir studies will be designated for this study. For up to 10 participants 
meeting the consent requirements for the HIV viral reservoirs study and for future use of 
residual study specimens by the ACSR, the AMC Biorepository will send 2 aliquots of 
PBMCs containing 5 million PBMCs each pre, end of cycle 3, and post therapy will be 
sent to the Baiocchi laboratory at Ohio State University. These aliquots will be apportioned 
from samples that are collected as described in Appendix XII. 
 
 


 
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APPENDIX XV: AMC-085 LYSARC PROTOCOL 
To expand international collaborations in the AMC and facilitate recruitment goals, participation 
in the phase II portion of the AMC-085 study was extended to The Lymphoma Study Association 
(LYSA), and being conducted by The Lymphoma Academic Research Organisation (LYSARC) 
in France. The content of the LYSA/LYSARC AMC-085 protocol does not vary from the original 
AMC-085 protocol. The AMC-085 protocol version that was approved by the French regulatory 
authority has been added as an appendix for reference in U.S. regulatory submissions. 
The protocol provided in this appendix applies only to the participating LYSA sites. Accrual 
at all LYSA sites concluded on 30 November 2017. 
 


 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
131 
  
 
 
 
INTERGROUP STUDY: AMC-085 
A Pilot Trial of AVD and Brentuximab Vedotin (SGN-35) in the treatment of 
stage III-IV HIV- associated Hodgkin Lymphoma 
A STUDY SPONSORED BY: LYSARC 
THE LYMPHOMA ACADEMIC RESEARCH ORGANISATION 
Centre Hospitalier Lyon Sud - Secteur Sainte Eugénie – Pavillon 6D 69495 Pierre Bénite 
Cedex– France 
COORDINATING GROUP: AMC (AIDS MALIGNANCY CONSORTIUM) 
Cet essai, soutenu par l’Institut National du Cancer, est réalisé dans le cadre de la collaboration 
entre le National Cancer Institute américain et l’Institut National du Cancer. 
COORDINATING INVESTIGATOR 
CO- COORDINATING 
INVESTIGATOR 
Pr. Caroline BESSON 
Pr. Nicolas MOUNIER 
PROTOCOL CHAIR 
PROTOCOL CO-CHAIR 
Dr. Paul G. RUBINSTEIN 
Dr. Ariela NOY 
STATISTICAL COORDINATOR 
Milan Bimali, AMC Statistical Center 
PATHOLOGICAL COORDINATOR 
Pr. Sophie Prevot (Hopital Beclere) and  
Dr. Bettina Fabiani (Hopital Saint Antoine) 
COORDINATION CENTER 
LYSARC 
REGISTRATION 
SEE SECTION 11.1 
AE AND SAE REPORTING 
SEE SECTION 13 
Version and date of Protocol: 6.0 final on 15/04/2019 
EudraCT number: 2014-003678-18 
ClinicalTrials.gov ID: 02298257 
 
 
 


 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
132 
CONFIDENTIALITY STATEMENT 
The information contained in this document is the property of The Lymphoma Academic Research 
Organisation (LYSARC) and therefore is provided to you in confidence for review by you, your 
staff, an applicable Ethics Committee/Institutional Review and regulatory authorities. It is 
understood that the information will not be disclosed to others without prior written approval from 
the Lymphoma Academic Research Organisation (LYSARC), except to the extent necessary to 
obtain informed consent from those persons to whom the medication may be administered. 
 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
0 
PROTOCOL SIGNATURE PAGE 
AMC-085 
A PILOT TRIAL OF AVD AND BRENTUXIMAB VEDOTIN (SGN-35) IN THE TREATMENT OF 
STAGE III-IV HIV-ASSOCIATED HODGKIN LYMPHOMA 
LYSARC 
 
 
  
 
Name: Pascal DESCHASEAUX 
Date Title: General Manager 
 
COORDINATING INVESTIGATORS 
 
 
  
 
Name: Dr Caroline BESSON 
Date 
Title: Coordinating Investigator 
 
 
  
 
Name: Prof Nicolas MOUNIER 
Date 
Title: Co-Coordinating Investigator 
 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
1 
1.0 
SYNOPSIS 
Study ID 
Eudract N° 
AMC-085 
2014-003678-18 
Title of the study 
A Pilot Trial of AVD and Brentuximab Vedotin (SGN-
35) in the treatment of stage III-IV HIV-associated 
Hodgkin Lymphoma 
Development phase of the study 
Phase II 
Investigational product 
Brentuximab Vedotin 
Protocol version 
1 
Sponsor 
LYSARC 
Coordinating investigator  
Co- coordinating investigator 
Pr Caroline BESSON 
Pr Nicolas MOUNIER 
Centres 
7 centers 
Study Objectives and endpoints 
Primary objective: 
• To establish an estimate of the two-year 
progression-free survival (PFS) for patients with 
HIV-associated stage III-IV Hodgkin lymphoma 
when treated using brentuximab vedotin plus the 
AVD chemotherapy regimen. 
See paragraph 6.1 
Secondary objectives: 
• To evaluate the toxicity of AVD and brentuximab 
vedotin with highly active antiretroviral therapy 
(HAART). 
• To estimate the partial response (PR) rate, complete 
response (CR) rate, overall survival (OS), and event 
free survival (EFS) at 2 and 5 years. 
• To evaluate the effect of AVD and brentuximab 
vedotin on CD4 and CD8 counts after cycle 1, 4, at 
the end of therapy, and every 3 months after 
treatment completion for one year. 
• To investigate the prognostic value of FDG-
PET/CT scans at baseline, after cycle 2, and at 
treatment completion, with respect to 2-year 
progression free survival. 
• To evaluate HAART status at baseline and to 
correlate this with tumor response to therapy and 
OS and PFS. 
• To characterize the histologic subtypes in HIV-HL in 
the HAART era. 
• To assess the neurotoxicity of HAART in 
combination with AVD and brentuximab 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
2 
vedotin. 
• To evaluate effect of AVD and brentuximab vedotin 
on viral load after cycle 1, 4, at the completion of 
therapy, and every 3 months after treatment 
completion for one year. 
See paragraph 6.2 
Study design 
This study is a multicenter, phase II trial. 
See paragraph 7 
Duration of the study 
Patients will receive brentuximab vedotin 1.2 mg/kg in 
conjunction with standard, fixed, doses of doxorubicin 
25 mg/m², vinblastine 6 mg/m², and dacarbazine 375 
mg/m² on days 1 and 15 of a 28-day cycle for 6 cycles. 
Patients will be followed for a total of 5 years, every 3 
months for the first 2 years and every 6 months for years 
3 to 5 of follow up. 
Patients who discontinue all protocol therapy after 
having a CR or PR are followed for up to 5 years after 
treatment for recurrence and survival. Patients who 
discontinue protocol therapy due to disease progression 
or other reasons (Section12) are followed for survival 
only for up to 5 years after treatment or until death, 
whichever occurs first. Patients who cross over to non-
protocol therapy (if PR or stable disease at physician 
discretion), or other reasons will be followed for 
survival for up to 5 years after treatment. Participants 
removed from study for unacceptable adverse event(s) 
will be followed until resolution or stabilization of the 
adverse event. 
Duration of recruitment : 24 months 
Duration of treatment per patient: 6 cycles of 4 weeks = 
24 weeks Duration of follow up: 5 years 
Number of patients 
20 patients in France among 51 patients in protocol 
developed by AMC 
The title of the AMC study is AMC PROTOCOL #085: 
A Pilot Trial of AVD and Brentuximab Vedotin (SGN-
35) in the treatment of stage II-IV HIV-associated 
Hodgkin Lymphoma. 
Inclusion criteria 
1. Age ≥ 18 years. Because no dosing or adverse 
event data are currently available on the use of 
brentuximab vedotin in combination with AVD 
in patients <18 years of age, children are 
excluded from this study. 
2. HIV-1 positive. Documentation of HIV-1 
infection by means of one of the following: 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
3 
3. Documentation of HIV diagnosis in the medical 
record by a licensed health care provider; 
4. Documentation of receipt of ART by a licensed 
health care provider; 
5. HIV-1 RNA detection by a licensed HIV-1 RNA 
assay demonstrating > 1000 RNA copies/mL; 
6. Any licensed HIV screening antibody and/or 
HIV 
antibody/antigen 
combination 
assay 
confirmed by a second licensed assay such as a 
HIV-1 Western blot confirmation or HIV rapid 
multispot antibody differentiation assay. 
7. Histologic diagnosis of CD30-positive classical 
HL as defined by the 2008 WHO Classification 
of Hematological diseases. Nodular lymphocyte 
predominant Hodgkin Lymphoma is not eligible. 
8. Stage III or IV disease as defined by the Ann 
Arbor Staging System. 
9. Participants must have previously untreated 
HIV-cHL, with the exception of up to 14 
consecutive 
days 
of 
steroids, 
emergency 
radiation, or 1 prior cycle of cyclophosphamide 
to 
reduce 
tumor 
burden 
and 
improve 
hyperbilirubinemia in the setting of lymphoma 
related liver involvement. 
10. Normal baseline cardiac ejection fraction ≥ 50%. 
11. Serum creatinine of ≤ 1.5 mg/dL. If creatinine 
>1.5 mg/dL (133 micromol/L), creatinine 
clearance must be ≥ 60 mL/minute according to 
MDRD/Cockroft-Gault formula. 
12. ANC ≥ 1000/µL and platelets ≥ 75,000/µL 
unless related to bone marrow involvement by 
HIV-cHL. 
13. Total bilirubin must be < 1.5x the upper limit of 
normal, unless the elevation of bilirubin is 
thought to be seconday to Gilbert’s syndrome or 
cART. 
• If, however, the elevated bilirubin is felt to 
be secondary to antiretroviral therapy, the 
total bilirubin must be ≤ 3.5 mg/dL (60 
µmol/L), provided that the direct bilirubin is 
normal and the AST and ALT ≤ 3 x the upper 
limit of normal. 
• If the elevation of bilirubin is thought to be 
secondary to Gilbert’s syndrome, the total 
bilirubin must be ≤ 3x the upper limit of 
normal or the direct bilirubin must be ≤ 1.5x 
the upper limit of normal. 
• Also, if the elevated bilirubin is thought to be 
secondary to cHL the same criteria for 


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hyperbilirubemeimia should be applied; 
however 1 prior cycle of cyclophosphamide 
is permitted in attempt to make the 
participant eligible (see section 8.1.5). 
Patients should not be excluded from study 
participation unless dosing cannot be safely 
established per Section 10.6.2. 
14. Female subjects must have a negative pregnancy 
test within 1 week of enrollment and all subjects 
must agree to use two reliable methods of 
contraception simultaneously if conception is 
possible during the study. 
15. Should a woman subject become pregnant or 
suspect she is pregnant while the subject is 
participating in this study, she should inform her 
treating physician immediately. The patient will 
then be removed from protocol therapy. 
16. Subjects who father a child while participating in 
the study will be permitted to continue with the 
protocol. The subject, however, is required to 
notify the investigator if he fathers a child. 
17. Ability to understand and the willingness to sign 
a written informed consent document. 
18. Karnofsky performance status > 30% (given the 
aggressiveness of this disease and the often 
severely debilitated nature of the patients at 
initial presentation). See Appendix 20.5. 
19. Measurable or non-measurable (evaluable) 
tumor parameter(s). Nonmeasurable tumor 
parameters will be defined as not having bi-
dimensional measurements (i.e., gastric or 
marrow involvement) but can be followed for 
response by other diagnostic tests such as 
gallium, PET imaging and/or bone marrow 
biopsy. 
20. Patients already receiving erythropoietin or 
GCSF for treatment of HIV-related cytopenia 
are eligible. 
21. CD4 count ≥ 100 cells/μl and serum HIV viral 
load <50copies/ml. 
22. Subjects are required to be on antiretroviral 
regimens that are in accordance with the current 
International 
AIDS 
Society 
guidelines 
concurrently 
with 
chemotherapy. 
Use 
of 
experimental antiretroviral agents or those 
containing zidovudine (including Combivir and 
Trizivir) or ritonavir (includes Norvir® or 
Kaletra®), cobicistat, or Didanosine (Videx® or 
Videx EC®), or similar potent CYP3 inhibitors 


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are prohibited, as explained in Section Error! 
Reference source not found.. In order to be 
eligible, patients taking zidovudine or ritonavir 
or didanosine, or cobicistat or Didanosine, or 
other CYP3 inhibitors must change to a different 
regimen 7 days prior to therapy initiation. 
Subjects must be on HAART for at least 7 days 
prior to therapy. See section 10.3 
23. Patients will be required to obtain a pulmonary 
function test, despite the exclusion of bleomycin 
from protocol regimen. The subject’s diffusing 
capacity of the lung for carbon monoxide 
(DLCO) adjusted for hemoglobin must be 
greater than 70% predicted to enter the study and 
to continue with brentuximab vedotin. 
24. Negative for Hepatitis B, or if infected with 
Hepatitis B, receiving anti- Hepatitis B therapy. 
All subjects will be required to be screened for 
Hepatitis B. Per IDSA and AASD guidelines, 
those subjects that show no immunity, defined 
by the lack of Hepatitis B surface antibody, and 
show evidence of chronic infection (i.e., 
HBsAg+, HBcore+, HBsAB-) will be required to 
be on anti-Hepatitis B therapy during the study 
in order to be eligible. Patients will be permitted 
to enroll in the study provided normal liver 
function tests (see Section 9.3) and no evidence 
of cirrhosis. The exact Hepatitis B therapy will 
be at the discretion of the infection disease 
specialist or investigator. However all patients 
who present with acute hepatitis B or show 
normal transaminases and are HBsAg+ and 
IgM+ for Hepatitis core antigen will not be 
eligible for trial enrollment. 
25. Patients diagnosed with Hepatitis C who are 
Hepatitis C antibody positive, whether Hepatitis 
C RNA level is measurable or not, must have no 
evidence of cirrhosis and have liver function 
tests that conform to Section 9.3. 
26. Brentuximab vedotin is partially metabolized via 
the CYP3A4 pathway and is cleared from the 
cells via the P-glycoprotein pump. Therefore, 
participants must discontinue use of the 
following agents at least 7 days prior to therapy 
as per Appendix 20.9. 
27. Strong CYP 3A4 inhibitors that treat HIV, see 
8.1.16. 
28. Other strong CYP3A inhibitors. 


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29. Moderate CYP3A4 inhibitors should be used 
with Caution but are not excluded. If 2 moderate 
CYP3A4 inhibitors are used concurrently, one 
must be discontinued at least 7 days (1 week) 
prior to the initiation of chemotherapy. 
30. P-glycoprotein inhibitors. 
31. If patients are taking any of these excluded 
medications, they must be discontinued at least 7 
days (1 week) prior to the initiation of 
chemotherapy. 
All concomitant medications must be reviewed by 
the study chair or co-chair prior to enrollment by 
email. 
Because the lists of these agents are constantly 
changing, it is important to regularly consult a 
frequently-updated medical reference for a list of 
drugs to avoid or minimize use of. 
 
See paragraph 8.1 
Exclusion criteria 
Patients who do not fulfill the criteria as listed in Section 
8.1, are ineligible. Additionally, the presence of any of 
the following conditions will exclude a subject from 
study enrollment: 
1. Patients with prior anthracycline therapy will be 
excluded. 
2. Female subjects who are pregnant or breast-
feeding. Confirmation that the subject is not 
pregnant must be established by a negative serum 
b-human 
chorionic 
gonadotropin 
(b-hCG) 
pregnancy test result obtained during screening. 
Pregnancy testing is not required for post-
menopausal or surgically sterilized women. 
3. Medical illness unrelated to HL, which in the 
opinion of the study physician will preclude 
administration of chemotherapy safely. This 
includes patients with uncontrolled infection 
(including opportunistic), chronic renal failure, 
myocardial infarction (MI) within the past 6 months, 
unstable angina, or cardiac  arrhythmias other than 
chronic atrial fibrillation. 
4. Prior malignancy within 5 years of enrolment 
other than curatively treated cutaneous basal 
cell or squamous cell carcinoma, carcinoma in 
situ of the cervix, anal intraepithelial neoplasia, 
or cutaneous Kaposi’s sarcoma (KS). 
5. Grade 2 or greater peripheral neuropathy. 
6. Evidence of PML identified on the pretreatment 


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MRI. 
7. Central nervous system disease. 
8. Patients with history of JC Virus identified in 
the CSF or previous history of PML will be 
excluded from the study. 
9. Cirrhosis secondary to any cause will be excluded. 
See paragraph 8.2 
Study treatment 
AVD dosing, in conjunction with brentuximab vedotin 
will be as described in Table 2. Drugs will be given on 
days 1 and 15 on a 28-day cycle for a total of 6 cycles. 
Brentuximab Vedotin will be administered after AVD 
(doxorubicin 
25 
mg/m2, 
vinblastine 
6 
mg/m2, 
dacarbazine 375 mg/m2). 
Doxorubicin 
Vinblastine 
Dacarbazine Brentuximab 
Vedotin 
Day 1, 15 
Of 28-day 
cycle 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day 
cycle 
Day 1, 15 
Of 28-day cycle 
25 mg/m2 
6 mg/m2 
375 mg/m2 
1.2 mg/kg 
Maximal 
dose=120 mg. 
See paragraph 10 
Assessment schedule 
See paragraph 9 
See flowchart 20.2 
Statistical consideration 
Sample size calculation 
In the Phase II portion of the study, 51 patients 
worldwide will be enrolled to estimate the 2-year 
progression free survival. Sample size calculation is 
based on providing an estimate of the PFS with a 95% 
confidence interval ±10% under the hypothesis that 2-
year PFS is 85%. 
Analysis plan 
The primary endpoint of the phase II portion will be 
to estimate the two-year progression-free survival 
for AVD-brentuximab vedotin which will be done 
using Kaplan-Meier estimates and corresponding 
95% confidence intervals based on standard errors 
using Greenwood’s formula. 
Descriptive summaries and exploratory analyses for 
secondary objectives will be conducted. Significance 


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for comparisons will be at the p<0.05 level. 
See paragraph 15 
 
 


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2.0 
TABLE OF CONTENTS 
PROTOCOL SIGNATURE PAGE ........................................................................................ 0 
1.0 
SYNOPSIS .................................................................................................................... 1 
2.0 
TABLE OF CONTENTS ............................................................................................ 9 
3.0 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS ............................. 12 
4.0 
RESPONSIBILITIES ................................................................................................ 15 
4.1 
Sponsor and Program Coordination Center ......................................... 15 
4.2 
Investigators ......................................................................................... 17 
4.3 
Laboratory Sites ................................................................................... 17 
5.0 
BACKGROUND AND STUDY RATIONALE ....................................................... 18 
5.1 
Hodgkin Lymphoma ............................................................................ 18 
5.2 
Hodgkin Lymphoma in HIV Patients .................................................. 18 
5.3 
Current treatment for HIV-related HL ................................................. 19 
5.4 
Rationale for the use of brentuximab vedotin in HIV-cHL ................. 21 
5.5 
Rationale for substitution of brentuximab vedotin for bleomycin in 
ABVD regimen .................................................................................... 22 
5.6 
Considerations regarding progressive multifocal leukoencephalopathy 
associated with HIV, brentuximab vedotin, and HIV-cHL ................. 23 
5.7 
Rationale for use of concurrent HAART with HL treatment .............. 24 
5.8 
Rational for use of PET scans in HIV patients and HIV-HL ............... 24 
5.9 
Brentuximab vedotin relevant preclinical data .................................... 25 
5.10 
Study Design and Rationale ................................................................. 25 
6.0 
STUDY OBJECTIVES .............................................................................................. 27 
6.1 
Primary Objective ................................................................................ 27 
6.2 
Secondary Objectives ........................................................................... 27 
7.0 
STUDY DESIGN ........................................................................................................ 28 
8.0 
STUDY POPULATION ............................................................................................ 29 
8.1 
Inclusion criteria .................................................................................. 29 
8.2 
Exclusion criteria ................................................................................. 31 
9.0 
STUDY FLOW CHART AND SCHEDULE OF ASSESSMENTS ...................... 32 
9.1 
Study flow chart ................................................................................... 32 
9.2 
Informed consent ................................................................................. 32 
9.3 
Baseline examination ........................................................................... 32 
9.4 
Evaluation during treatment ................................................................. 33 
9.5 
Follow-up assessments......................................................................... 34 
9.6 
Early Discontinuation of Therapy ........................................................ 35 


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10.0 
TREATMENTS.......................................................................................................... 36 
10.1 
Treatment schedule and design ............................................................ 36 
10.2 
Radiation Therapy ................................................................................ 36 
10.3 
HAART ................................................................................................ 36 
10.4 
Administration of chemotherapy ......................................................... 36 
10.5 
Drugs description, storage and handling .............................................. 37 
10.6 
Dose adjustments ................................................................................. 39 
10.7 
Drug Dispensation and accountability ................................................. 46 
10.8 
Concomitant treatment restrictions ...................................................... 47 
10.9 
Reporting requirements for concomitant medications ......................... 48 
10.10 Prophylactic measures ......................................................................... 48 
11.0 
STUDY PROCEDURES ........................................................................................... 49 
11.1 
Registration and inclusion procedure ................................................... 49 
11.2 
Pathological diagnosis ......................................................................... 49 
11.3 
Biological study/ samples .................................................................... 49 
12.0 
CRITERIA FOR PREMATURE DISCONTINUATION OF THE STUDY ....... 51 
12.1 
Premature withdrawal from trial intervention ...................................... 52 
12.2 
Withdrawal of Consent ........................................................................ 52 
12.3 
Patients Lost to Follow up ................................................................... 53 
12.4 
Premature discontinuation of the study ................................................ 53 
13.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS ................. 54 
13.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for 
Brentuximab Vedotin (SGN-35, NSC 749710) ................................... 54 
13.2 
Classification of AEs by Severity and Relationship to Study Drug 
Administration ..................................................................................... 60 
13.3  Expedited Adverse Event Reporting .................................................... 61 
13.4 
Routine Adverse Event Reporting ....................................................... 64 
13.5 
Secondary Malignancy ......................................................................... 64 
14.0 
EFFICACY AND SAFETY MEASUREMENTS ................................................... 65 
14.1 
Efficacy Measurements ........................................................................ 65 
14.2 
Response Assessment .......................................................................... 65 
14.3 
Safety Measures ................................................................................... 67 
15.0 
STATISTICAL CONSIDERATIONS ..................................................................... 68 
15.1  Study Design/Endpoints....................................................................... 68 
15.2 
Sample Size/Accrual Rate .................................................................... 69 
15.3 
Stratification Factors ............................................................................ 69 


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15.4 
Analysis of Secondary Endpoints ........................................................ 69 
16.0 
STUDY MONITORING ........................................................................................... 71 
16.1 
Responsibilities of investigators .......................................................... 71 
16.2 
Responsibilities of the sponsor ............................................................ 71 
16.3 
Source document requirements ............................................................ 71 
16.4 
Use and completion of electronic case report form (eCRF) ................ 71 
17.0 
ETHICAL AND REGULATORY STANDARDS .................................................. 73 
17.1 
Ethical Principles ................................................................................. 73 
17.2 
Laws and Regulations .......................................................................... 73 
17.3 
Informed Consent................................................................................. 73 
17.4 
Ethics Review Committee and Competent Authorities Submission .... 73 
18.0 
ADMINISTRATIVE PROCEDURES ..................................................................... 74 
18.1 
Curriculum Vitae ................................................................................. 74 
18.2 
Registration with CTEP ....................................................................... 74 
18.3 
Confidentiality Agreement................................................................... 74 
18.4 
Record Retention in Investigating Center(s) ........................................ 74 
18.5 
Ownership of Data and Use of the Study Results ................................ 74 
18.6 
Publication ........................................................................................... 74 
18.7 
Insurance Compensation ...................................................................... 75 
18.8 
Company Audits and Inspections by Regulatory Agencies ................. 75 
18.9 
Clinical study Report ........................................................................... 75 
18.10 Protocol Amendments .......................................................................... 75 
19.0 
REFERENCES ........................................................................................................... 77 
20.0 
APPENDIXES ............................................................................................................ 83 
20.1 
Appendix Study Design ....................................................................... 83 
20.2 
Appendix Schedule of Evaluations (study flow-chart) ........................ 84 
20.3 
Appendix Ann Arbor Staging .............................................................. 88 
20.4 
Appendix Body Surface Area Calculation ........................................... 89 
20.5 
Appendix Performance Status Criteria ................................................ 90 
20.6 
Appendix FACT-GOG-Neurotoxicity Questionnaire v4.0 .................. 91 
20.7 
Appendix Pathological Samples Review ............................................. 92 
20.8 
Appendix Biological samples for further ancillary studies .................. 93 


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3.0 
LIST OF ABBREVIATIONS AND GLOSSARY OF TERMS 
ABBREVIATION 
TERM 
ABVD ............................... Adriamycin (=Doxorubicin), Bleomycin, Vinblastine, Dacarbazine 
ADC ................................................................................................... Antibody-Drug Conjugate  
AdvantageEDCSM ................................................................ AMC Internet Data Entry System  
AE ........................................................................................................................ Adverse Event 
AIDS ............................................................................ Acquired ImmunoDeficiency Syndrome 
AJCC ............................................................................... American Joint Committee on Cancer 
ALCL .................................................................................... Anaplastic Large Cell Lymphoma 
ALT (SGPT) ........................ ALanine Transaminase (Serum Glutamic Pyruvic Transaminase)  
AMC ................................................................... AIDS Malignancy Consortium Clinical Trials 
ANC ................................................................................................. Absolute Neutrophil Count 
ASCO ........................................................................... American Society of Clinical Oncology 
ASCT ..................................................................................... Autologous Stem Cell Transplant 
AST (SGOT) ............... ASpartate Transaminase (Serum Glutamic Oxaloacetic Transaminase)  
AVD .................................................... Adriamycin (= Doxorubicin), Vinblastine, Dacarbazine 
AVD-BR .................................... Adriamycin, Vinblastine, Dacarbazine-BRentuximab vedotin  
AZT ............................................................................................................................ Zidovudine 
BCSAP .................................................................................... B-cell Specific Activator Protein 
βHCG ............................................................................... beta-Human Chorionic Gonadotropin 
BSA ............................................................................................................... Body Surface Area 
cART ...................................................................................... Combined Antiretroviral Therapy 
CBC............................................................................................................ Complete Blood Cell 
CFR ................................................................................................ Code of Federal Regulations 
cHL ............................................................................................. Classical Hodgkin Lymphoma 
cm ................................................................................................................................ centimeter 
CR ................................................................................................................ Complete Response 
CRF ................................................................................................................. Case Report Form 
CSF .............................................................................................................. Cerebrospinal Fluid 
CT .......................................................................................................... Computed Tomography 
CTCAE ...................................................... Common Terminology Criteria for Adverse Events 
CTEP ................................................................................. Cancer Therapy Evaluation Program  
CTEP ................................................................. AERS CTEP Adverse Event Reporting System  
DARF  ................................................................................... Drug Accountability Record Form 
DCTD ................................................................... Division of Cancer Treatment and Diagnosis 
DDI ............................................................................................................................ Didanosine 
DFS ........................................................................................................... Disease Free Survival 
DHHS ...................................................................... Department of Health and Human Services 
DLCO ..................................................... Diffusing Capacity of the Lung for Carbon Monoxide 
DLT ........................................................................................................ Dose Limiting Toxicity 
DNA ......................................................................................................... Deoxyribonucleic acid 
DTIC ........................................................................................................................ Dacarbazine 
DSUR .................................................................................. Development Safety Update Report 


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EBV.................................................................................... Epirubicin, Bleomycin, Vinorelbine 
EBVP .............................................................. Epirubicin, Bleomycin, Vinorelbine, Prednisone 
ECOG .............................................................................. Eastern Cooperative Oncology Group 
EFS ............................................................................................................... Event Free Survival 
ELISA ........................................................................... Enzyme Linked Immunosorbent Assay 
ESA ....................................................................................... Erythropoiesis Stimulating Agents 
FDA............................................................................................. Food and Drug Administration 
FDG-PET ................................................ Fluorodeoxyglucose-Positron Emission Tomography  
GCP .......................................................................................................... Good Clinical Practice 
GCSF............................................................................ Granulocyte Colony-Stimulating Factor 
HAART ............................................................................. Highly Active Antiretroviral therapy 
HBV ................................................................................................................. Hepatitis B Virus 
HIV ......................................................................................... Human Immunodeficiency Virus 
HL ............................................................................................................... Hodgkin Lymphoma 
HRS .............................................................................................................. Reed Stemberg Cell 
IDMC...............................................................................Independent Data Monitoring Committee 
IDSA ............................................................................. Infectious Diseases Society of America 
IP ............................................................................................................. Investigational Product 
IPI ................................................................................................ International Prognostic Index 
IPS ............................................................................................... International Prognostic Score 
IV ............................................................................................................................. IntraVenous 
JCV ....................................................................................................... John Cunningham Virus 
kg.................................................................................................................................... kilogram 
LDH ........................................................................................................ Lactic DeHydrogenase 
LVEF..................................................................................... Left Ventricular Ejection Fraction 
LYSA ................................................................................... The Lymphoma Study Association 
LYSARC ...................................................... The Lymphoma Academic Research Organisation 
miRNA ........................................................................................................... Mature microRNA 
MMAE ................................................................................................ Monomethyl Auristatin E 
MRI .............................................................................................. Magnetic Resonance Imaging 
MUGA ..................................................................................... Multiple Gated Acquisition scan 
NADC ............................................................................................. Non-AIDS Defining Cancer 
NCCN ....................................................................... National Comprehensive Cancer Network 
NCI ....................................................................................................... National Cancer Institute 
NHL ................................................................................................... Non-Hodgkin Lymphoma 
NLPHL .................................................. Nodular Lymphatic Predominant Hodgkin Lymphoma 
NNRT ............................................................. Non-nucleoside Reverse Transcriptase Inhibitors 
NSC ........................................................................................................ National Service Center 
ODMC........................................................................ Operations and Data Management Center 
OS ..................................................................................................................... Overall Survival 
PD ................................................................................................................ Progressive Disease 
PET ............................................................................ 18F-FDG Positon Emission Tomography 
PCR .................................................................................................. Polymerase Chain Reaction 


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PFS ..................................................................................................... Progression Free Survival 
PFT ...................................................................................................... Pulmonary Function Test 
PK ................................................................................................................... PharmacoKinetics 
PML .................................................................... Progressive Multifocal Leukoencephalopathy 
PO ................................................................................................................. Per oral [by mouth] 
PR ...................................................................................................................... Partial Response 
RNA ............................................................................................................ Ribose Nucleic Acid 
SAE ......................................................................................................... Serious Adverse Event 
SD ......................................................................................................................... Stable Disease 
SPD ................................................................................... Sum of the Product of the Diameters 
SPM................................................................................................ Second Primary Malignancy 
SUSAR .......................................................... Suspected Unexpected Serious Adverse Reaction 
SUV................................................................................................ Standardized Uptake Values 
TMA ............................................................................................................. Tissue Micro Array 
ULN ........................................................................................................ Upper Limit of Normal 
WHO ................................................................................................ World Health Organization 
 


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4.0 
RESPONSIBILITIES 
4.1  
Sponsor and Program Coordination Center 
4.1.1 Sponsor 
LYSARC (the Lymphoma Academic Research Organisation) 
: Centre Hospitalier Lyon Sud – Secteur Sainte Eugénie - Pavillon 6D F-
69495 Pierre Bénite Cedex 
: +33(4) 72 66 93 33 
Fax: +33(4) 72 66 93 71 
Email: amc-085@lysarc.org 
4.1.2 Coordinating Investigators 
Pr Caroline BESSON 
: Service d’hématologie et oncologie  
 
177, rue de Versailles - 78150 LE 
CHESNAY 
 France 
  0145212577 
Email : caroline.besson@bct.aphp.fr 
Prof Nicolas Mounier 
 CHU de Nice 
Service d'Onco-Hématologie - 
151 route St Antoine de 
Ginestière 06202 Nice 
FRANCE 
 
04 92 03 58 41 
Email : mounier.n@chu-nice.fr 
4.1.3 Protocol Chair 
Protocol Chair 
Paul G. Rubinstein, MD 
John H. Stroger Jr. Hospital of Cook 
County (Cook County Hospital) 
Section of Hematology/Oncology 
Administration Building 
1900 W. Polk Street, Suite 755 
Chicago, IL 60612 
Tel: 312-864-7277 
Fax: 312-864-9002 
Email: 
prubinstein@cookcountyhhs.org 
Protocol Co-Chair 
Ariela Noy, MD 
Memorial Sloan-Kettering 
Cancer Center Lymphoma 
Service 
1275 York Avenue  
New York, NY 10065  
Tel: 212-639-7423 
Fax: 646-422-2284 
Email: noya@mskcc.org 
 
 
 


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4.1.4 Program Coordination Center 
Protocol Statistician 
Milan Bimali, PhD 
AMC Statistical Center 
University of Arkansas for Medical 
Sciences  
4301 West Markham Street 
Little Rock, AR 72205  
Tel: 501-686-8204 
Fax: 501-526-6729 
Email: mbimali@uams.edu 
Data Management/Operations 
AMC Operations and Data 
Management Center 
The Emmes Corporation 
401 N. Washington Street,  
Suite 700 
Rockville, MD 20850 
Tel: 301-251-1161 
Fax: 240-238-2842 
Email: amcpm@emmes.com 
Project Manager 
Ombeline Vérité 
Clinical Project Managers 
 Centre Hospitalier Lyon Sud 
 
Secteur Sainte Eugénie - 
Pavillon 6D 69495 PIERRE-
BENITE Cedex – FRANCE 
 +33 (0) 4 72 66 93 33 
Fax: +33 (0) 4 72 66 38 57 
Email: ombeline.verite@lysarc.org 
 
4.1.5 Biological/Pathological coordinator 
Nadine VAILHEN, Director of Biological and Histopathological Operations 
 
CHU Henri Mondor - 51, av. du Maréchal de Lattre de Tassigny 94010 
CRETEIL – FRANCE 
 
Pathological coordinator: 
Dr. Bettina FABIANI 
 Hôpital Saint Antoine -Service d’Anatomie Pathologique - 184, rue du Fg Saint 
Antoine -75012 Paris – FRANCE 
 +33 (0)1 49 28 21 76 
Fax : +33 (0)1 49 28 28 78 
Email:bettina.fabiani@sat.ap-hop-paris.fr 
Biological coordinator: 
Dr. Yassine TAOUFIK 
 CHU Bicêtre - Service d’hématologie-immunologie biologiques 78, rue du 
Général Leclerc 94275 LE KREMLIN BICETRE 
 01 45 21 35 94 
Email: yassine.taoufik@bct.aphp.fr 
 


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4.2 
Investigators 
All participating LYSA centers from France may include patients in this study. Before 
any inclusion, each center must be declared to the Ethical Committee and national 
competent authority according to each country regulations and have had the initiation 
visit/call. To be declared as a participating center, the principal investigator must send 
to the LYSARC all administrative documents required for regulatory submission (e.g., 
Curriculum vitae, for France the affiliation medical association number [e.g., CNOM, 
RPPS] etc.). 
4.3 
Laboratory Sites 
Laboratories of each study center must provide their normal values and an updated 
accreditation for quality control. 


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5.0 
BACKGROUND AND STUDY RATIONALE 
5.1 
Hodgkin Lymphoma 
Hodgkin lymphoma (HL) is a lymphoid neoplasm first described by Thomas Hodgkin 
in the 1890s2. The disease presents with or without splenomegaly, fevers, night sweats, 
weight loss and occasionally pruritus. In 2008, 8,220 new cases of HL were diagnosed 
resulting in 1,350 deaths1,3. The transformed cell that defines classic Hodgkin 
lymphoma (cHL) is the Reed Sternberg cell (HRS), a large multinuclear cell expressing 
surface antigens CD15 and CD30 without B or T cell surface antigens1. The cell of 
origin was unclear until the mid-1990s, when it was shown that the tumor originated 
from germinal B cell lymphocytes, as demonstrated by the expression of PAX 5, B-cell 
Specific Activator Protein (BCSAP), and B cell clonality based on single cell PCR of 
the IgH gene4-8. Based on these data, the World Health Organization (WHO) changed 
the name from Hodgkin disease to Hodgkin lymphoma1. The four histological subtypes 
of cHL recognized by the WHO are mixed cellularity, nodular sclerosis, lymphocytic 
depletion, and lymphocyte predominant HL1. Nodular lymphocytic predominant HL 
(NLPHL) is quite different from cHL in that HRS present in NLPHL expresses mature 
B cell antigens, CD20, CD79a, does not express CD15 or CD30, and has a slow 
progressive course1. This trial will only include patients with HIV infection and cHL 
(HIV-cHL) in light the lack of CD30 expression, differences in disease biology, and the 
rarity of NLPHL in the HIV-positive population. 
5.2 
Hodgkin Lymphoma in HIV Patients 
HIV-cHL is one of the most common non-acquired immunodeficiency syndrome 
(AIDS)-defining tumors9. Multiple large database studies of linked cancer and 
HIV/AIDS registries from 1992-2005 in the United States showed that HL represents 
the second to third most common non-AIDS defining cancer (NADC)9,10. One of these 
studies showed that the risk for HIV-cHL was 68% higher in 1996-2002, the post 
HAART era (SIR 13.6), than in 1990-1995 (SIR 8.1)10. In a comparative study 
conducted from 1992 to 2003, the trend over time in cancer rates for the HIV- cHL was 
elevated despite stable rates of HL in the general population11. Studies on HRS 
microenvironment in non- HIV associated HL showed that the HRS were surrounded 
by B and CD4 cells, eosinophils, macrophages, and fibroblasts, all of which affect its 
survival and disease course12,13. This trophic effect, due in part to CD4 cells, has been 
postulated to explain the increase in incidence of HIV-cHL in the post HAART era12-
14. In addition, many observational studies consistently showed that HIV-HL patients 
present with higher CD4 counts compared to other HIV-associated lymphoproliferative 
disorders, with the exception of Burkitt’s lymphoma9-14. 
As a population, patients with HIV have a 10-25 fold increase risk of developing HL, 
and they present with many high-risk characteristics that distinguish it from non-HIV 
cHL15. 
The 
differences 
are 
seen 
in 
patient 
presentation, 
histology, 
immunohistochemistry, molecular changes, and overall outcome15. The International 
Prognostic Score (IPS) for patients with advanced non HIV-HL defined the following 
adverse risk factors: age over 45 years, male gender, stage IV disease, low albumin, 
anemia, lymphopenia, and leukocytosis16. Eighty percent of patients with HIV-cHL 
present with stage III/IV disease, and 70-96% presents with B symptoms15. B 
symptoms, defined as one of the following: 1) drenching night sweats, 2) fever of over 
100.4°F / 38°C for 3 consecutive days, and 3) a weight loss exceeding 10% of body 
weight in 6 months. These are also poor prognostic signs in stage I/II non-HIV HL. The 
two most aggressive histological forms of HL, mixed cellularity and lymphocytic 
depletion are predominate in HIV- cHL compared to the non-HIV population15. In 


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addition, histologically, the HRS is found in much higher concentrations in HIV-cHL 
than non HIV-cHL15. HIV-cHL is associated in 80-100% of the cases with EBV co-
infection of the HRS, though in the non-HIV cHL patients this occurs only with a 
frequency of 30-40%15,17,18. The expression of the Epstein-Barr Virus (EBV) has been 
identified by both single cell polymerase chain reaction (PCR) and co-
immunohistochemical analysis of the HRS in HIV-infected patients 15,17,18. The HRS in 
non-HIV patients are derived from germinal center B cell lymphocytes, on the other 
hand, the origin of HIV-associated HRS have been linked to post germinal lymphocytes 
19. It is interesting to note that diffuse large B-cell lymphoma derived from non-germinal 
center have a worse prognosis than germinal cell derived large cell lymphoma in most 
studies. It is unclear the role each factor plays in disease outcome (i.e., HRS origin, 
EBV co-infection status, presentation, and histology) but it is clear that outcomes for 
patients with HIV-cHL are inferior to HIV-negative patients. 
For HIV-cHL, the median complete remission rate is about 58% with a median survival 
8-20 months in the pre HAART era, which is substantially lower than the median 
complete remission rate of approximately 90% with a median survival of 7 years for 
HIV-negative patients 15,20,21. Retrospective data showed improved overall survival in 
the post HAART compared to treatment without HIV therapy 21,22. Both studies showed 
an improved 2 year overall survival while taking HAART, ranging from 16 to 42% 
depending on the study 21,22. Similarly, of the four HIV-HL trials completed while 
utilizing combined antiretroviral therapy (cART), the overall survival has varied from 
86% at 2 years to 51% at 3 years, an improvement compared to the historical controls 
in the pre HAART era, but still lagging behind historical controls of non-HIV infected 
patients 23-26. Explanations for poorer survival are likely multifactorial, including 
treatment-related toxicity, EBV status, HRS non-germinal cell of origin, tumor biology, 
histology, and presentation. More prospective trials and newer treatments are needed to 
improve on the outcomes of HIV-positive patients to where they are comparable to the 
HIV-negative population. 
5.3 
Current treatment for HIV-related HL 
Currently, no standard of care exists for the upfront treatment of HIV-cHL. Outcomes 
of clinical trials for HIV-cHL in the pre- and post-HAART era are summarized in Table 
1. In the pre-HAART era, the AIDS Clinical Trials Group (ACTG 149) performed a 
prospective multi-institutional clinical trial of ABVD with supportive GCSF27. 
Antiretroviral therapy was not used. Among 21 patients enrolled between 1992 and 
1996, 90% had B symptoms at presentation, and 67% had stage IV disease. Complete 
remission (CR) was attained in only 9 patients (43%; 95% CI: 24%-63%), a partial 
remission (PR) in 4 subjects (19%), resulting in a 2 year OS was 48%27. Even with 
routine GCSF use, 10 patients developed severe neutropenia and opportunistic 
infections (OIs) occurred in 6 patients (29%) during the study. A similar study with 
EBVP utilizing only zidovudine (AZT) or didanosine (DDI) as HIV therapy showed an 
equivalent 2 year OS of 40% 28. 
Retrospective data showed a positive effect of HAART on OS, disease free survival 
(DFS), and infectious complications, though these benefits have been limited to studies 
implementing HAART. As illustrated above, the difference between no HAART and 
single agent antiretroviral therapy is minimal 27, 28. Comparing sequential HIV- cHL 
studies with ABVD with cART and without HAART, the OS improved from 48% at 2 
years to 76% at 5 years. 27, 24 
In the post HAART era, only 5 prospective studies have been completed all with cART 


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23-26,30. A study of therapy with ABVD regimen in patients with advanced stage HIV-HL 
assessed the outcome in 62 patients (1996-2005) with advanced stage HL from multiple 
centers in Spain24. Six patients died during induction, 54 (87%) achieved CR and 2 had 
resistant disease. After a median follow up of 39 and 47 months, 5 year EFS probability 
was 71% and OS was 76% 24. An immunological response was observed in 56% and a 
virological response in 68%. The immunological response to HAART had a positive 
impact on OS and EFS24. 
The VEBEP, Stanford V, and BEACOPP standard studies included all stages of HIV-
cHL, and despite the inclusion of earlier stages, OS in each study did not compare well 
to ABVD, (see Table 1) 23-33. The BEACOPP regimen did show an improved CR rate 
compared to ABVD (100% vs. 87%), but only 66% of subjects were able to tolerate the 
6 courses of BEACOPP compared to 82% in the ABVD trial. Also, 3 of the 12 
participants in the BEACOPP trial died during chemotherapy (25%). Thus, based on 
OS, adverse events, and PFS, ABVD currently is the most promising regimen studied 
for advanced stage HIV-cHL 23-30. 
Table 1: Summary of Retrospective and Prospective Trials of HIV-cHL 
Regimen 
Trial Type 
HAART 
# Patients 
Year 
Stage 
III/IV% 
OS% (Months) 
MOPP or ABVD or 
MOPP/ABVD +/- RT 31 
Retrospective 
Pre-
HAART 
71 
1992 
80% 
Median Survival 
(14) 
MOPP or ABVD or 
MOPP/ABVD +/- RT 32 
Retrospective 
Pre-
HAART 
45 
1993 
75% 
Median Survival 
(20) 
MOPP or ABVD or 
MOPP/ABVD +/- RT 28 
Retrospective 
Pre-
HAART 
46 
1994 
89% 
Median Survival 
(15) 
MOPP or ABVD or 
MOPP/ABVD +/- RT 28 
Retrospective 
Pre-
HAART 
24 
1991 
92% 
Median Survival 
(15) 
MOPP or ABVD or 
MOPP/ABVD +/- RT 28 
Retrospective 
Pre-
HAART 
23 
1991 
74% 
Median Survival (8) 
MOPP/ABVD +/- RT 28 
Retrospective 
Pre-
HAART 
13 
1988 
92% 
Median Survival 
(14) 
EBV 29 
Prospective 
No- 
HAART 
17 
1994 
88% 
11 months 
ABVD 27 
Prospective 
No-
HAART 
21 
1992-6 
67% 
48% (24) 
EBVP 28 
Prospective 
AZT or 
DDI 
35 
1993-7 
66% 
40% (24) 
ABVD 30 
Prospective 
HAART 
8 
2002 
75% 
43 Months 
Stanford V 23 
Prospective 
HAART 
56 
2005 
71% 
59% (60) 
BEACOPPstd 26 
Prospective 
HAART 
12 
2002 
92% 
75% (36) 
VEBEP 25 
Prospective 
HAART 
28 
1996-05 
71% 
69% (24) 
ABVD 24 
Prospective 
HAART 
62 
2007 
100% 
76% (60) 
Regimen abbreviations: ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), VEBEP 
(vinorelbine, epirubicin, bleomycin, cyclophosphamide, prednisone), EBVP (epirubicin, bleomycin, 


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vinorelbine, prednisone), EBV (epirubicin, bleomycin, vinorelbine), BEACOPPstd (bleomycin, 
etoposide, 
doxorubicin, 
cyclophosphamide, 
vincristine, 
procarbazine, 
prednisone), 
MOPP 
(mechlorethamine, vincristine, procarbazine, and prednisone), and RT (radiation therapy). 
5.4 
Rationale for the use of brentuximab vedotin in HIV-cHL 
Brentuximab vedotin (SGN-35) is a CD30-directed antibody-drug conjugate (ADC) 
consisting of three components: 
(a) the antibody cAC10, specific for human CD30, (b) the highly potent anti-
microtubule agent, monomethyl auristatin E (MMAE), and (c) a protease-cleavable 
linker that covalently attaches MMAE to cAC1034. The biological activity of 
brentuximab vedotin results from a multi-step process. Binding of the ADC to CD30 
on the cell surface initiates internalization of the ADC-CD30 complex, which then 
traffics to the lysosomal compartment. Within the cell, a single defined active species, 
MMAE, is released via proteolytic cleavage 34. Binding of MMAE to tubulin prevents 
its polymerization, thus disrupting the microtubule network within the cell, inducing 
cell cycle arrest, and apoptotic death of the CD30-expressing tumor cell34. MMAE was 
found to be a quasi-irreversible, mechanism- based CYP3A inhibitor, and, to the limited 
extent that metabolism occurred, the primary metabolites were formed by CYP3A4 34,35. 
CD30, a member of the TNF-receptor (TNF-R) super family, is a transmembrane 
glycoprotein receptor normally found on the surface of activated T cells but present on 
a variety of cell types of hematopoietic origin. The CD30 antigen has a very low 
expression on normal cells but is found on the HRS cells of HL, anaplastic large cell 
lymphoma (ALCL), and other T cell lymphoproliferative disorders. While the function 
of CD30 has not been clearly defined, CD30 has been implicated both in cell death and 
proliferation 34,35. The utility of CD30 as a diagnostic marker for malignancies 
(including HL and ALCL), its limited normal tissue expression profile, and its 
apoptosis-inducing characteristics have led to the investigation of this antigen as a 
target for immunotherapy. Brentuximab vedotin has been studied and is FDA approved 
in the relapsed/refractory setting for ALCL and non- HIV cHL 36-40. In the frontline 
setting, a phase I study is currently ongoing with brentuximab vedotin for non-HIV-
cHL in combination with AVD 41. 
A phase 1 study of brentuximab vedotin was performed in relapsed and refractory CD30 
positive malignancies, including ALCL and HL. Patients had a median of 3 prior 
chemotherapy regimens (range 1-7) with 73% of patients having previously received 
an autologous stem cell transplant (ASCT) 36. The brentuximab vedotin dose levels 
ranged from 0.1 to 3.6 mg/kg (2-hr outpatient IV infusion) every 3 weeks. Brentuximab 
vedotin was generally well- tolerated in the study. The most common adverse events, 
which occurred in 20% of patients or more, were fatigue, pyrexia, nausea, and diarrhea. 
The neutropenia observed appeared to be dose-related. The maximum tolerated dose 
was 1.8 mg/kg every 3 weeks. One patient treated at 3.6 mg/kg developed febrile 
neutropenia and presumed sepsis, and died 14 days after the first dose of brentuximab 
vedotin. Neuropathy was also observed in some patients, especially after repeated 
dosing. Approximately 75%  of  patients  reporting  B  symptoms  at  baseline 
experienced symptom resolution while on study. Despite a median 3 prior 
chemotherapy regimens per patient including 75% with prior ASCT, 88% of the 
patients in the study experienced tumor reductions. The objective response rate 
(CR+PR) was 46% (n=13), with a CR rate of 25% (n=7). Two additional PRs were 
observed in the 0.6 mg/kg cohort. Median response duration to date was 22 weeks 
(range, 0.1+ to 38+ weeks) 39-41. 
A phase 2 study of brentuximab vedotin (SGN-35) studied 102 patients with relapsed 


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or refractory HL post autologous stem cell transplant 41. Patients received brentuximab 
vedotin every three weeks at a dose of 1.8 mg/kg. The median duration of brentuximab 
vedotin treatment was 27 weeks (range 3-54). The most common treatment-related 
adverse events (AEs) of any grade in >15% of patients were peripheral sensory 
neuropathy (43%), fatigue (40%), nausea (35%), neutropenia (19%), diarrhea (18%), 
and pyrexia (16%). Most events were Grade 1 or 2. The Grade 3 treatment-related AEs 
reported in more than 1 patient were neutropenia (14%), peripheral sensory neuropathy 
(5%), thrombocytopenia and hyperglycemia (3% each), and fatigue (2%). The only 
Grade 4 treatment-related events were neutropenia (4%), and thrombocytopenia, 
abdominal pain, and pulmonary embolism (1% each). There we no related Grade 5 
events. Eighteen patients discontinued treatment due to an adverse event41. While no 
interim analysis was presented with respect to overall response rate, there was a 95% 
reduction of tumor size and an 83% resolution of B symptoms 41. 
5.5 
Rationale for substitution of brentuximab vedotin for bleomycin in ABVD 
regimen 
Bleomycin is associated with significant pulmonary toxicity, particularly in the setting 
of radiation involving lung fields as is typically prescribed in the context of bulky 
mediastinal Hodgkin lymphoma. There are no large studies addressing the incidence of 
bleomycin-associated pneumonitis in the setting of HIV-HL. Outside of HIV, the 
incidence of bleomycin-associated pneumonitis with ABVD in HL has been reported 
in the range 10-15%. A randomized trial comparing ABVD to Stanford V (25% of the 
bleomycin dose) reported a 10% versus 2% incidence of pulmonary toxicity, 
respectively, requiring early discontinuation of bleomycin in 20/23 subjects 42,80. A 
separate, single institution retrospective study demonstrated a 15% incidence in 
bleomycin pneumonitis in 184 HL patients treated with ABVD 43. In this study, low 
albumin and use of GCSF were the factors most predictive of bleomycin toxicity. These 
factors are both likely to occur with high incidence in the HIV HL population where 
more advanced HL presentation is typical and the increased risk of marrow suppression 
with chemotherapy, use of GCSF is often required to maintain or approximate optimal 
chemotherapy dose density in the setting of HIV and aggressive lymphomas. 
The substitution of brentuximab vedotin for bleomycin is being explored in the general 
HL population. A phase 1, open-label, multicenter study is currently underway to 
evaluate the safety of brentuximab vedotin when administered in combination with 
standard therapy with AVD (ClinicalTrials.gov #NCT01060904) as the combination 
with ABVD had intolerable pulmonary toxicity41. Patients have received doses of 0.6, 
0.9, or 1.2 mg/kg brentuximab vedotin with standard doses of ABVD or 1.2 mg/kg 
brentuximab vedotin with AVD, depending upon cohort assignment. The combination 
regimens were administered on Days 1 and 15 of each 28-day cycle for up to 6 cycles 
of therapy. Each regimen evaluated a dose limiting toxicity (DLT) period, defined as 
any Cycle 1 toxicity requiring a delay of ≥7 days in standard ABVD or AVD therapy41. 
This is the first trial to dose brentuximab vedotin every two weeks and in combination 
with multi-agent chemotherapy. Interim data of the first 31 patients treated were 
recently presented41. Six patients received 0.6 mg/kg, 13 received 0.9 mg/kg, and 6 
received 1.2 mg/kg with ABVD; 6 patients received 1.2 mg/kg with AVD. Patient 
baseline characteristics included: Stage IV, 55%; IPS score ≥4, 29%; male, 77%; 
median age, 35 years (range, 19-59). The combination of chemotherapy and 
brentuximab vedotin treatment had no DLT observed up to 1.2 mg/kg in either 
regimen41. AEs reported in ≥45% of patients, regardless of severity, were nausea and 
neutropenia (77% each); peripheral sensory neuropathy (48%); and fatigue (45%). 


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Infusion-related reactions occurred in 23% of patients. Grade 3/4 AEs observed in 
>10% of patients were neutropenia (74%), febrile neutropenia (16%), and anemia 
(13%). No Grade 5 AEs were observed. Overall, 6 patients discontinued combination 
treatment due to an adverse event. In the ABVD cohorts (n=25), AEs of pulmonary 
toxicity, dyspnea, and interstitial lung disease that could not be distinguished from 
bleomycin toxicity led to discontinuation of bleomycin in 7 patients. Five of these 7 
patients continued treatment with AVD and brentuximab vedotin41. The expansion 
cohort of approximately 20 patients is currently enrolling at the 1.2 mg/kg brentuximab 
vedotin dose combined with AVD therapy 41. An international phase III study 
comparing ABVD versus AVD in combination with brentuximab vedotin is currently 
under development. This AMC trial will help define more clearly how this regimen can 
be used in the HIV-infected population. 
While it is desirable to replace bleomycin with a less toxic alternative in the general HL 
population, the argument is even more compelling in the HIV-HL population with a 
higher prevalence of risk factors associated with bleomycin toxicity, i.e., intercurrent 
infection, and a higher prevalence of tobacco use. In replacing bleomycin, risk of 
reduced efficacy exists. Given this, as well as the preliminary efficacy data of 
brentuximab vedotin + AVD in the general HL population, a dose de-escalation design 
is chosen for this study to maximize anti-tumor activity of the regimen for each cohort. 
5.6 
Considerations regarding progressive multifocal leukoencephalopathy associated 
with HIV, brentuximab vedotin, and HIV-cHL 
Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the 
central nervous system caused by the lytic replication of the John Cunningham Virus 
(JCV). It typically occurs in immunocompromised individuals and is nearly uniformly 
fatal 48-54. In a clinical study conducted by Koralnik et al, 80% of reported PML patients 
had AIDS, 13% had hematologic malignancies, 5% were transplant recipients, and 2% 
had chronic inflammatory diseases 49. Presenting features 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 
PML patients (approximately 20%) 48. The onset of neurological deficits may occur 
over weeks to months48. In a retrospective study, data showed the incidence of PML in 
patients with NHL is 8 per 100,000 patient years, though the incidence in cHL or HIV-
cHL is not known. In the onset of the HIV epidemic, the incidence of the PML was 3.4 
per 1000 patient years at risk with HIV 50,51. But in the era of HAART, the incidence 
has decreased to 1.3 patients per 1000 patient years51. In a Swiss HIV cohort study, a 
multivariate analysis showed that of the 226 patients diagnosed with PML from 1998 
to 2007, HAART was associated with a hazard ratio of 0.22 (p<0.01). A trend was seen 
for decreased incidence with elevated CD4 counts52. Compared to patients with CD4 
counts below 50 cells/µl, the hazard ratio for patients with CD4 counts above 100 
cells/µl was 0.75 (p<0.38)52. 
Recently PML has been reported in HIV negative patients receiving antibody based 
immunomodulatory therapies for lymphoma, multiple sclerosis, and collagen vascular 
diseases treated with antibodies rituximab, efalizumab, and natalizumab 53. To date 3 
patients treated with brentuximab vedotin have developed PML, each in the relapsed 
refractory setting, with 3 to 6 chemotherapeutic regimens before treatment with 
brentuximab vedotin54. To curtail the risk of PML in this study, no patients with a CD4 
count below 50 cells/µl will be permitted on study, all participants will be required to 
take HAART, and MRI scans pre-study will be required. In addition, we will 
incorporate stopping rules should any patient develop PML with a CD4 count > 50 at 


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the time of PML diagnosis. 
5.7 
Rationale for use of concurrent HAART with HL treatment 
The improvement in outcomes of HIV-cHL patients to standard treatment in the 
HAART era is partially related to the HAART therapy itself. Given this and concerns 
above regarding HIV viremia with CD30 perturbation and PML, we will require 
patients to be on HAART. Chemotherapy-HAART interactions have become more 
pronounced in the transition from single agent HIV therapies to the era of cART as 
protease inhibitors (PI) and non-nucleoside reverse transcriptase inhibitors (NNRT) are 
potent inhibitors or inducers of the cytochrome p450 system 55. In early studies with 
HIV-cHL treated with EBVP, where only AZT or DDI was used as antiviral therapy, 
1% neurotoxicity all grades, 7% Grade 3/4 leukopenia, and 3% G3/4 anemia were 
observed. However, in a single institution retrospective study of 23 patients treated with 
ABVD, while taking HAART, 31% were found to have neuropathy (all grades), 68% 
G3/4 neutropenia, and 57% G3/4 anemia 56. Correlations were then made comparing all 
adverse events with HAART therapy. Of the patients with neuropathy, 13% had grade 
3 sensory neuropathy and each developed the symptoms before cycle 2 of ABVD. Many 
had symptoms years after therapy. One hundred percent of the patients with neuropathy 
were taking ritonavir based HAART56. Similarly, 75% of the patients who were taking 
ritonavir based HAART developed G3/4 neutropenia, as opposed to only 21% taking 
non- ritonavir based HIV-therapy. Lastly, it was noted that 82% of the patients with 
Grade 3/4 anemia were taking ritonavir and or AZT in some combination. Based on 
these data, at this institution made a policy to utilize only non- ritonavir and non-AZT 
based HAART regimens during treatment for HIV-cHL57. Twelve patients were 
subsequently treated, and neuropathy, febrile neutropenia, G4 neutropenia, and G4 
anemia had decreased by 100%, 100%, 20%, and 15% respectively 57. 
One concern to be managed in the current study is the overlapping toxicities of 
brentuximab vedotin and vinblastine, both of which have been shown to cause 
neuropathy and neutropenia. To prevent potentiating any adverse events, we will 
require subjects’ HAART regimens to exclude ritonavir or AZT. Cobisistat, another 
potent inhibitor of the CYP 3A4 enzyme system, will also be excluded from the study. 
Any new forthcoming CYP 3A4 inhibitors will be excluded. 
Despite these changes, many of the HAART drugs undergo metabolism by and can 
induce or inhibit various CYP450s enzyme systems. Therefore, all patients will be 
closely monitored for AEs throughout the entire study. In addition, pharmacokinetics 
will be studied in a subset of patients to confirm whether alterations in exposure 
correlate with the AEs. 
5.8 
Rational for use of PET scans in HIV patients and HIV-HL 
The use of FDG-PET scans in HL patients is increasingly being used for prognostic 
significance in during treatment in the HIV negative setting. Data by Galamini et al. 
showed a FDG-PET scan done at the completion of cycle 2 was more prognostic than 
the IPS score for advanced Hodgkin lymphoma 58,59. A negative PET scan after two 
cycles of ABVD predicted a 96% 2-year PFS. Similar data reported in abstract form 
regarding ABVD and rituximab showed a negative PET correlated with a 5-year EFS 
of 93% vs. 75% for those who remained PET positive (p=0.05)58-60. The prognostic 
significance of PET scanning in the HIV patients with HL is unknown. At issue is FDG-
PET scanning in the setting of HIV alone without malignancy is frequently positive. 
One report suggested FDG activity might correlate with detectable HIV viral loads61. 
Thus, it is important to correlate FDG-PET in combination with CT scans (FDG-


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PET/CT scan). Experience with PET scanning in the HIV setting with malignancy 
requires further study. Therefore, we plan to use baseline, post cycle #2 interim, and 
post-treatment FDG-PET/CT scans prospectively in this study, to correlate scan 
positivity with PFS and OS. The Deauville 5 point criteria will be used to record the 
interim FDG-PET scan 91,92. The Deauville criteria capture gradations of FDG uptake 
from no uptake (1 point) to new disease (5 points). For the purposes of this study, we 
will record the Deauville score and determine whether scores of 3-5 or 4-5 are 
predictive of relapse. Notably, SUVs can be affected by inflammation related to therapy 
as in the case of rituximab or HIV related inflammation. 
5.9 
Brentuximab vedotin relevant preclinical data 
Little to no data exists on the dosing of 1.2mg/kg of brentuximab vedotin to be used in 
this study, and no information exists on its interactions with anti-HIV medications. The 
data summarized below were obtained using 1.8mg/kg. 
Pharmacokinetic parameters for individual patients were determined using 
concentrations of serum brentuximab vedotin ADC, plasma MMAE, serum TAb, and 
actual sampling times relative to the start of the infusion. The maximum concentrations 
for the serum PK of brentuximab vedotin ADC following an IV dose of 1.8 mg/kg were 
typically observed at the end of infusion. A multi-exponential decline in ADC serum 
concentrations was observed with a terminal half-life (t1/2) of approximately 4 to 6 
days. Exposures were approximately dose proportional. After administration of 
multiple doses of brentuximab vedotin, steady-state was achieved by 21 days, 
consistent with the t1/2 estimate. Minimal to no accumulation was observed with 
multiple doses with the q3wk regimen, and ADC exposure did not decrease with 
subsequent doses. 
The plasma PK profile of MMAE following an IV dose of 1.8 mg/kg brentuximab 
vedotin appeared to follow metabolite kinetics, with the elimination of MMAE 
appearing to be limited by its rate of release from ADC. Tmax ranged from 
approximately 1 to 3 days. Exposures were linear and approximately dose proportional 
with MMAE exposures decreasing after multiple doses with approximately 50% to 80% 
of the exposure of the first dose observed at subsequent doses. After administration of 
multiple doses of brentuximab vedotin, MMAE steady-state was achieved by 21 days, 
similar to ADC. Total antibody exposures were approximately dose proportional and 
higher than brentuximab vedotin ADC exposures while Tmax was similar. 
5.10 
Study Design and Rationale 
Based on the evidence presented above, specifically the remarkably high response of 
brentuximab vedotin in the relapse setting, the AMC has proposed a phase 1 clinical 
trial with a de-escalation design evaluating 3 doses of brentuximab vedotin (1.2 mg/kg, 
0.9 mg/kg, and 0.6 mg/kg) given every 2 weeks with AVD in a 28-day cycle followed 
by a phase 2 clinical trial. 
Overall fifty-one patients (20 in France) in the phase II trial will be treated for 6 cycles 
for a 5-year follow up. The primary end point of the phase II portion will estimate the 
two-year progression free survival for AVD-brentuximab vedotin. The secondary 
endpoints of both phases will be to evaluate AVD-brentuximab vedotin with regard to 
1) the toxicity of patients taking concurrent HAART, 2) the effects on viral load, CD4, 
and CD8 counts, and 3) PR, OS, EFS. Other non-treatment related endpoints for both 
phases will be the predictive value of FDG-PET on 2 year PFS and a characterization 
of HIV-cHL subtypes in the post HAART era. 


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We hypothesize that AVD-brentuximab vedotin will 1) improve HIV-cHL OS to be 
more consistent with the non-HIV population 2) be administered safely with cART 
regimens lacking ritonavir or AZT. We also anticipate cycle 2 FDG/PET-CT will be 
prognosticate OS in the HIV population. 
We will collect biological samples to be able to participate in correlative studies to 
monitor the effects brentuximab vedotin will have on the viral replication of HIV. With 
respect to HIV replication, we will assess viral loads and CD4 counts every 2 cycles 
during therapy and every 3 months for 1 year post treatment. 


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6.0 
STUDY OBJECTIVES 
6.1 
Primary Objective 
Establish an estimate of the two-year progression free survival for patients with HIV-
associated stage III-IV Hodgkin lymphoma when treated using brentuximab vedotin 
plus the AVD chemotherapy regimen. 
6.2 
Secondary Objectives 
• 
To evaluate the toxicity of AVD and brentuximab vedotin with HAART. 
• 
To estimate the partial response (PR) rate, complete response (CR) rate, overall 
survival (OS), and event free survival (EFS) at 2 and 5 years. 
• 
To evaluate the effect of AVD and brentuximab vedotin on CD4 and CD8 counts 
after cycle 1, 4, at the end of therapy, and every 3 months after treatment 
completion for one year. 
• 
To investigate the prognostic value of FDG-PET/CT scans at baseline, 
after cycle 2, and at treatment completion, with respect to 2 year 
progression free survival. 
• 
To evaluate HAART status at baseline and to correlate this with tumor response to 
therapy and OS and PFS. 
• 
To characterize the histologic subtypes in HIV-HL in the highly active antiretroviral 
therapy (HAART) era. 
• 
To assess the neurotoxicity of HAART in combination with AVD and brentuximab 
vedotin. 
• 
To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 
1, 4, at completion of therapy, and every 3 months after treatment completion 
for one year. 


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7.0 
STUDY DESIGN 
This study is a multicenter, phase II trial. 
Patients will be recruited over 2 years and followed until 5 years after the completion 
of therapy. 
The anticipated study dates (start / end) are: 
• 
1st patient included (FPFV): 01/JUN/2015 
• 
Last patient included (LPFV): 01/JUN/2017 
It is expected that a total of 20 patients in France among the 51 patients needed in the 
protocol developed by AMC will be included in the study. 
The duration of the treatment period is 6 cycles of 4 weeks of chemotherapy. 
End of study is defined by the last visit planned by the protocol of the last patient in 
follow-up. 
 
 


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8.0 
STUDY POPULATION 
Previously untreated individuals diagnosed with stage III-IV, HIV-associated, CD30-
positive, classic Hodgkin Lymphoma (cHL), as defined by the 2008 WHO 
classification of hematological malignancies1. 
All protocol participants must meet all stated eligibility criteria. Participating sites must 
have documentation that each eligibility requirement is satisfied prior to subject 
enrollment. In compliance with CTEP policy, no exceptions to eligibility criteria will 
be granted under any circumstance. 
8.1 
Inclusion criteria 
1. Age ≥ 18 years. Because no dosing or adverse event data are currently available on 
the use of brentuximab vedotin in combination with AVD in patients <18 years of 
age, children are excluded from this study. 
2. HIV-1 positive. Documentation of HIV-1 infection by means of one of the 
following: 
• Documentation of HIV diagnosis in the medical record by a licensed health care 
provider; 
• Documentation of receipt of ART by a licensed health care provider; 
• HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstration > 1000 
RNA copies/mL; 
• Any licensed HIV screening antibody and/or HIV antibody/antigen 
combination assay confirmed by a second licensed HIV assay such as a HIV-1 
Western blot confirmation or HIV rapid multisport antibody differentiation 
assay. 
3. Histologic diagnosis of CD30-positive classical HL as defined by the 2008 WHO 
Classification of Hematological diseases. Nodular lymphocyte predominant 
Hodgkin Lymphoma is not eligible. 
4. Stage III or IV disease as defined by the Ann Arbor Staging System. 
5. Participants must have previously untreated HIV-cHL, with the exception of up to 
14 consecutive days of steroids, emergency radiation, or 1 prior cycle of 
cyclophosphamide to reduce tumor burden and improve hyperbilirubinemia in the 
setting of lymphoma related liver involvement. 
6. Normal baseline cardiac ejection fraction ≥ 50%. 
7. Serum creatinine of ≤ 1.5 mg/dL. If creatinine >1.5 mg/dL (133 micromol/L), 
creatinine clearance must be ≥ 60 mL/minute according to MDRD/Cockroft-Gault 
formula. 
8. ANC ≥ 1000/µL and platelets ≥ 75,000/µL unless related to bone marrow 
involvement by HIV-cHL. 
9. Total bilirubin must be < 1.5x the upper limit of normal, unless the elevation of 
bilirubin is thought to be secondary to Gilbert’s syndrome or cART. 
• If, however, the elevated bilirubin is felt to be secondary to antiretroviral 
therapy, the total bilirubin must be ≤ 3.5 mg/dL (60 µmol/L), provided that the 
direct bilirubin is normal and the AST and ALT ≤ 3 x the upper limit of normal. 
• If the elevation of bilirubin is thought to be secondary to Gilbert’s syndrome, 
the total bilirubin must be ≤ 3x the upper limit of normal or the direct bilirubin 
must be ≤ 1.5x the upper limit of normal. 
• Also, if the elevated bilirubin is thought to be secondary to cHL the same criteria 
for hyperbilirubinemia should be applied however 1 prior cycle of 
cyclophosphamide is permitted in attempt to make the participant eligible (see 
section 8.1.5). Patients should not be excluded from study participation unless 


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dosing cannot be safely established per Section 10.6.2. 
10. Female subjects must have a negative pregnancy test within 1 week of enrollment 
and all subjects must agree to use two reliable methods of contraception 
simultaneously if conception is possible during the study. 
a. Should a woman subject become pregnant or suspect she is pregnant while the 
subject is participating in this study, she should inform her treating physician 
immediately. The patient will then be removed from protocol therapy. 
b. Subjects who father a child while participating in the study will be 
permitted to continue with the protocol. The subject, however, is required 
to notify the investigator if he fathers a child. 
11. Ability to understand and the willingness to sign a written informed consent 
document. 
12. Karnofsky performance status > 30% (given the aggressiveness of this disease and 
the often severely debilitated nature of the patients at initial presentation). See 
Appendix 20.5. 
13. Measurable or non-measurable (evaluable) tumor parameter(s). Non-measurable 
tumor parameters will be defined as not having bi-dimensional measurements (i.e., 
gastric or marrow involvement) but can be followed for response by other 
diagnostic tests such as gallium, PET imaging and/or bone marrow biopsy. 
14. Patients already receiving erythropoietin or GCSF for treatment of HIV-related 
cytopenia are eligible. 
15. CD4 count ≥ 100 cells/µl and serum HIV viral load <50copies/ml 
16. Subjects are required to be on antiretroviral regimens that are in accordance with 
the current International AIDS Society guidelines concurrently with chemotherapy. 
Use of experimental antiretroviral agents or those containing zidovudine (including 
Combivir and Trizivir) or ritonavir (includes Norvir® or Kaletra®),, cobicistat or 
Didanosine (Videx® or Videx EC®), or similar potent CYP3 inhibitors are 
prohibited, as explained in Section 5.7. In order to be eligible, patients taking 
zidovudine or didanosine or ritonavir, or cobicistat or Didanosine, or other CYP3 
inhibitors must change to a different regimen 7 days prior to therapy initiation. 
Subjects must be on HAART for at least 7 days prior to therapy. See section 10.3 
17. Patients will be required to obtain a pulmonary function test, despite the exclusion 
of bleomycin from protocol regimen. The subject’s diffusing capacity of the lung 
for carbon monoxide (DLCO) adjusted for hemoglobin must be greater than 70% 
predicted to enter the study and to continue with brentuximab vedotin. 
18. Negative for Hepatitis B, or if infected with Hepatitis B, receiving anti-Hepatitis B 
therapy. All subjects will be required to be screened for Hepatitis B. Per IDSA and 
AASD guidelines, those subjects that show no immunity, defined by the lack of 
Hepatitis B surface antibody, and show evidence of chronic infection (i.e., HBsAg+, 
HBcore+, HBsAB-) will be required to be on anti-Hepatitis B therapy during the 
study in order to be eligible. Patients will be permitted to enroll in the study 
provided normal liver function tests (see Section 9.3) and no evidence of cirrhosis. 
The exact Hepatitis B therapy will be at the discretion of the infection disease 
specialist  or investigator. However all patients who present with acute hepatitis B 
or show normal transaminases and are HBsAg+ and IgM+ for Hepatitis core antigen 
will not be eligible for trial enrollment. 
19. Patients diagnosed with Hepatitis C who are Hepatitis C antibody positive, whether 
Hepatitis C RNA level is measurable or not, must have no evidence of cirrhosis and 
have liver function tests that conform to Section 9.3. 


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20. Brentuximab vedotin is partially metabolized via the CYP3A4 pathway and is 
cleared from the cells via the P-glycoprotein pump. Therefore, participants must 
discontinue use of the following agents within 7 days prior to therapy as per 
Appendix 20.9: 
• Strong CYP 3A4 inhibitors that treat HIV, see 3.1.16. 
• Other strong CYP3A inhibitors. 
• Moderate CYP3A4 inhibitors should be used with Caution but are not 
excluded. If 2 moderate CYP3A4 inhibitors are used concurrently, one must 
be discontinued at least 7 days (1 week) prior to the initiation of 
chemotherapy. 
• P-glycoprotein inhibitors. 
• If patients are taking any of these excluded medications, they must be 
discontinued at least 7 days (1 week) prior to the initiation of chemotherapy. 
All concomitant medications must be reviewed by the study chair or co-chair 
prior to enrollment by email. 
Because the lists of these agents are constantly changing, it is important to 
regularly consult a frequently-updated medical reference for a list of drugs to 
avoid or minimize use of. 
8.2 
Exclusion criteria 
Patients who do not fulfill the criteria as listed in Section 8.1 above, are ineligible. 
Additionally, the presence of any of the following conditions will exclude a subject 
from study enrolment: 
1. Patients with prior anthracycline therapy will be excluded. 
2. Female subjects who are pregnant or breast-feeding. Confirmation that the subject 
is not pregnant must be established by a negative serum b-human chorionic 
gonadotropin (b-hCG) pregnancy test result obtained during screening. Pregnancy 
testing is not required for post-menopausal or surgically sterilized women. 
3. Medical illness unrelated to HL, which in the opinion of the study physician will 
preclude administration of chemotherapy safely. This includes patients with 
uncontrolled infection (including opportunistic), chronic renal failure, myocardial 
infarction (MI) within the past 6 months, unstable angina, or cardiac arrhythmias 
other than chronic atrial fibrillation. 
4. Prior malignancy within 5 years of enrollment other than curatively treated 
cutaneous basal cell or squamous cell carcinoma, carcinoma in situ of the cervix, 
anal intraepithelial neoplasia, or cutaneous Kaposi’s sarcoma (KS). 
5. Grade 2 or greater peripheral neuropathy. 
6. Evidence of PML identified on the pretreatment MRI. 
7. Central nervous system disease. 
8. Patients with history of JC Virus identified in the CSF or previous history of PML 
will be excluded from the study. 
9. Cirrhosis secondary to any cause will be excluded. 
 
 


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9.0 
STUDY FLOW CHART AND SCHEDULE OF ASSESSMENTS 
9.1 
Study flow chart 
See on appendix 20.2. 
9.2 
Informed consent 
To participate in this study and before any baseline or screening evaluation, a written 
informed consent must be signed by each patient. Written informed consents for 
biological and genetic studies must be signed before sampling. These consents are 
signed after investigator gave all information required to the patient. 
The patient and the investigator will date and sign the informed consent form. 
An original copy of the signed consent will be provided to the patient; the original will 
be maintained in the investigator’s study file. 
9.3 
Baseline examination 
Unless otherwise specified, the following evaluations must be performed within 6 
weeks prior to patient registration: 
1. Medical history, history of drug allergies, history of current and past anti-retroviral 
regimens, if available; and history of any prior AIDS-defining conditions. Date of 
initial lymphoma diagnosis is required, with a copy of the pathology report in the 
medical record. Presence of systemic “B” symptoms should be noted, as well as 
other symptoms of cHL. Current concomitant medication list, including all anti-
retroviral, anti- viral, antibiotics, and opportunistic prophylaxis should be obtained. 
2. Physical examination, including performance status (see Appendix 20.5 
Performance Status Scale), vital signs (weight, height, body surface area), 
neurological examination, and if available, two dimensional measurement of all 
palpable, peripheral lymph nodes and measurement of other sites of disease present 
on physical exam. 
3. A combined FDG-PET/CT or FDG-PET + CT scan with and without IV contrast is 
required for this study. If a patient has an allergy to IV contrast, a non-IV contrast 
CT scan will be permitted. To ensure consistency between all centers, FDG-
PET/CT scans at diagnosis should be conducted no more than 28 days before 
enrolment. 
If the CT scan of a PET/CT hybrid is performed with both oral and IV contrast with 
contrast enhancement in the arterial and/or portal venous phase, with at least a 2-
slice CT, and is acquired with at least 80 mAs and CT scans are obtained with 
contiguous sections (with a maximum of 5 mm slice thickness), then the pre- 
treatment PET/CT scan alone will suffice for patients enrolled on this trial. If no 
contrast is used in the FDG- PET/CT, an additional CT scan with contrast is 
required of the neck, chest, abdomen, and pelvis, see paragraph 9.3. 
4. CT scan of the neck (if palpable lymphadenopathy only), chest, abdomen and pelvis 
with and without IV contrast will be required. If the CT portions of the FDG-
PET/CT combination scan is a non-contrast CT scan, then a separate CT scan with 
and without IV contrast will be required. 
5. MRI of the brain with and without IV gadolinium contrast, to look for early 
evidence of PML. 
6. Determination of LVEF by MUGA scan or echocardiogram. 
7. PFTs with volumes, spirometry, DLCO and room air pulse oximetry. Patients will 
be required to obtain a pulmonary function test, despite the exclusion of bleomycin. 
The DLCO adjusted for hemoglobin must be greater than 70% predicted to enter 
the study and to continue with brentuximab vedotin. 


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8. Bone marrow biopsy for histology and determination of percent bone marrow 
involvement. If bone marrow involvement by lymphoma has already been 
documented after bone marrow biopsy performed more than 6 weeks prior to 
registration, the biopsy does not have to be repeated. 
9. Central pathology review for confirmation of histology of lymphoma specimen: 
Biopsy material at diagnosis will be sent to confirm HL and histologic subtype. 
(See Appendix 20.1 and 20.7 for the acceptable specimens required for central 
review and for handling instructions). 
All specimens will be reviewed by a panel of pathologists and must be submitted 
within 30 days of study enrollment. Patients who are found not to have HIV-HL 
will be withdrawn from the study 
10. Laboratory tests, including: 
• 
CBC with differential and sedimentation rate (within 2 weeks prior to patient 
registration). 
• 
Serum chemistries: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, and 
phosphorus), glucose, blood urea nitrogen (BUN), creatinine, total bilirubin, 
alkaline phosphatase (ALP), LDH, total protein, albumin, AST and ALT (within 
2 weeks prior to patient registration). 
• 
CD4 and CD8 cell count. 
• 
HIV-1 RNA viral load assessed by any approved viral load assay at the local 
laboratory. This must be performed within 21 days prior to Cycle 1, Day 1. (The 
HIV viral load assay must detect at minimum viremia >200 copies/mL to be 
consistent with the DHHS HIV treatment guidelines). 
• 
Assessment for Hepatitis C antibody, Hepatitis B core antibody, Hepatitis B 
surface antigen (HBsAg), and Hepatitis B surface antibody. 
• 
Serum pregnancy test for women of childbearing potential (within 7 days prior 
to Cycle 1 chemotherapy). (See Section 13.1.1 under pregnancy and 
breastfeeding for guidelines on the use of pregnancy category D medications, 
which includes brentuximab vedotin and dacarbazine.) 
11. Blood collection for biological analyses (cf. Appendix 20.7) after signature of 
informed consents for biological and genetic studies. 
9.4 
Evaluation during treatment 
1. Update medical history prior to each cycle of chemotherapy. History to include 
concomitant medication changes and any signs and symptoms. Reportable adverse 
events must be recorded in AdvantageEDC. To be performed within 48 hours prior 
to or on first day of each cycle. 
2. Physical examination prior to each cycle of chemotherapy. Examination to include 
performance status (Appendix 20.5). All subjects will be evaluated for clinical 
response by physical examination prior to receiving treatment on each cycle. The 
exam should occur within 2 days prior to the start of each cycle but may occur on 
Day 1 of cycle. Disease measurable by physical examination will be recorded in 
two dimensions if possible. To be performed within 48 hours prior to or on first day 
of each cycle. 
3. FDG-PET/CT. Combined FDG-PET/CT or FDG-PET + CT scans with and 
without IV contrast are required for this study. If a patient has an allergy to IV 
contrast, a CT scan without contrast will be permitted. 
• 
Restaging evaluation by a full body FDG-PET/CT within Day 22-28 of Cycle 2 
(i.e., 7-13 days after the Cycle 2 Day 15 doses of AVD-BV). If the CT portion 
of the PET/CT is a non-contrast CT, an additional CT scan with and without 
contrast must be obtained. Tumor measurements and SUVs must be 


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documented. A neck CT must be included if palpable neck nodes were present 
at baseline and a diagnostic CT is being performed. 
• 
As the false positive rate of FDG-PET scans may be higher in the HIV 
population, a biopsy of an unexpected FDG-PET avid lesion is recommended 
but remains at the discretion of the investigator. 
4. PFT with volumes, spirometry, DLCLO, and room air pulse oximetry will be 
performed after every 2 cycles, on day 1 of cycles 3 and 5, within 7 days of cycle 
initiation. The DLCO adjusted for hemoglobin must be greater than 70% predicted 
to continue with therapy. 
5. Neuropathy 
evaluation 
by 
completing 
the 
FACT/GOG-neurotoxicity 
questionnaire at the beginning of each cycle. To be performed once within 48 
hours prior to or on first day of each cycle (Appendix 20.6). 
6. CBC with differential within 48 hours of day 1 and 15 of each cycle. Results of 
CBC must be known prior to treatment. 
7. Serum chemistries within 48 hours of day 1 and 15 of each cycle: electrolytes (Na, 
K, Cl, bicarbonate, Ca, Mg, and phosphorus), glucose, blood urea nitrogen (BUN), 
creatinine, total bilirubin, alkaline phosphatase (ALP), LDH, total protein, albumin, 
AST and ALT. Results do not need to be known prior to treatment unless clinically 
indicated. 
8. CD4/CD8 count will be performed within 48 hours of cycle 2 and cycle 5 day 1 
along with the CBC evaluation. 
9. HIV-1 RNA viral load, assessed by any approved viral load assay at the local 
laboratory. This will be performed within 48 hours of cycle 2 and cycle 5 day 1 
along with the CBC evaluation. (The HIV viral load assay must detect at minimum 
viremia >200 copies/mL to be consistent with the DHHS HIV treatment 
guidelines). 
For patients with undetectable HIV viral at baseline: If the viral load rises above 
200 copies per mL, HIV resistance testing will be required. Both viral load and 
resistance testing information must be shared in real time with the primary HIV 
provider if different from the protocol investigator. (The HIV viral load assay must 
detect at minimum viremia >200 copies/mL to be consistent with the DHHS HIV 
treatment guidelines). 
10. Serum pregnancy test for women of childbearing potential will be performed per 
institutional guidelines during the study. 
9.5 
Follow-up assessments 
The studies listed below will be repeated post-therapy within 6-8 weeks of the last 
treatment dose (6-8 weeks after Cycle 6 Day 15) and then every 3 months (+/- 7 days) 
thereafter for 2 years; every 6 months (+/- 7 days) for the third through the fifth years 
unless otherwise specified. All study subjects should be followed for up to 5 years after 
treatment discontinuation or until death if occurring before 5 years of treatment 
discontinuation. Patients who discontinue all protocol therapy after a CR or PR are 
followed for up to 5 years after treatment for recurrence and survival. Patients who 
discontinue protocol therapy due to disease progression or other reasons are followed 
for survival for up to 5 years after treatment discontinuation. No additional studies 
except follow up for survival are required after disease progression. In those instances 
in which a third party payer denies payment for some or all of these laboratory analyses, 
absence of these test results will not be considered a protocol violation. 
1. Medical history. 
2. Physical examination, including performance status (see Appendix 20.5, 


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Performance Status Scale), vital signs (weight, height, body surface area), 
neurological examination, and if possible, two dimensional measurement of all 
palpable, peripheral lymph nodes and measurement of other sites of disease present 
on physical exam. 
3. At the conclusion of chemotherapy, a full body FDG-PET/CT scan will be done 
between 6-8 weeks post the final treatment dose, Cycle 6 Day 15. This will be the 
final FDG-PET/CT needed for the study. A combined FDG-PET/CT or FDG-PET 
+ CT scans with and without IV contrast are required for the post- treatment scan. 
If a patient has an allergy to IV contrast, a CT scan without contrast will be 
permitted. As the false positive rate of FDG-PET scans may be higher in the HIV 
population, a biopsy of an unexpected FDG-PET avid lesion is recommended but 
remains at the discretion of the investigator. 
4. CT scan with oral/IV contrast every 6 months for 5 years. To begin 6 months from 
the post treatment FDG- PET/CT scan, obtained 6-8 weeks post the final 
chemotherapy dose (See Section 9.5). 
5. PFT with volumes, spirometry, DLCO and pulse oximetry for any patient with a 
DLCO corrected for hemoglobin ≤ 70% during therapy. To be repeated at all post-
treatment evaluations until normalization. 
6. Bone marrow biopsy need only be performed to confirm a CR if positive at baseline 
(only once, within 8 weeks of the last treatment dose). 
7. CBC with differential at all post treatment evaluations. 
8. Serum chemistries: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, and phosphorus), 
glucose, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline 
phosphatase (ALP), LDH, total protein, albumin, AST and ALT at all post 
treatment evaluations. 
9. CD4 and CD8 cell count beginning with the first follow up visit and every 3 
months after treatment completion for one year. 
10. HIV-1 RNA viral load, assessed by any approved viral load assay at the local 
laboratory beginning with the first follow up visit and every 3 months after 
treatment completion for one year. (The HIV viral load assay must detect at 
minimum viremia >200 copies/mL to be consistent with the DHHS HIV treatment 
guidelines). 
9.6 
Early Discontinuation of Therapy 
Subjects discontinuing therapy early (i.e., PD or stable disease, administrative reasons, 
subject non- compliance, etc.) will have a medical history update and complete physical 
examination. The examination will include performance status and blood drawn for the 
following studies within 1 month after treatment discontinuation, unless otherwise 
noted. See Section 12 for a list of reasons for study termination. Subjects will be 
followed for survival only for 5 years after the last date of treatment: 
• 
CBC with differential. 
• 
Serum chemistries: electrolytes (Na, K, Cl, bicarbonate, Ca, Mg, and phosphorus), 
glucose, blood urea nitrogen (BUN), creatinine, total bilirubin, alkaline phosphatase 
(ALP), LDH, total protein, albumin, AST and ALT. 
• 
CD4 and CD8 cell count (do not repeat if done within 1 month from removal from 
treatment). 
• 
HIV-1 RNA viral load to be evaluated at the local laboratory, do not repeat if done 
within 1 month from removal from treatment). 
 


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10.0 
TREATMENTS 
10.1 
Treatment schedule and design 
AVD dosing, in conjunction with brentuximab vedotin will be as described in Table 2. 
Drugs will be given on days 1 and 15 on a 28-day cycle for a total of 6 cycles. 
Brentuximab Vedotin will be administered after AVD (doxorubicin 25 mg/m2, 
vinblastine 6 mg/m2, dacarbazine 375 mg/m2). 
If treatment is delayed (<7 days if during cycle 1, or <2 weeks if occurring during 
subsequent cycles) once treatment is resumed the next dose will be scheduled two 
weeks after treatment is restarted. 
Table 2: Schema for AVD-BV regimen* 
Doxorubicin 
Vinblastine 
Dacarbazine 
Brentuximab Vedotin** 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day cycle 
Day 1, 15 
Of 28-day cycle 
25 mg/m2 
6 mg/m2 
375 mg/m2 
1.2 mg/kg** 
 
*GCSF will be administered on Days 2-10 and 16-24 throughout each 28-day cycle using standard 
doses. Pegfilgrastim may be substituted on days 2 and 16. (See Section 10.10.1) 
**For participants with weight exceeding 100kg, the dosage of Brentuximab Vedotin will be calculated 
based on a weight of 100kg. Maximal dose = 120 mg. 
10.2 
Radiation Therapy 
Involved field radiotherapy should be given at the discretion of the investigator after 
chemotherapy if there was bulky (>10cm) disease at diagnosis as suggested in the 
NCCN guidelines. Radiation therapy initiation will be within 2 weeks after protocol 
therapy. Radiotherapy may be performed during the follow-up period according to 
institutional standards. 
10.3 
HAART 
HAART is a requirement for the duration of the study. Patients must be on HAART 
therapy for at least 7 days before therapy. The specific agents are at the discretion of 
the Investigator. Protease Inhibitors and Integrase Inhibitors boosted with ritonavir or 
cobistat are contraindicated. Non-nucleosides reverse transcriptase (NNRTIs) are not 
recommended, however, in the absence of alternative therapy, their use will be 
discussed in the presence of a pharmacologist in the national “RCP” (réunion de 
concertation pluridisciplinaire) for patients with HIV associated lymphomas. 
The sponsor will not provide the HAART as it is considered as standard care for HIV 
patients. HAART is to be used according to summary of product characteristics. 
10.4 
Administration of chemotherapy 
The sponsor will not provide the chemotherapy (AVD) as it is considered as standard 
care for Hodgkin lymphoma. Chemotherapy products are to be used according to 
summary of product characteristics. 
10.4.1 Doxorubicin 
Doxorubicin is an anthracycline antibiotic that binds tightly with DNA, inhibits 
nucleic acid synthesis and causes DNA strand breaks. Although active 
throughout the cell cycle, cells in S phase are most sensitive. Common side 
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and may be severe. Drug-induced cardiomyopathy which may result in 
congestive heart failure, is a cumulative dose-dependent effect and risk becomes 
considerable at total doses exceeding 500 mg/m2. Doxorubicin is given 
intravenously and is a vesicant causing severe local necrosis at the site of 
injection if extravasation occurs. Nausea and vomiting are frequent. 
10.4.2 Vinblastine 
Vinblastine is the salt of an alkaloid derived from Vinca rosea Linn, a common 
herb known as the periwinkle. Mechanism of Action: Tissue culture studies 
suggest an interference with metabolic pathways of amino acids leading from 
glutamic acid to the citric acid cycle and to urea. A number of studies in vitro 
and in vivo have demonstrated its stathmokinetic effect and various atypical 
mitotic figures. Other studies indicate an effect on cell energy production 
required for mitosis and the interference with nucleic acid synthesis. Reversal 
of antitumor effect by glutamic acid and tryptophan has been observed. 
Leukopenia is the usual dose-limiting side effect, with the nadir falling four to 
seven days post-injection. Thrombocytopenia and anemia may occur. 
Gastrointestinal toxicities include nausea, vomiting, diarrhea or constipation, 
abdominal pain, ileus, peptic ulcer, rectal bleeding and anorexia. Fever and 
phlebitis have also been seen when the drug is given as an infusion. 
Extravasation may lead to tissue necrosis. Ten percent of the patients will 
experience peripheral neuropathy. Alopecia can also occur. 
10.4.3 Dacarbazine (DTIC) 
Three hypotheses have been offered as the mechanism(s) of action of DTIC: 
inhibition of DNA synthesis by acting as a purine analog, action as an alkylating 
agent, and/or interaction with SH groups. 
Myelosuppression is the dose-limiting toxicity. The predominant side effect 
observed in humans has been anorexia, nausea and vomiting. This occurs with 
maximal intensity on the first day of a five-day course, and in many patients, it 
is less with each subsequent day. Myelosuppression consisting of 
thrombocytopenia and leukopenia occurs in approximately one-quarter of 
patients after a five-day course of 250 mg/m2. The time course for this 
myelosuppression is generally maximal approximately three weeks after 
administration with the period of recovery variable. Other reported side effects 
include infrequent flu-like syndrome associated with fever and myalgia, 
phlebitis, liver necrosis, hepatic toxicity, anaphylaxis, photosensitivity, 
alopecia, and facial flushing. Rarely, DTIC has caused diarrhea. 
10.5 
Drugs description, storage and handling 
10.5.1 Description of investigational product: Brentuximab Vedotin (NSC 749710) 
Other Names: AdcetrisTM, SGN-35 
Classification: Monoclonal Antibody CAS 
Registry Number: 914088-09-8  
M.W.: 153 kDa 
Mode of Action: A CD-30 directed antibody-drug conjugate (ADC) consisting 
of 3 components: (1) the chimeric IgG1 antibody cA10, specific for human 


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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. 
Preparation: Consists of 2 steps: dilution of the stock solution and dilution of 
the final solution. 
• 
Step 1: To make a 5 mg/mL concentration. 
1. Reconstitute the 50 mg lyophilized powder SGN-35 with 10.5 mL 
Sterile Water for Injection, USP. Final concentration is 5 mg/mL 
(Note: total volume is 11 mL). 
2. Swirl the vial gently. Do not shake. 
3. Let the reconstituted vial settle for one minute to eliminate bubbles. 
The reconstituted solution should be colorless, clear to slightly 
opalescent and should NOT have visible particulates. 
4. Store the reconstituted vial under refrigeration (2– 8°C), protect from 
light if not used immediately. Discard after 8 hours. 
• 
Step 2: Further dilute the IV solution. Use vials from the same Lot number 
for each dose. 
1. Withdraw the calculated amount of drug from the 5 mg/mL 
reconstituted vial in step 1. 
2. Inject the required amount of drug into a 50 mL to 250 mL of 0.9% 
NS, Lactated Ringer’s Solution, USP, or dextrose 5% in Water (D5W), 
USP to a final concentration between 0.4 – 1.8 mg/mL. 
3. Brentuximab  vedotin  solution  is  compatible  in  polyvinylchloride  
(PVC),  ethylene  vinyl  acetate (EVA), polyolefin, or polyethylene. 
4. Do not shake. Gently invert the bag. 
5. The prepared IV bag is to be stored at 20 – 80 C and must be used 
within 24 hours of initial product reconstitution. Protect the prepared 
IV solution from direct sunlight if not used immediately. 
6. Prior to administration, inspect the IV bag for discoloration or floating 
particulates. Do not use the IV solution if the solution is discolored 
or/and have particulates. 
CAUTION: The single-use lyophilized dosage form contains no antibacterial 
preservatives. Therefore, it is advised that the reconstituted product be discarded 
8 hours after initial entry. 
Route(s) of Administration: Intravenous. Do not administer as an IV Push or 
bolus. 
Method of Administration: Infuse the prepared IV solution over 30 minutes. Do 
not mix with other medications. Do not use an in-line filter for the IV 
administration. The IV bag does NOT need light protection during the IV 
administration. 
Patient Care Implications: 
• 
New signs and symptoms of CNS system abnormalities may indicate 
progressive multifocal leukoencephalopathy (PML). 


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• 
Tumor lysis syndrome, particularly in patients with highly proliferative 
tumors or high tumor burden prior to treatment. 
• 
Infusion-related reactions, including anaphylaxis, may occur. Refer to 
protocol for the management of infusion- related reactions. 
• 
Signs and symptoms of peripheral neuropathy such as tingling or numbness 
of the hands, feet, or any muscles weakness. 
• 
Steven-Johnson syndrome 
• 
High fever (≥38°C) or other signs of potential infection. 
10.5.2 Packaging and labelling 
SGN-35 will be supplied as a single use, preservative free vial containing 50 mg 
of white to off-white lyophilized powder for Injection. Inactive ingredients are 
trehalose, sodium citrate, and polysorbate 80. The pH is 6.6 once reconstituted 
in Sterile Water for Injection. 
Study drug labels will contain information to meet the applicable regulation 
requirements. The investigational product will be labelled as open label 
material. 
10.5.3 Storage conditions and handlings 
Storage: Store the intact vials refrigerated at 2-8°C. Protect from direct sunlight. 
Stability: The stability testing of the intact vials is ongoing. Reconstituted 
agent must be diluted and administer within 24 hours. 
Refer to investigator brochure for additional information regarding storage and 
handling. 
10.6 
Dose adjustments 
10.6.1 Brentuximab Vedotin Dose Modifications 
10.6.1.1 Intrapatient. Dose Reductions for Starting Dose of 1.2 mg/kg Every 
2 Weeks 
No further dose reductions will be permitted beyond 0.6 mg/kg of 
brentuximab vedotin. Patients not tolerating a dose of 0.6mg/kg 
will continue with standard dose AVD at the discretion of the 
investigator. 
Dose Level: 
• 1.2 mg/kg 
• 0.9 mg/kg 
• 0.6 mg/kg 
10.6.1.2 Treatment Modification Guidelines for Brentuximab Vedotin for All 
Cycles 


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Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Allergic reactions, 
or Acute infusional 
reactions/cytokine 
release syndrome 
Grade 1-2 
For first reaction: 
• Hold the infusion and wait 30 to 60 minutes (depending upon 
the reaction severity) 
• Treat reactions with diphenhydramine 1 mg/kg (max 50 mg), or 
follow local institution guidelines. Depending on the reaction 
severity, dexamethasone 0.2mg/kg (max 10mg) IV should be 
used or follow local institutions guidelines. 
• 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. paracetamol 
can also be considered. Brentuximab vedotin may be administered at 
half of the previously administered rate at the discretion of the 
investigator. 
For subsequent doses: 
• Utilize diphenhydramine with or without paracetamol as pre-
treatment for all subsequent infusions. 
• Dosing will be administered over the shortest infusion period that was
well tolerated. 
If Grade 1-2 infusion reactions recur despite the above measures, either 
during re- challenge or subsequent treatments: 
• Take the measures outlined above 
• With subsequent dosing, add dexamethasone 0.2 mg/kg (max 
10mg) IV or equivalent to medications above prior to infusion. 
Grade 3 
• Stop infusion immediately 
• Administer diphenhydramine hydrochloride 1 mg/kg IV (max 50 
mg), dexamethasone 0.2mg/kg (max 10mg) IV (or equivalent), 
bronchodilators for bronchospasms, and other medications as 
medically indicated 
• Once symptoms recover, brentuximab vedotin should not be resumed 
for that course 
• Subsequent courses of brentuximab vedotin may be considered at 
physicians’ discretion, after a discussion and approval by one of the 
French coordinator. 
• All subsequent infusions will use the following premedications  prior 
to infusion, diphenhydramine hydrochloride 1 mg/kg IV (max 50 mg), 
dexamethasone 0.2mg/kg (max  10mg) IV (or equivalent). In addition, 
the infusion will be administered at 50% of the previous infusion rate 
 
Grade 4 
• Stop infusion immediately 
• Administer diphenhydramine hydrochloride 1 mg/kg 
(max 50mg) IV, dexamethasone 0.2 mg/kg (max 10mg) 
IV (or equivalent), and other anaphylaxis medications as 
indicated 
• Adrenaline or bronchodilators at the discretion of the investigator will
be administered as indicated. 
• Hospital admission for observation may be indicated. 
• Discontinue brentuximab vedotin 
Anaphylaxis 
Any Grade 
• If anaphylaxis occurs, immediately and permanently  discontinue
administration of brentuximab vedotin and administer appropriate
medical therapy. 


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Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
Pancreatitis 
Grade 2 
• 
Withhold dose until toxicity has returned to baseline, then continue 
on protocol therapy but resume at one dose reduction. 
• 
If Grade 2 pancreatitis recurs after one dose reduction, the 
patient must be removed from protocol therapy. 
 
Grades 3-4 
• 
Permanently discontinue brentuximab vedotin. 
Peripheral 
Neuropathy 
Grade 1 
Continue at same dose level. 
Grade 2 
• Treatment is to be delayed until neuropathy improves to Grade 1 or 
baseline 
• Brentuximab vedotin will be reduced by one dose level for subsequent 
treatments once peripheral neuropathy returns to baseline or returns 
to grade 1. 
• Patients who experience a delay of over 7 days in cycle 1 will be 
removed from the study. For subsequent cycles, if two sequential 
doses of brentuximab vedotin are held due to unresolved toxicity, 
leading to a treatment delay of an additional 2 weeks (i.e., 4 weeks 
between doses), participant will discontinue brentuximab vedotin. 
Participants will have the option to discontinue protocol therapy or 
continue study with AVD with dose adjustments in vinblastine as 
clinically necessary based on the level of neuropathy on the day of 
treatment as per standard label/summary product characteristics. 
Grade 3 
• Treatment is to be delayed until neuropathy improves to Grade 1 or
baseline. 
• Brentuximab vedotin will be reduced by one dose level for 
subsequent treatments once a peripheral neuropathy returns to 
baseline or returns to grade 1. 
• Patients who develop grade 3 neuropathy after dose reduction will 
have to discontinue brentuximab vedotin. Subjects will have the option 
to be taken off protocol or continue study with AVD with dose 
adjustments as clinically necessary. 
• Patients who experience a delay of over 7 days in cycle 1 will be 
removed from the study. For subsequent cycles, if two sequential doses 
of brentuximab vedotin are held due to unresolved toxicity, leading to 
a treatment delay of an additional 2 weeks (i.e., 4 weeks between 
doses), the participant will discontinue brentuximab vedotin.. 
Participants will have the option to discontinue protocol therapy or 
continue study with AVD with dose adjustments in vinblastine as 
clinically necessary, based on the level of neuropathy on the day of 
treatment as per standard label/Summary product characteristics. 
 
Grade 4 
Discontinue brentuximab vedotin. 
Neutropenia 
occurring on the 
day of treatment 
Grade 1-2 
Continue at same dose level. 


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Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
 
Grade 3-4 
• Reinstitute growth factor support (GCSF) for treatment of 
neutropenia until recovery to ANC ≥1,000/mm3. 
• If myeloid growth factor support was inadvertently omitted in 
the previous dose, patients should receive the same full dose 
of brentuximab vedotin in the next treatment dose, along with 
myeloid growth factor support 
• If, as per protocol, the participant was on myeloid growth factor 
support with the previous dose and presents with treatment day 
neutropenia, reinstitute myeloid growth factor support (GCSF) until 
recovery to ANC ≥1,000/mm3 and reduce brentuximab vedotin one 
dose level for all remaining cycles. 
• Dose reduction below brentuximab vedotin 0.6 mg/kg is not 
allowed. Brentuximab vedotin should not be given for any 
subsequent cycles. 
• If participants have febrile neutropenia, please see Section 10.6 for 
dose modifications. 
Thrombocytopenia 
Grade 1-2 
Continue at same dose level. 
 
Grade 3-4 
• Withhold dose until toxicity is ≤ Grade 2 or has returned to 
baseline, then continue on protocol therapy but at one dose 
reduction 
• Patients who experience Grade 3-4 thrombocytopenia after dose 
reduction must be removed from protocol therapy 
• Patients who experience a delay of over 7 days in cycle 1 will be 
removed from the study. For subsequent cycles, if two sequential doses 
of brentuximab vedotin are held due to unresolved toxicity, leading to 
a treatment delay of an additional 2 weeks (i.e., 4 weeks between 
doses), the patient will be taken off protocol therapy. 
Lymphopenia 
Grade 1-4 
Continue at same dose level. 
Non-hematologica 
events (not 
including 
electrolyte 
abnormalities) 
or febrile 
neutropenia) 
(See Section 
10.6.1.5 for 
treatment 
modifications for 
febrile neutropenia) 
Grade 1-2 
Continue at same dose level. 


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Event 
CTCAE.v4.0 
Grade 
Action to be Taken 
 
Grade 3-4 
• Withhold dose until toxicity is ≤ Grade 2 or has returned to 
baseline, then continue on protocol therapy but resume at one 
dose reduction of brentuximab vedotin. 
• If non-hematological Grade 3-4 toxicity recurs after one dose 
reduction, the patient must be removed from protocol therapy 
• Patients who experience a delay of over 7 days in cycle 1 will be 
removed from the study. For subsequent cycles, if two sequential doses 
of brentuximab vedotin are held due to unresolved toxicity, leading to 
a treatment delay of an additional 2 weeks (i.e., 4 weeks between 
doses), the patients will be taken off protocol therapy, and brentuximab 
vedotin will be discontinued. Participants will have the option to be 
taken off protocol or continue study with just AVD without 
brentuximab vedotin. 
Electrolyte 
Abnormalities 
Grade 1-4 
• Continue at same dose level, provided electrolyte toxicity is 
not medically consequential and has been readily corrected 
• If electrolyte abnormality is medically consequential, refer to
guidelines above for non-hematologic events 
a Patients who develop Grade 3 or 4 electrolyte laboratory abnormalities may continue study treatment without 
interruption but should receive appropriate medical therapy at the discretion of the investigator. 
b GCSF will be administered on Days 2-10 and 16-24 throughout each 28-day cycle using standard doses. 
Pegfilgrastim may be substituted for GCSF and administered on days 2 and 16. 
10.6.1.3 Dose Modifications for Progressive Multifocal Leukoencephalopathy 
(PML) 
PML is a rare demyelinating disease of the brain that is caused by the 
John 
Cunningham 
virus 
(JCV). 
It 
typically 
occurs 
in 
immunocompromised individuals and can be fatal. Presenting 
features 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 PML patients (approximately 20%). Cognitive decline 
without accompanying deficits in motor or sensory function is 
uncommon. Optic nerve involvement, fever, and spinal cord disease 
are not typically associated with PML. In addition, peripheral 
neuropathy, which has been reported with brentuximab vedotin 
treatment, is not commonly reported with PML. 
If PML is suspected, a diagnostic work-up must be performed. The 
work-up may include, but is not limited to the following: 
• 
Neurologic examinations and neurology consultation, as 
warranted 
• 
Brain MRI. Features suggestive of PML include presence of 
unifocal or multifocal lesions, mainly of the white matter, 
which are typically non-enhancing and do not have mass 
effect. 
• 
PCR analysis. JCV DNA, detectable in CSF or in a brain biopsy, 
is suggestive of PML. 


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• 
Brentuximab vedotin dosing must be held if PML is 
suspected. If PML is confirmed, brentuximab vedotin must 
be permanently discontinued. 
10.6.1.4 Dose Modifications for Pulmonary Toxicity 
Pulmonary toxicity will be defined by grade 3 or 4 dyspnea, 
pneumonitis, and/or hypoxia that persists for at least three days. There 
must be no evidence of other etiologies, including left atrial 
hypertension, congestive heart failure, infection, metabolic 
abnormalities, or cancer related causes (e.g., malignant pericarditis). 
Patients who develop pulmonary toxicity associated with 
brentuximab vedotin may benefit from treatment with corticosteroids. 
However, there are no published guidelines to suggest the most 
appropriate dosing or duration of treatment. Administration of 100 
mg of oral or intravenous prednisolone in single daily or two divided 
doses has been reported to improve symptoms in adults with 
pulmonary toxicity secondary to gemcitabine. The suggested dose for 
patients who develop pulmonary toxicity is methylprednisolone 1 
mg/kg IV every 12 hours for a minimum of seven days. Patients who 
develop pulmonary toxicity meeting the above definition will be 
taken off protocol therapy. 
See Section 13.1 for a complete listing of potential adverse events 
and Section 13.1.1 for special precautions and safety issues. 
10.6.1.5 Dose Modifications for Febrile Neutropenia 
For participants already dosed reduced for reasons other than febrile 
neutropenia (e.g., neuropathy), dose reduction must start from the 
level at which the febrile neutropenia occurs. 
Treatment Modification Guidelines for AVD-Brentuximab Vedotin 
for All Cycles. 
Episode of Febrile Neutropenia 
Action 
First Episode of Febrile 
Neutropenia 
Maintain current brentuximab vedotin 
dose with quinolone prophylaxis, or 
reduce one dose level (investigator’s 
discretion). 
Second Episode of Febrile 
Neutropenia 
Quinolone prophylaxis and reduce one 
dose level. 
Third Episode of Febrile 
Neutropenia 
Quinolone prophylaxis and reduce one 
dose level. 
Fourth Episode of Febrile 
Neutropenia 
Quinolone prophylaxis and reduce one 
dose level. 
 
Dose Level 
Brentuximab 
Vedotin 
AVD 
1 
1.2 mg/kg 
Full dose 
-1 
0.9 mg/kg 
Full dose 


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-2 
0.6 mg/kg 
Full dose 
-3 
0 
Full dose 
-4 
0 
0.75 
Quinolone prophylaxis: antibacterial therapy is required for all cycles 
after an initial episode of febrile neutropenia. Suggested regimen can 
be altered based on availability, allergies, or ANC trends (e.g., 
levofloxacin 750 mg PO daily, Days 6-13 and Days 20-27). 
Participants who are unable to receive at least 4 doses of brentuximab 
vedotin will not receive further therapy on study. 
See Section Error! Reference source not found. for a complete 
listing of potential adverse events and Section Error! Reference 
source not found. for special precautions and safety issues. 
10.6.2 AVD-Brentuximab Vedotin Dose Modifications (applies to all cycles) 
Hematologic Toxicity 
 
Although it is common practice to attenuate doses or delay treatment due to 
cytopenias alone, recent studies have shown that in the non-HIV setting for cHL 
patients receiving delays results in suboptimal treatment outcomes 77,78. 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. 
Febrile Neutropenia 
If febrile neutropenia occurs, then prophylaxis with antibacterial therapy is 
recommended for the subsequent cycle (e.g., levofloxacin 500 mg PO daily, Days 6-
13 and Days 20-27 unless neutropenia occurred earlier in the cycle). Continued anti- 
bacterial antibiotic use thereafter is at the discretion of the treating physician. If a 
second febrile neutropenia episode occurs, decrease the doses of vinblastine and 
doxorubicin to 75% of the previous dose received for the next cycle (in addition to 
above antibiotic and GCSF supportive care measures). Re-escalation is at the 
discretion of the treating physician. If a third episode of febrile neutropenia occurs, 
patients should be maintained on therapy with supportive measures unless infection 
is life threatening. 
Transfusions 
Erythrocyte and platelet transfusions will be administered as needed at the discretion 
of the treating physician. 
Severe Infection 
Severe infection (NCI CTC Version 5.0, Grade 3 or 4) due to chemotherapy- related 
neutropenia requires a decrease in 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 
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Impaired Hepatic 
Function 
All patients with direct bilirubin ≤ 2 x the upper limit of normal (ULN) will receive 
a full initial dose of doxorubicin and vinblastine. If the direct 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 direct bilirubin is ≤ 2 x ULN. If the direct bilirubin rises to > 5 x ULN, 
doxorubicin and vinblastine should be discontinued for that cycle. If the direct 
bilirubin has not recovered to ≤ 2 x ULN by the time the next cycle is due, then 
remove patient from protocol treatment. In cases of obstruction of the biliary duct by 
a tumor mass, a biliary drainage stent should be placed prior to chemotherapy. Values 
must be within protocol eligibility at treatment initiation. 
Direct Bilirubin with appropriate Doxorubicin and Vinblastine Dose Adjustments 
≤ 2 x ULN = 100% of last dose received 
> 2 - 5 x ULN = 50% of last dose received 
> 5 x ULN = discontinue (i.e., do not administer) 
Neuropathy 
Once brentuximab vedotin has been discontinued, patients experiencing Grade 3 
vinblastine-neuropathy (e.g., obstipation, weakness) will have the dose of vinblastine 
reduced by 50% for all further cycles of AVD. Patients experiencing Grade 4 
vinblastine neuropathy will have this drug omitted from all future cycles of AVD. 
Pulmonary Toxicity 
Every 2 cycles PFT will be performed. The DLCO adjusted for hemoglobin must be 
greater than 70% to continue with brentuximab vedotin. 
Weight 
If a subject's weight has changed more than 10% from baseline or the prior dose, the 
new BSA must be used on the next cycle. For a weight change of 10% or less,  doses  
may  be  adjusted  according  to  the  BSA  or  remain  the  same  in conjunction with 
institutional guidelines. 
10.7 
Drug Dispensation and accountability 
10.7.1 Responsibilities 
All drug packages are to be inspected upon receipt at the study site prior to being 
drawn up. If any particulate matter is detected, the packaging is not to be used. 
Damaged packaging is to be reported to the sponsor and stored until instructions 
have been given. 
The Investigator, the Hospital Pharmacist, or other personnel allowed to store 
and dispense Investigational Product (SGN-35 / Brentuximab Vedotin) are 
responsible for ensuring that the Investigational Products used in the clinical 
trial are securely maintained as specified by the Sponsor  and  in accordance  
with the  applicable  regulatory requirements. All Investigational Medical 
Products are stored in accordance with labelling and shall be dispensed in 
accordance with the Investigator's prescription. The Investigator is in charge of 
ensuring that an accurate record of Investigational Product issued and returned 
is maintained. Any quality issue noticed with the receipt or use of an 
Investigational Product (deficient IP in condition, appearance, pertaining 
documentation, labelling, expiry date, etc.) should be promptly notified to the 
Sponsor, who will initiate a complaint procedure. Under no circumstances will 
the Investigator supply Investigational Product to a third party, allow the 
Investigational Product to be used other than as directed by this Clinical Trial 
Protocol, or dispose of Investigational Product in any other manner. 
The responsible investigator at each participating institution must be registered 
with CTEP, DCTD through an annual submission of FDA form 1572 (Statement 
of Investigator), Curriculum Vitae, Supplemental Investigator Data Form (IDF), 


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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 principal investigator at that 
institution. 
10.7.2 Retrieval or destruction 
All partially used or unused treatments will be verified by the Sponsor. A 
detailed treatment log of the returned Investigational Product will be established 
with the Investigator (or the pharmacist) and countersigned by the Investigator 
(or the Pharmacist) and the Sponsor representative. The Investigator (or the 
pharmacist) will not destroy the unused Investigational Product unless the 
Sponsor provides written authorization. In case of a potential defect in the 
quality of Investigational Product, the Sponsor may initiate a recall procedure. 
In this case, the Investigator will be responsible for promptly addressing any 
request made by the Sponsor, in order to recall Investigational Product and 
eliminate potential hazards. 
10.7.3 Accountability and compliance 
The investigator, or a responsible party designated by the investigator, must 
maintain a careful record of the inventory and disposition of all agents received 
from DCTD using the NCI Drug Accountability Record Form (DARF). (See 
the NCI Investigator’s Handbook for Procedures for Drug Accountability and 
Storage.) 
The investigator or pharmacist will inventory and acknowledge receipt of all 
shipments of the investigational product. The investigator or pharmacist will 
also keep accurate records of the quantities of the study treatments dispensed 
and used for each patient, to assess the patient treatment compliance. The 
sponsor representative will periodically check the supplies of investigational 
products held by the investigator or pharmacist to verify accountability of all 
investigational products used. All unused investigational products and all 
medication containers will be destroyed by the study sites. The Sponsor will 
verify that a final report of drug accountability at the unit dose level is 
maintained and archived in the investigator study file. Administration of the 
study treatment will be supervised by the investigator or sub-investigator. 
10.8 
Concomitant treatment restrictions 
10.8.1 Medications prohibited for enrollment and the duration of the study 
Experimental antiretroviral agents or those containing zidovudine (including 
Combivir and Trizivir) or ritonavir (including Kaletra), Cobicistat or similar 
potent CYP3 inhibitors are prohibited for enrollment and the duration of the 
study. 
10.8.2 Potential Drug Interactions of Brentuximab Vedotin 
In vitro data, one of SGN-35 active metabolites, monomethyl auristatin E 
(MMAE) is a substrate and an inhibitor of CYP3A4 but is not a sensitive 
substrate nor a strong inhibitor/inducer of CYP3A4. However, patients should 
be monitored for potential drug-interaction when administered drugs known to 
be a strong CYP 3A4 inhibitor/inducer with SGN-35. In vitro, MMAE is a 
substrate of P-gp transporter and is not an inhibitor of P-gp. 


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10.9 
Reporting requirements for concomitant medications 
All medications must be reported in the site’s source documents at baseline. All 
medications will be reviewed and updated in the site’s source documents at all visits 
where indicated in the schedule of evaluations (Appendix I). Only a subset of 
medications will be reported in the Concomitant Medications CRFs after study entry, 
as listed below: 
1. Anti-seizure medications 
2. Prophylactic medications 
• 
Antiviral 
• 
Antifungal 
• 
Quinolone/Antibiotic therapy 
• 
Any other medications used for prophylaxis of opportunistic infections 
3. Hepatitis medications 
4. Growth colony stimulation factors (GCSF) 
5. Erythropoiesis Stimulating Agents (ESA) 
6. Anti-retroviral medications. Note: Antiretroviral therapy will be collected in the On 
Study Form. If the subject remains on the same anti-retroviral medications 
throughout study participation that have already been reported in the On Study 
Form, then do not report them in the Concomitant Medications Form. If the subject 
changes or discontinues anti-retroviral therapy for any reason, then update the 
Concomitant Medication Form with the start and stop date of the discontinued 
medication(s) and start date of the new (if applicable) medication(s). 
7. Receipt of disallowed medications (CYP3A4 or P-glycoprotein inhibitors) after 
study enrolment, as per Appendix 20.9. 
10.10 Prophylactic measures 
10.10.1 Growth Factor 
GCSF will be administered on Days 2-10 and 16-24 throughout each 28-day 
cycle using standard doses. Pegfilgrastim may be substituted for GCSF and 
administered on days 2 and 16. 
10.10.2 Pneumocystis prophylaxis 
Trimethoprim sulfamethoxazole (Bactrim) (one double strength tablet twice 
daily three days per week or one single strength daily) must be given at the onset 
of therapy for Pneumocystis and Toxoplasmosis prophylaxis. Alternatively, 
dapsone (50 mg PO twice daily), atovaquone, or aerosolized pentamidine may 
be substituted for Pneumocystis prophylaxis in subjects allergic to 
sulfonamides. Pneumocystis prophylaxis will be continued once therapy has 
been discontinued. 
10.10.3 Mycobacterium avium complex (MAC) prophylaxis 
Azithromycin 1,200 mg PO once weekly must be initiated for prophylaxis if the 
CD4 count falls below 50 cells/µL or is expected to drop below 50 cells/µl while 
on chemotherapy. Prophylaxis may be discontinued once the CD4 count is 
deemed reliably above 50 cells/µL by the treating investigator. 
10.10.4 Pre-infusion prophylaxis 
Pre-infusion prophylaxis (e.g., diphenhydramine) may be administered per 
institutional guidelines. 


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11.0 
STUDY PROCEDURES 
11.1 
Registration and inclusion procedure 
After it has been determined that the subject is eligible and an informed consent has 
been signed by the subject, the subject must be registered on-line via the AMC 
AdvantageEDCSM Internet Data Entry System (AdvantageEDC). Enrollment and data 
collection will occur via the AMC Internet Data Entry System. 
The participating site will ensure a subject meets all eligibility criteria prior to 
completing the protocol-specific eligibility checklist in AdvantageEDC for enrolment. 
Subjects will be enrolled on-line via AdvantageEDC no more than 1 week prior to the 
initiation of treatment (enrollment 1 day prior to or on the day of treatment is strongly 
encouraged). Once the eligibility checklist is submitted a system-generated 
confirmation email will be sent to the enroller upon successful completion of the subject 
enrollment. If the on-line system is inaccessible, the site should notify the AMC ODMC 
(via email at amcpm@emmes.com or via phone at 001 301-251-1161) for further 
instructions. 
The investigator should fax (+33 4 72 66 93 71) at the same time the following 
documents: anonym copy of the pathology report (see appendix 20.7). The LYSARC 
coordination center (Tel: +33 4.72.66.93.33) will be the contact for any request. 
11.2 
Pathological diagnosis 
The pathological diagnosis of Hodgkin lymphoma should have been performed locally 
before the inclusion for each patient. 
Histopathology central review process has become in the last years a common and 
prerequisite procedure for clinical trials in the field of lymphomas. A mandatory 
pathological review will therefore be organized for all patients included in the trial at 
diagnosis. The goal of this central review will be to confirm the diagnosis and to precise 
its classification according to the WHO classification 2008. 
The pathological review will be centralized at the LYSA-Pathology (LYSA-P) institute, 
Hôpital Henri Mondor, Créteil. For each patient, the investigator will be requested to 
join with the form of inclusion a copy of the anonymised histopathological report where 
the name and address of the pathologist having diagnosed the lymphoma will be easily 
identified as well as a copy of the bone marrow report. 
All requested tumor paraffin embedded blocks from the formalin fixed sample (that 
have been used for diagnosis), or 10 unstained slides will be sent to the LYSA-P, 
according to the process described in Appendix 20.7 “Pathological samples review”. 
At reception, routinely stained sections will be performed and an appropriate panel of 
antibodies according to morphological aspects will be applied. A pathological review, 
performed by at least 2 experts hematopathologists will be organized at the LYSA-P 
and a consensus diagnosis will be established. A LYSA-P pathological report will then 
be sent to the clinical coordinator and to the initial pathologist. 
Initial tumor block will also be used to make tissue microarray (TMA) and DNA/RNA 
extraction. 
11.3 
Biological study/ samples 
Blood samples will be collected at inclusion and sent to Bicêtre hospital. The specific 
informed consents must be signed before any sample procedure. These samples will be 
integrated in a comprehensive collaborative studies. This may include proteomic, 
genetic, virological and immunology studies. 


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The samples processing is described on Appendix 20.7. 
The following sample will be collected at baseline, before treatment: 
• 
For proteomic (plasma storage for protein analyses): 10mL (2 tubes) of 
blood on Heparin Lithium tubes (provided by LYSARC). 
• 
For genetic (cells storage for DNA extraction): 10mL (2 tubes) of blood on EDTA 
tubes 
• 
For immunology and virological studies (EBV viral load in mononuclear 
cells and in plasma, analyse of immune response anti-EBV, cytokines 
analyses): 20mL (4 tubes) of blood on Heparin Lithium tubes (provided by 
LYSARC). 
On the day of blood sampling, the sample will be sent at room temperature by carrier 
and centralized to the Bicêtre hospital. 


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12.0 
STUDY COMMITTEES 
12.1 
Independent Data Monitoring Committee 
An Independent Data Monitoring Committee (IDMC), including at least three independent 
members (2 experts in HL including 1 expert in VIH) will be established. The IDMC will 
meet periodically to review the safety and efficacy data from the trial. 
More details about IDMC operation will be provided in the IDMC Chapter. 
The first IDMC is planned to occur after the 1st SAE for hematologic or neurologic toxicity 
after the approval of this current version of protocol or after the completion of 4 cycles 
according of two first patients according this current version of protocol. 
 
 


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13.0 
CRITERIA FOR PREMATURE DISCONTINUATION OF THE STUDY 
13.1 
Premature withdrawal from trial intervention 
After enrollment, subjects will be permanently withdrawn from study treatment for any 
of the following reasons. In the event of withdrawal from treatment, the reason for study 
treatment removal and the date the subject was removed must be documented in the Off 
Protocol Treatment Form in AdvantageEDCSM. See Section 9.6 on evaluations to be 
performed at early discontinuation of therapy. 
1. Participants who experience a delay of over 7 days in cycle 1 will be removed from 
the study. For subsequent cycles, if two sequential doses of AVD + BV or AVD 
alone are held due to unresolved toxicity, leading to a treatment delay of an 
additional 2 weeks (i.e., 4 weeks between doses), the participant will be taken off 
protocol therapy. The participant will be followed for survival and may resume 
AVD treatment off study. 
2. Severe toxicities as outlined in Section 10.6.1. 
3. Progressive lymphoma at any time while on study. 
4. Voluntary withdrawal. 
5. The investigator has the right to remove subjects from study for clinical reasons 
which he or she believes to be life threatening or resulting in significant morbidity 
to the subject. 
6. Any subject who develops HBV reactivation or acute Hepatitis B as defined by 
the reappearance of a previously suppressed hepatitis B surface antigen, a positive 
IgM hepatitis B core antibody, and a positive viral load. Any patient with 
Hepatitis B or C who has worsening liver function as defined by Section 10.6.2 
will also be removed from study. 
7. Any subject who on repeat PFT is found to have a DLCO when corrected for anemia 
less than 70%. 
8. Subjects who become pregnant or breast-feed. 
9. Subjects with progressive disease at the end of cycle 2 will be removed from 
study treatment, while patients with stable disease may be removed from the 
study treatment at the discretion of the local responsible investigator. 
Progressive or stable disease defined at cycle 2 will be based by CT criteria 
only, as FDG-PET has yet to be validated in HIV-associated HL. 
10. If found by central pathology review to not have the diagnosis of HL. 
11. If the subject has had two cycles of AVD + brentuximab vedotin and develops 
recurrent Grade 3 peripheral neuropathy despite dose reductions of brentuximab 
vedotin and vinblastine, the subject may continue the study receiving AVD with 
dose adjustments in vinblastine as clinically necessary, keeping in mind to 
maintain the dose and schedule as in standard therapy, or may be removed from 
protocol treatment. This decision will be at the discretion of the investigator. 
13.2 
Withdrawal of Consent 
Patients are free to withdraw from the study at any time without prejudice to their 
treatment. When a patient decides to withdraw from the study, she/he should always be 
contacted in order to obtain information about the reason for withdrawal and to record 
any adverse events. When possible, the patient should return for a study visit at the time 
of, or soon after withdrawal, and the relevant assessments should be performed. 
If the patient explicitly states his/her wish not to contribute further data to the study, the 
relevant LYSARC contact should be informed and the withdrawal of consent should be 
documented by the investigator in the patient’s case report form. However, data up to 
the time of consent withdrawal will be included in the data reported for the study. 


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13.3 
Patients Lost to Follow up 
Every effort will be made to contact patients who fail to return for scheduled visits. A 
patient is considered lost to follow-up if no information has been obtained when the last 
patient has completed the clinical phase of the study. During this time site investigator 
must document attempts to contact the patient either by phone or letter. 
13.4 
Premature discontinuation of the study 
The sponsor reserves the right to stop the trial at any time. The investigators will be 
informed of this decision in writing. 
The same applies to any investigator wanting to discontinue his/her participation to the 
trial. The investigator must immediately inform the sponsor in writing of this decision. 
An early stopping rule will be established such that the trial will be terminated if either 
or both of the following conditions hold: 
1. If more than 10% of the subjects experience a grade 3 motor or sensory 
neurotoxicity lasting for more than 4 weeks, the trial will be terminated. The first 
10 patients in the phase II portion of the study at the 1.2 mg/kg dose will be 
monitored for this outcome. If more than 3 out of the first 10 patients in the phase 
II study experience grade 3 neurotoxicity, this will be considered sufficient to 
stop the trial. With an underlying probability of grade 3 neuropathy of no more 
than 10%, the probability of observing > 3 patients with grade 3 neuropathy is 
less than 5%. 
2. If any PML case is diagnosed when the CD4 count is above 50, the trial will be 
terminated. 


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14.0 
ADVERSE EVENTS: LIST AND REPORTING REQUIREMENTS 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. 
The following list of expected AEs (see section 13.1) and the characteristics of an 
observed AE (see section 13.2) will determine whether the event requires expedited 
(via CTEP-AERS) in addition to routine reporting (via AdvantageEDCSM). 
The CTEP Version 5.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized for AE reporting. The CTEP Version 5.0 of the CTCAE is 
identified and located on the CTEP website at 
 http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTEP Version 5.0 
of CTCAE. 
This study will be monitored by the Clinical Data Update System (CDUS). Cumulative 
CDUS data will be submitted quarterly to CTEP by electronic means. Reports are due 
January 31, April 30, July 31, and October 31. 
A conference call, every 2 months, between French and American coordinators will be 
conducted to discuss all adverse events encountered. 
14.1 
Comprehensive Adverse Events and Potential Risks Lists (CAEPRs) for SGN-35 
(Brentuximab Vedotin, NSC 749710) 
The Comprehensive Adverse Events and Potential Risks list (CAEPR) provides a 
single list of reported and/or potential adverse events (AE) associated with an agent 
using a uniform presentation of events by body system. In addition to the 
comprehensive list, a subset, the Specific Protocol Exceptions to Expedited Reporting 
(SPEER), appears in a separate column and is identified with bold and italicized text. 
This subset of AEs (SPEER) is a list of events that are protocol specific exceptions to 
expedited reporting to NCI (except as noted below).  Refer to the 'CTEP, NCI 
Guidelines: Adverse Event Reporting Requirements' 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/aeguidelines
.pdf for further clarification. Frequency is provided based on 798 patients. Below is 
the CAEPR for SGN-35 (brentuximab vedotin).  
NOTE: Report AEs on the SPEER ONLY IF they exceed the grade noted in 
parentheses next to the AE in the SPEER.  If this CAEPR is part of a combination 
protocol using multiple investigational agents and has an AE listed on different 
SPEERs, use the lower of the grades to determine if expedited reporting is 
required. 
 
 


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Version 2.5, February 13, 20191 
 
 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
BLOOD AND LYMPHATIC SYSTEM DISORDERS 
  
 
Anemia 
 
 Anemia (Gr 2) 
 
 
Febrile neutropenia 
  
GASTROINTESTINAL DISORDERS 
  
 
Abdominal pain 
 
  
 
 
 Colitis2 
  
 
Constipation 
 
 Constipation (Gr 2) 
Diarrhea 
 
 
 Diarrhea (Gr 2) 
 
 
 Enterocolitis 
  
 
 
Gastrointestinal hemorrhage3 
  
 
 
Gastrointestinal obstruction4 
  
 
 
Gastrointestinal perforation5 
  
 
 
Gastrointestinal ulcer6 
  
 
 
Ileus 
  
Nausea 
 
 
 Nausea (Gr 2) 
 
 
Pancreatitis 
  
 
Vomiting 
 
 Vomiting (Gr 2) 
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 
  
 
Chills 
 
  
 
Edema limbs 
 
  
Fatigue 
 
 
 Fatigue (Gr 2) 
 
Fever 
 
 Fever (Gr 2) 
 
Pain 
 
  
HEPATOBILIARY DISORDERS 
  
 
Hepatobiliary disorders - Other 
(hepatotoxicity)7 
 
  
IMMUNE SYSTEM DISORDERS 
  
 
 
Anaphylaxis 
  
INFECTIONS AND INFESTATIONS 
  
 
Lung infection 
 
  
  
Upper respiratory infection 
 
 Upper respiratory infection (Gr 2) 
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 
  
 
 
Infusion related reaction 
  
INVESTIGATIONS 
  
 
Alanine aminotransferase 
increased 
 
  
 
Aspartate aminotransferase 
increased 
 
  
Neutrophil count decreased 
 
 
 Neutrophil count decreased (Gr 4) 
 
Platelet count decreased 
 
  
 
Weight loss 
 
  
 
White blood cell decreased 
 
  
METABOLISM AND NUTRITION DISORDERS 
  
 
Anorexia 
 
 Anorexia (Gr 2) 
 
Hyperglycemia 
 
  
 
 
Tumor lysis syndrome 
  
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 
  
 
Arthralgia 
 
 Arthralgia (Gr 2) 
 
Back pain 
 
  
 
Muscle cramp 
 
  
 
Myalgia 
 
 Myalgia (Gr 2) 


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 Adverse Events with Possible  
 Relationship to SGN-35 (brentuximab vedotin) 
 (CTCAE 5.0 Term) 
[n= 798] 
 
 
 Specific Protocol Exceptions to 
Expedited Reporting (SPEER)  
Likely (>20%) 
Less Likely (<=20%) 
Rare but Serious (<3%) 
 
 
 
Pain in extremity 
 
  
NERVOUS SYSTEM DISORDERS 
  
 
Dizziness 
 
  
 
Headache 
 
 Headache (Gr 2) 
 
 
Nervous system disorders - Other 
(progressive multifocal 
leukoencephalopathy) 
  
 
Paresthesia 
 
  
 
Peripheral motor neuropathy 
 
 Peripheral motor neuropathy (Gr 2) 
Peripheral sensory 
neuropathy 
 
 
 Peripheral sensory neuropathy (Gr 2) 
PSYCHIATRIC DISORDERS 
  
 
Anxiety 
 
  
 
Insomnia 
 
  
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 
  
 
Cough 
 
 Cough (Gr 2) 
 
Dyspnea 
 
  
 
Oropharyngeal pain 
 
  
 
 
Respiratory, thoracic and 
mediastinal disorders - Other 
(pulmonary toxicity)8 
  
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
  
 
Alopecia 
 
 Alopecia (Gr 2) 
 
Hyperhidrosis 
 
  
 
Pruritus 
 
 Pruritus (Gr 2) 
 
Rash maculo-papular 
 
 Rash maculo-papular (Gr 2) 
 
 
Stevens-Johnson syndrome 
  
 
 
Toxic epidermal necrolysis 
  
 
1This table will be updated as the toxicity profile of the agent is revised.  Updates will be distributed to 
all Principal Investigators at the time of revision.  The current version can be obtained by contacting 
PIO@CTEP.NCI.NIH.GOV.  Your name, the name of the investigator, the protocol and the agent 
should be included in the e-mail. 
2Colitis may also include the term neutropenic colitis. 
3Fatal and/or serious gastrointestinal hemorrhages have been observed in SGN-35 (brentuximab 
vedotin) treated patients. Gastrointestinal hemorrhage includes Anal hemorrhage, Cecal hemorrhage, 
Colonic hemorrhage, Duodenal hemorrhage, Esophageal hemorrhage, Esophageal varices 
hemorrhage, Gastric hemorrhage, Hemorrhoidal hemorrhage, Ileal hemorrhage, Intra-abdominal 
hemorrhage, Jejunal hemorrhage, Lower gastrointestinal hemorrhage, Oral hemorrhage, Pancreatic 
hemorrhage, Rectal hemorrhage, Retroperitoneal hemorrhage, and Upper gastrointestinal 
hemorrhage under the GASTROINTESTINAL DISORDERS SOC. 
4Fatal and/or serious gastrointestinal obstructions have been observed in SGN-35 (brentuximab 
vedotin) treated patients. Gastrointestinal obstruction includes Colonic obstruction, Duodenal 
obstruction, Esophageal obstruction, Ileal obstruction, Jejunal obstruction, Obstruction gastric, Rectal 
obstruction, Small intestinal obstruction, and other sites under the GASTROINTESTINAL 
DISORDERS SOC. 
5Fatal and/or serious gastrointestinal perforations have been observed in SGN-35 (brentuximab 
vedotin) treated patients.  Gastrointestinal perforation includes Colonic perforation, Duodenal 
perforation, Esophageal perforation, Gastric perforation, Ileal perforation, Jejunal perforation, Rectal 
perforation, and Small intestinal perforation under the GASTROINTESTINAL DISORDERS SOC.  
Lymphoma with preexisting GI involvement may increase the risk of perforation. 
6Fatal and/or serious gastrointestinal ulcers have been observed in SGN-35 (brentuximab vedotin) 
treated patients.  Gastrointestinal ulcer includes Anal ulcer, Colonic ulcer, Duodenal ulcer, 


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Esophageal ulcer, Gastric ulcer, Ileal ulcer, Jejunal ulcer, Rectal ulcer, and Small intestine ulcer under 
the GASTROINTESTINAL DISORDERS SOC. 
7Hepatotoxicity may manifest as increased ALT/AST, bilirubin, alkaline phosphatase, and/or GGT. 
8Pulmonary toxicity, which may manifest as pneumonitis, interstitial lung disease, or adult respiratory 
distress syndrome (ARDS), has been observed in patients treated in brentuximab vedotin 
monotherapy trials as well as in combination with bleomycin. 
 
 


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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. 
 
14.1.1 Special Precautions/Safety Issues 
Infusion-Related Reactions 
Some patients experienced an infusion-related reaction during or soon after 
SGN-35 treatment. Symptoms of infusion-related reactions included chills, 
nausea, cough, itching, and shortness of breath. Two patients experienced a 
serious allergic reaction (wheezing/difficulty breathing, hives, itching, 
swelling) that required immediate medical attention and treatment 
discontinuation. 
Peripheral Neuropathy 
Some patients who received SGN-35 developed peripheral neuropathy. 
Symptoms reported by these patients included burning sensation, pain, 
weakness, numbness and tingling of hands and/or feet, and severe abnormal 
nerve function that caused difficulty walking. 
Neutropenia 
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SGN-35. This  could result in  an increased risk of infection. 
Infection Risk 
SGN-35 may cause patients to be less resistant to infections, including severe 
infections. 
Other Important Side Effects 
The following important or potentially life-threatening side effects have been 
reported infrequently in patients treated with SGN-35: 
• 
Serious allergic reaction (wheezing/difficulty breathing, hives, itching, 
swelling) during or soon after SGN- 35 treatment, which requires immediate 
medical attention and treatment discontinuation 
• 
Severe leukopenia, fever, and possible infection that resulted in death 
• 
Stevens-Johnson syndrome (unexplained widespread skin pain, blisters on 
skin and mucous membranes, hives, tongue swelling, a red or purple skin 
rash that spreads, or unexplained shedding of skin) 
• 
Tumor lysis syndrome (TLS) is a potentially life-threatening complication. 
TLS usually occurs within a few days of the start of cancer treatment and 
may result in metabolic complications. Potential complications may include 
nausea, vomiting, edema (swelling), shortness of breath, heart rhythm 
disturbances, and acute renal failure. 
• 
Progressive Multifocal Leukoencephalopathy (PML) is a rare, serious brain 
infection caused by a certain virus. People with a weakened immune system 
can experience PML. PML can result in death or severe disability. Care 
providers should be mindful of confusion or problems thinking, loss of 
balance or problems walking, difficulty speaking, decreased strength or 
weakness on one side of your body, blurred vision or loss of vision. 
Pregnancy and Breastfeeding 
Brentuximab vedotin is pregnancy category D; therefore patients should not 
receive SGN-35 if they are pregnant because of the risk to the fetus. SGN-35 
affects the testes in animals; therefore, men should not get their partner pregnant 
while being treated with SGN-35. 
• Female study volunteers of reproductive potential (defined as girls who have 
reached menarche and pre- menopausal women who have not had a 
sterilization procedure such hysterectomy, bilateral oophorectomy or 
salpingectomy) must have a negative serum or urine pregnancy test 
performed within 48 hours before initiating the protocol-specified 
medication(s). Women are considered menopausal if they have not had a 
menses for at least 12 months and have a FSH of greater than 40 IU/L or, if 
FSH testing is not available, they have had amenorrhea for 24 consecutive 
months. 
• All study volunteers, male and female, must agree not to participate in a 
conception process (e.g., active attempt to become pregnant or to impregnate, 
sperm donation, or in vitro fertilization) 
• If participating in sexual activity that could lead to pregnancy, all study 
volunteers must agree to use two reliable methods of contraception 
simultaneously while receiving protocol-specified medication(s) and for 6 
months after stopping the medication(s). 
• If the female volunteer is not of reproductive potential (defined above) or the 


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man has documented azoospermia, contraception is not required. 
Patients who could become pregnant or who have partners who could become 
pregnant must use birth control during the study and for 6 months after stopping 
treatment. If a patient or a patient’s partner becomes pregnant while taking part 
in this study or within 30 days after stopping treatment, the patient should 
inform the study doctor right away. Seattle Genetics will follow the pregnancy 
to term. In addition, the resultant progeny will be followed for potential side 
effects for some period of time after birth. 
It is not known whether SGN-35 or its breakdown products end up in breast 
milk. If it does end up in breast milk, it could cause harm to a nursing baby. 
Therefore, breast feeding is prohibited while on study drug and for 6 months 
after the last dose of study drug. 
Possible Risks in Combination with Other Therapies 
Concomitant use of SGN-35 and bleomycin is contraindicated due to pulmonary 
toxicity. In a clinical trial that studied SGN-35 with bleomycin as part of a 
combination regimen (ABVD), the rate of noninfectious pulmonary toxicity 
was higher than the historical incidence reported with ABVD. Monotherapy 
with SGN-35 has not been associated with a clinically meaningful risk of 
pulmonary toxicity. 
An ongoing phase 1 study is investigating the combination of SGN-35 with 
ABVD or AVD as front-line therapy for HL. Noninfectious pulmonary toxicity 
was observed in some patients treated with SGN-35 in combination with 
ABVD. The incidence of pulmonary toxicity in the ABVD + SGN-35 arm of 
the trial was approximately 40% (10 of 25 patients), compared to an incidence 
of 10% to 25% most commonly reported in the literature with bleomycin-based 
regimens 79-81. Patients presented with cough and dyspnea. Interstitial infiltration 
and/or inflammation were observed on X-ray and computed tomography of the 
chest. Five patients had a maximum severity ≥ Grade 3 (3 with Grade 3 and 2 
with Grade 4). Most patients responded favorably to corticosteroid therapy. 
14.2 
Classification of AEs by Severity and Relationship to Study Drug Administration 
14.2.1 Adverse Event 
Any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom or disease temporally associated with the use of a medical 
treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite). 
14.2.2 Life-threatening Adverse Event 
Any AE that places the subject or subject, in view of the Investigator, at 
immediate risk of death from the reaction. 
14.2.3 Serious Adverse Event (SAE) 
Any AE occurring at any dose that results in any of the following outcomes: 
Death, a life-threatening AE, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/ incapacity, or a 
congenital anomaly/birth defect. Medical and scientific judgment should be 
exercised in deciding whether expedited reporting is appropriate in other 


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situations, such as important medical events that may not be immediately life- 
threatening or result in death or hospitalization but may jeopardize the patient 
or may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also usually be considered serious. 
14.2.4 Hospitalization 
Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or 
unexpected, and attribution. For example, do not report an admission for 
pharmacokinetic sampling, but do report an admission for a myocardial 
infarction. 
14.2.5 Toxicity 
Toxicity is a term NOT clearly defined by regulatory organizations. Toxicity 
has been described as an AE that has an attribution of possibly, probably or 
definitely related to investigational treatment. To minimize confusion the NCI 
would recommend that the term toxicity NOT be utilized for AE reporting 
purposes. The CTCAE continues to use the term ‘toxicity’ because of 
familiarity. 
14.2.6 Unexpected Adverse Event 
Any AE that is not listed in available sources including the package insert, the 
Investigator’s Brochure, or the protocol. 
14.2.7 CTEP Adverse Event Reporting System (CTEP-AERS) 
An electronic system for expedited submission of AE reports. 
14.2.8 Attribution 
The determination of whether an AE is related to a medical treatment or 
procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent. 
Probable – The AE is likely related to the investigational agent.  
Possible – The AE may be related to the investigational agent.  
Unlikely – The AE is doubtfully related to the investigational agent.  
Unrelated   – The AE is clearly NOT related to the investigational agent. 
14.3 
Expedited Adverse Event Reporting 
14.3.1 Expedited AE reporting 
Expedited AE reporting for this study must use CTEP-AERS (CTEP Adverse 
Event 
Reporting 
System) 
accessed 
via 
the 
CTEP 
home 
page 
(http://ctep.cancer.gov). The reporting procedures to be followed are presented 
in the “CTEP, NCI Guidelines: Adverse Event Reporting Requirements” which 
can be downloaded from the CTEP home page (http://ctep.cancer.gov). These 
requirements are briefly outlined in the table below (Section 13.3). 
A 24-hour notification is to be made to CTEP by telephone at 301-897-7497 
only when Internet connectivity is disrupted. Once Internet connectivity is 
restored, a 24-hour notification phoned in must be entered electronically into 


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CTEP-AERS by the original submitter at the site. 
14.3.2 CTEP-AERS 
CTEP-AERS is programmed for automatic electronic distribution of reports to 
the following individuals: Protocol Chair, Principal Investigator at the local 
AMC treating institution and AMC Operations and Data Management Center. 
CTEP-AERS provides a copy feature for other e-mail recipients. 
14.3.3 Phase 1 and Early Phase 2 Studies: 
Expedited Reporting Requirements for Adverse Events that Occur on Studies 
under an IND/IDE within 30 Days of the Last Administration of the 
Investigational Agent/Intervention1, 2 
Note: A death on study requires both routine and expedited reporting 
regardless of causality, unless as noted below. Attribution to treatment or 
other cause must be provided. 
Death due to progressive disease should be reported as Grade 5 “Neoplasms 
benign, malignant and unspecified (incl cysts and polyps) - Other (Progressive 
Disease)” under the system organ class (SOC) of the same name. Evidence that 
the death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with 
a disease process) should be submitted. 
FDA REPORTING REQUIREMENTS FOR SERIOUS ADVERSE EVENTS (21 CFR Part 312) 
NOTE: Investigators MUST immediately report to the 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 and Grade 2 
Timeframes 
Grade 3-5 Timeframes 
Resulting in Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 Calendar Days 
Not resulting in Hospitalization ≥ 24 hrs 
Not required 


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NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the Specific 
Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR. 
Expedited AE reporting timelines are defined as: 
• “24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours of learning 
of the AE, followed by a complete expedited report within 5 calendar days of the initial 24-hour report. 
• “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: 
• All Grade 3, 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 1 and grade 2 AEs resulting in hospitalization or prolongation of hospitalization 
2 For studies using PET or SPECT IND agents, the AE reporting period is limited to 10 radioactive half-lives, 
rounded UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above applies 
after this reporting period. 
 
• 
Expedited AE reporting timelines defined: 
o “24 hours; 5 calendar days” – The investigator must initially report the 
AE via CTEP-AERS within 24 hours of learning of the event followed 
by a complete CTEP-AERS report within 5 calendar days of the initial 
24-hour report. 
o “10 calendar days” - A complete CTEP-AERS report on the AE must be 
submitted within 10 calendar days of the investigator learning of the 
event. 
• 
Any medical event equivalent to CTCAE grade 3, 4, or 5 that precipitates 
hospitalization (or prolongation of existing hospitalization) must be reported 
regardless of attribution and designation as expected or unexpected with the 
exception of any events identified as protocol-specific expedited adverse 
event reporting exclusions. 
• 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS if 
the event occurs following treatment with an agent under a CTEP IND. 
• 
Use the NCI protocol number and the nine-digit AMC subject ID assigned 
during trial registration on all reports. 
14.3.4 Clinical Laboratory Results 
Clinical laboratory results that are outside of the institution’s reference ranges 
must be reported as adverse events if they are deemed clinically significant by 
the investigator(s). 
• 
A clinical laboratory abnormality should be deemed clinically significant if 
any one of the following conditions is met: 
• 
The laboratory abnormality is not otherwise proved false by a repeat 
confirmation test. 
• 
The abnormality suggests a disease and/or organ toxicity that is new or has 
worsened from baseline. 
• 
The abnormality is of a degree that requires additional active management, 
e.g., change of dose, discontinuation of the drug(s), close observation, more 


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frequent follow-up assessments, or further diagnostic investigation. 
• 
In this protocol the following clinical laboratory abnormalities are expected 
and will not be considered AEs: 
o HIV viral load  
o T Cell subsets  
o LDH 
14.4 
Routine Adverse Event Reporting 
All AEs that require expedited reporting via CTEP-AERS must also be reported in 
routine study data submissions (Adverse Event Form CRF). Routine reporting of all 
AEs attributed to therapy (possible, probable or definitely), regardless of grade, should 
be reported on the Adverse Event Form CRF. Similarly, if patients require radiotherapy, 
post-treatment AEs related to radiation therapy do not require routine reporting. All 
Grade 5 events, regardless of attribution to therapy, must be reported in the Adverse 
Event and Death Forms in AdvantageEDCSM. 
14.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy 
(e.g., treatment with investigational agent/intervention, radiation or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
Acute myeloid leukemia (AML)/Myelodysplastic syndrome (MDS) events must be 
reported via CTEP-AERS (in addition to your routine AE reporting mechanisms). In 
CTCAE v4.0, the event(s) may be reported as either: 1) Leukemia secondary to 
oncology chemotherapy, 2) MDS, or 3) Treatment-related secondary malignancy. 
Whenever possible, the CTEP-AERS report should include the following: tumor 
pathology; history of prior tumors; prior treatment/current treatment including duration; 
any associated risk factors or evidence regarding how long the tumor may have been 
present; when and how the tumor was detected; molecular characterization or 
cytogenetics of the original tumor (if available) and of any new tumor; and tumor 
treatment and outcome, if available. These events should be reported for the duration 
of the study treatment and during the protocol-specified follow-up period. 


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15.0 
EFFICACY AND SAFETY MEASUREMENTS 
15.1 
Efficacy Measurements 
All subjects will be evaluated for clinical response by physical examination prior to 
receiving treatment on each cycle. The exam should occur within 3 days prior to the 
start of each cycle, but may occur on Day 1 of cycle. 
All subjects will be evaluated for clinical response by imaging studies after by FDG-
PET/CT at the completion of cycle 2 and at the completion of therapy (See Section 
10.6.1). 
15.2 
Response Assessment 
Response is currently assessed on the basis of clinical, radiologic, and pathologic (i.e., 
bone marrow) criteria. 
15.2.1 Definition of Response 
The response definitions used for this study are the 2007 Cheson criteria. A 
major distinction in the 2007 criteria is that PET/Gallium studies are used to 
facilitate the distinction between persistent tumor and scar/fibrosis. 
15.2.2 Complete Response (CR) 
1. Complete disappearance of all detectable clinical evidence of disease and 
disease-related symptoms if present before therapy. 
2a. Typically FDG-avid lymphoma: In patients with no pretreatment PET scan 
or when the PET scan was positive before therapy, a post-treatment 
residual mass of any size is permitted as long as it is PET negative. 
2b. Variably FDG-avid lymphomas/FDG avidity unknown: In patients without 
a pretreatment PET scan, or if a pretreatment PET scan was negative, all 
lymph nodes and nodal masses must have regressed on CT to normal size 
(1.5 cm in their greatest transverse diameter for nodes > 1.5 cm before 
therapy). Previously involved nodes that were 1.1 to 1.5 cm in their long 
axis and more than 1.0 cm in their short axis before treatment must have 
decreased to 1.0 cm in their short axis after treatment. 
3. The spleen and/or liver, if considered enlarged before therapy on the basis 
of a physical examination or CT scan, should not be palpable on physical 
examination and should be considered normal size by imaging studies, and 
nodules related to lymphoma should disappear. However, determination of 
splenic involvement is not always reliable because a spleen considered 
normal in size may still contain lymphoma, whereas an enlarged spleen 
may reflect variations in anatomy, blood volume, the use of hematopoietic 
growth factors, or causes other than lymphoma. 
4. If the bone marrow was involved by lymphoma before treatment, the 
infiltrate must have cleared on repeat bone marrow biopsy. The biopsy 
sample on which this determination is made must be adequate (with a goal 
of >20 mm unilateral core). If the sample is indeterminate by morphology, 
it should be negative by immunohistochemistry. 
15.2.3 Partial Response (PR) requires all of the following: 
1. At least a 50% decrease in sum of the product of the diameters (SPD) of 
up to six of the largest dominant nodes or nodal masses. These nodes or 
masses should be selected according to all of the following: they should be 
clearly measurable in at least two perpendicular dimensions; if possible 
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mediastinal and retroperitoneal areas of disease whenever these sites are 
involved. 
2. No increase should be observed in the size of other nodes, liver, or spleen. 
3. Splenic and hepatic nodules must regress by 50% in their SPD or, for 
single nodules, in the greatest transverse diameter. 
4. With the exception of splenic and hepatic nodules, involvement of other 
organs is usually assessable and no measurable disease should be present. 
5. Patients who achieve a CR by the above criteria, but who have persistent 
morphologic bone marrow involvement will be considered partial 
responders. When the bone marrow was involved before therapy and a 
clinical CR was achieved, but with no bone marrow assessment after 
treatment, patients should be considered partial responders. 
6. No new sites of disease should be observed. 
7. Typically FDG-avid lymphoma: for a patient with no pretreatment PET 
scan or if the PET scan was positive before therapy, the post-treatment 
PET should be positive in at least one previously involved site. 
8. Variably FDG-avid lymphomas/FDG-avidity unknown: if a pretreatment 
PET scan was negative, CT criteria should be used. 
15.2.4 Stable Disease (SD) is defined as the following: 
1. A patient is considered to have SD when he or she fails to attain the 
criteria needed for a CR or PR, but does not fulfill those for progressive 
disease (see Relapsed Disease [after CR]/Progressive Disease [after PR, 
SD]) below. 
2. Typically FGD-avid lymphomas: the PET should be positive at prior sites 
of disease with no new areas of involvement on the post- treatment CT or 
PET. 
3. Variably FDG-avid lymphomas/FDG-avidity unknown: if the pretreatment 
PET was negative, there must be no change in the size of the previous 
lesions on the post-treatment CT scan. 
15.2.5 Relapsed Disease (after CR)/Progressive Disease (after PR, SD): 
1. Lymph nodes should be considered abnormal if the long axis is more than 
1.5 cm regardless of the short axis. If a lymph node has a long axis of 1.1 
to 1.5 cm, it should only be considered abnormal if its short axis is more 
than 1.0. Lymph nodes 1.0 x 1.0 cm will not be considered as abnormal for 
relapse or progressive disease. 
2. Appearance of any new lesion more than 1.5 cm in any axis during or at 
the end of therapy, even if other lesions are decreasing in size. Increased 
FDG uptake in a previously unaffected site should only be considered 
relapsed or progressive disease after confirmation with other modalities.  
In patients with no prior history of pulmonary lymphoma, new lung 
nodules identified by CT are mostly benign. Thus, a therapeutic decision 
should not be made solely on the basis of the PET without histologic 
confirmation. 
3. At least a 50% increase from nadir in the SPD of any previously involved 
nodes, or in a single involved node, or the size of other lesions (e.g., 
splenic or hepatic nodules). To be considered progressive disease, a lymph 
node with a diameter of the short axis of less than 1.0 cm must increase by 
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least a 50% increase in the long est. diameter of any single previously 
identified node more than 1 cm in its short axis. Lesions should be PET 
positive if observed in a typical FDG-avid lymphoma or the lesion was 
PET positive before therapy unless the lesion is too small to be detected 
with current PET systems (< 1.5 cm in its long axis by CT). 
15.2.6 Recurrent Disease 
Recurrent Disease is defined as the appearance of tumor following 
documentation of a complete remission. 
15.2.7. Time to Response 
Time to Response is defined as time from the first dose of chemotherapy until 
documentation of first response. 
15.2.8. Time to Progression 
Time to Progression is defined as time from initiation of chemotherapy to 
documentation of first progression. 
15.2.9 Response Duration 
Response Duration is defined as the time from first documentation of response 
to documentation of first progression. 
15.3 
Safety Measures 
All AE will be monitored by ongoing review of reported adverse events by the protocol 
chair and the AMC Operations and Data Management Center, and will be discussed 
during the monthly investigators’ Lymphoma Working Group conference calls (see 
Section 12.4 for rules for early study termination). 


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16.0 
STATISTICAL CONSIDERATIONS 
Statistical analysis will be performed by AMC Statistical Center on pooled data 
obtained by French participants and US participants. 
16.1  Study Design/Endpoints 
This multicenter, Phase II open label study will determine the safety and tolerability of 
patients with stage III/IV HIV- associated Hodgkin Lymphoma and evaluate the 
treatment effect of AVD in addition to brentuximab vedotin (SGN- 35). The primary 
objective of the Phase II portion of the  study  is  to  establish an estimate of the  two-
year progression-free survival for patients using brentuximab vedotin plus AVD 
regimen with HIV-associated advanced stage Hodgkin lymphoma. 
The primary endpoint will estimate the two-year progression-free survival for AVD-
brentuximab vedotin which will be done using a one sample nonparametric survival 
analysis. 
Secondary objectives include: 
1. To evaluate toxicity of AVD and brentuximab vedotin with HAART. 
2. To estimate the partial response (PR) rate, complete response (CR) rate, overall 
survival (OS), event free survival at 2 and 5 years. 
3. To evaluate effect of AVD and brentuximab vedotin on CD4 and CD8 counts 
after cycle 1, 4, at the end of therapy, and every 3 months after treatment 
completion for one year. 
4. To investigate the prognostic value of FDG-PET/CT scans at baseline, after cycle 
2, and at treatment completion, with respect to 2 year progression free survival. 
5. To evaluate HAART status at baseline and to correlate this with tumor response to 
therapy and OS and PFS. 
6. To characterize the histologic subtypes in HIV-HL in the highly active 
antiretroviral therapy (HAART) era. 
7. To assess the neurotoxicity of HAART in combination with AVD and 
brentuximab vedotin. 
8. To evaluate effect of AVD and brentuximab vedotin on viral load after cycles 1, 4, 
at completion of therapy, and every 3 months after treatment completion for one 
year. 
9. To perform pharmacokinetic and immunogenicity studies to determine drug levels 
during therapy (not applicable for French participants). 
10. To perform miRNA profile analysis on the HIV-HL tumor specimens and to 
correlate miRNA expression with OS, PFS, tumor response to therapy, histologic 
subtype of HIV-HL, and HIV disease characteristics not applicable for French 
participants). 
11. To perform tissue microarray analysis on HIV-HL tumor specimens and to 
correlate the markers studied with OS, PFS, and tumor response to therapy (not 
applicable for French participants). 
12. To identify EBV associated tumor derived DNA in the plasma of study patients, 
and to correlate these levels during therapy with disease response and OS (not 
applicable for French participants). 
13. To identify cytokines in the plasma of patients during therapy, that can be used as 
tumor and prognostic markers. (Not applicable for French participants). 
14. To assess latent and expressed HIV reservoirs before, during, and post 
chemotherapy. To understand how cytotoxic chemotherapeutic agents effect HIV 
expression (not applicable for French participants). 


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16.2 
Sample Size/Accrual Rate 
In the Phase II portion of the study, 51 patients will be enrolled worldwide to estimate 
the 2-year progression free survival. Sample size calculation is based on providing an 
estimate of the PFS with a 95% confidence interval ±10% under the hypothesis that 2-
year PFS is 85%. 
The primary endpoint of the phase II portion will be to estimate the two-year 
progression-free survival for AVD- brentuximab vedotin which will be done using 
Kaplan-Meier estimates and corresponding 95% confidence intervals based on standard 
errors using Greenwood’s formula. 
16.3 
Stratification Factors 
No stratification is planned for this study. 
16.4 
Analysis of Secondary Endpoints 
Descriptive summaries and exploratory analyses for secondary objectives will be 
conducted. Significance for comparisons will be at the p<0.05 level. 
Secondary objectives include: 
1. To evaluate toxicity of AVD and brentuximab vedotin with HAART. 
2. To estimate the partial response rate, complete response rate, overall survival 
(OS), event free survival at 2 and 5 years. 
3. To evaluate effect of AVD and brentuximab vedotin on CD4 and CD8 counts 
after 2 cycles, 6 cycles, and every 3 months after treatment completion for one 
year. 
4. To evaluate effect of AVD and brentuximab vedotin on viral load after 2 cycles, 6 
cycles, and every 3 months after treatment completion for one year. 
5. To investigate the prognostic value of FDG-PET scans at baseline and after 2 
cycles in patient with HIV and HL with respect to 2 year progression free 
survival. 
6. To evaluate HAART status at baseline for difference in outcome. 
7. The characterization of histologic subtypes in HIV-HL in the HAART era. 
8. To assess additional neurotoxicity in combination with HAART and AVD and 
brentuximab vedotin. 
The frequency of AEs and their severity will be tabulated to evaluate tolerance of AVD 
and brentuximab vedotin with HAART. Further, binomial probabilities and their 95% 
confidence intervals will be used to estimate the response rates (i.e., partial response 
rate, complete response rate, overall response rate) and event free survival at 2 and 5 
years of AVD and brentuximab vedotin for a treatment of patients with stage III/IV 
HIV-associated Hodgkin Lymphoma. 
Repeated measures analysis of variance (ANOVA) models will be used to  evaluate the 
effect of  AVD and brentuximab vedotin on CD4 counts, CD8 counts and viral load 
after 1, 4, and 6 cycles, and every 3 months after treatment completion for one year. 
Log-rank analysis will be used to investigate the prognostic value of FDG-PET scans 
at baseline, after 2 cycles and post-therapy in patients with HIV and HL with respect to 
progression free survival. 
After cycle 2 and post-therapy, progression-free survival will be estimated for patients 
whose FDG-PET findings were negative and those whose findings were positive using 
Kaplan-Meier estimates and corresponding 95% confidence intervals based on standard 
errors using Greenwood’s formula. Positive predictive value after 2 cycles and post-
therapy will be estimated as the proportion of PET-positive patients who progress or 


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die before two years; negative predictive value after 2 cycles and post-therapy will be 
estimated as the proportion of PET-negative patients who are progression-free and alive 
at two years. Sensitivity of FDG-PET at cycle 2 and post-therapy will be estimated as 
the proportion of patients who progressed or died prior to year 2 whose FDG-PET was 
positive. Specificity of FDG-PET at cycle 2 and post-therapy will be estimated as the 
proportion of patients who are alive and progress-free at 2 years whose FDG-PET was 
positive. Exact two-sided 95% confidence intervals will be used for all estimates. 
Log-rank analysis will be used to evaluate HAART status at baseline for difference in 
outcome in terms of overall survival and progression free survival. The frequency and 
proportion of different histologic subtypes will be calculated. 
The frequency of neurotoxicity in patients taking AVD and brentuximab vedotin in 
combination with/without HAART will be tabulated. A binomial test of proportions 
will be used to test the difference in additional toxicity between those patients taking 
AVD and brentuximab vedotin on HAART vs. those patients not on HAART. 
 


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17.0 
STUDY MONITORING 
17.1 
Responsibilities of investigators 
The investigator(s) undertake(s) to perform the study in accordance with Good Clinical 
Practice and specifically either European 2001/20/CE and 2005/28/CE directives, ICH E6 or 
US regulations 21 CFR - Part 312 subpart D and guidelines for the monitoring of clinical 
investigations. 
The investigators ensure compliance with respect to the investigational drug schedule, visit 
schedule and procedures required by the study. The investigators agree to provide all 
information requested in the case report form in an accurate and legible manner according to 
instructions provided. 
As may be required by the local legislation, the investigators will check that the patients are 
directly or indirectly affiliated to the national health insurance or coverage system if there is 
any. 
17.2 
Responsibilities of the sponsor 
The sponsor (LYSARC) of this study in France has responsibilities to health authorities to take 
all reasonable steps to ensure the proper conduct of the study as regards ethics, study adherence, 
integrity and validity of the data recorded on the case report forms. Thus, the main duty of the 
sponsor project leader and of the Sponsor clinical research support team (LYSARC) is to help 
the investigator maintaining a high level of ethical, scientific, technical and regulatory quality 
in all aspects of the study. 
At regular intervals during the study, the center will be contacted, through site visits, letters or 
telephone calls, by a representative of the project team (LYSARC) to review study progress, 
investigator and subject adherence to study requirements and any emergent problems. 
During monitoring visits, the following points will be assessed with the investigator or a 
designee for each patient selected and included: subject informed consent signature, patient 
eligibility (inclusion and exclusion criteria), subject recruitment and follow-up, subject 
compliance to the study treatment, study treatment accountability (if applicable), concomitant 
therapy use, evaluations of response, serious/non serious adverse event documentation and 
reporting, and quality of data. Sections of Case Report Forms may be collected/entered (in case 
of e-CRF) on a visit per visit basis. A monitoring plan will be written describing monitoring 
process. 
17.3 
Source document requirements 
According to the guidelines on Good Clinical Practice, the sponsor representative will check 
the case report form entries against the source documents. These personnel, bound by 
professional secrecy, will not disclose any personal identity or personal medical information. 
17.4 
Use and completion of electronic case report form (eCRF) 
An electronic Case Report Form (eCRF) will be completed for each study subject. It is the 
investigator’s responsibility to ensure the accuracy, completeness, legibility and timeliness of 
the data reported in the subject’s eCRF. 
Access to the internet data entry system for this study, AdvantageEDCSM, and instructions for 
recording of study data on CRFs will be provided by the AMC ODMC at 
www.AIDScancer.org. Participating institutions are responsible for submitting data and/or data 
forms via AdvantageEDC in accordance with the AMC Data Entry Guide and specific form 
instructions, within the timelines specified by the AMC’s Standards of Procedure for Site 
Performance Measures. 
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the study and should document the dates and details of study procedures, adverse events and 
subject status. 
The investigator, or designated representative, should complete the eCRF pages as soon  as 
possible  after information is collected, preferably on the same day that a study subject is seen 
for an examination, treatment, or any other study procedure. Any outstanding entries must be 
completed immediately after the final examination. An explanation should be given for all 
missing data. 
All data entry and corrections are recorded in the audit trail (date of data entry/correction, name 
of person, type of action). 


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18.0 
ETHICAL AND REGULATORY STANDARDS 
18.1 
Ethical Principles 
This study is in accordance with the principles laid down by the 18th World Medical Assembly 
(Helsinki, 1964) and subsequent amendments and will be conducted according to ICH/GCP 
guidelines. 
18.2 
Laws and Regulations 
This study is performed also in accordance with applicable laws and regulations of each 
country involved in the trial, as well as any applicable guidelines. 
All data of the patients collected by the sponsor will be anonymized. 
18.3 
Informed Consent 
It is the responsibility of the investigator to obtain informed consent in compliance with 
national requirements from each subject prior to entering the trial or, where relevant, prior to 
evaluating the patient's suitability for the study. 
The informed consent document used by the investigator for obtaining subject's informed 
consent must be reviewed and approved by LYSARC prior to Ethics Review Committee 
submission. 
The investigator must explain to potential patient the aims, methods, reasonable anticipated 
benefits and potential hazards of the trial and any discomfort it may entail. Patients will be 
informed that they are free not to participate in the trial and that they may withdraw consent to 
participate at any time. They will be told which alternative treatments are available if they 
refuse to take part and that such refusal will not prejudice future treatment. 
The consent form will include a statement by which the patients allow the sponsor's duly 
authorized personnel (trial monitoring team) to have direct access to source data which 
supports data on the case report forms (e.g., patient's medical file, appointment books, original 
laboratory records, etc.). 
The patient should receive a signed and dated copy of the informed consent form and patient 
information leaflet. The randomization/inclusion process will be documented in each patient’s 
medical records. 
For biological studies, a specific informed consent form will be signed and dated by patients 
18.4 
Ethics Review Committee and Competent Authorities Submission 
The sponsor must submit this study to country central ethics review committee, and to 
competent authorities and it is required to forward a copy of written approvals/advices signed 
to the investigators. 


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19.0 
ADMINISTRATIVE PROCEDURES 
19.1 
Curriculum Vitae 
An updated copy of the curriculum vitae of each investigator and sub-investigator will be 
provided to LYSARC prior to the beginning of the study. 
19.2 
Registration with CTEP 
The responsible investigator at each participating institution must be registered with CTEP, 
DCTD through an annual submission of FDA form 1572 (Statement of Investigator), 
Curriculum Vitae, Supplemental Investigator Data Form (IDF), 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. 
19.3 
Confidentiality Agreement 
All goods, materials, information (oral or written) and unpublished documentation provided to 
the investigators (or any company acting on their behalf), inclusive of this study, the patient 
case report forms are the exclusive property of LYSARC. 
They may not be given or disclosed by the investigator or by any person within his authority 
either in part or in totality to any unauthorized person without the prior written formal consent 
of LYSARC. 
It is specified that the submission of this study and other necessary documentation to the Ethics 
Review Committee or a like body is expressly permitted, the Ethics Committee members 
having the same obligation of confidentiality. 
The investigator shall consider as confidential and shall take all necessary measures to ensure 
that there is no breach of confidentiality in respect of all information accumulated, acquired or 
deduced in the course of the trial, other than that information to be disclosed by law. 
19.4 
Record Retention in Investigating Center(s) 
The investigator must maintain all study records, patient files and other source data for the 
maximum period of time permitted by the hospital, institution or private practice. 
However national regulations should be taken into account, the longest time having to be 
considered. 
For trials performed in the European Community, the investigator is required to arrange for the 
retention of the patient identification codes for at least 15 years after the completion or 
discontinuation of the trial. 
Any center will notify the sponsor before destroying any data or records. 
19.5 
Ownership of Data and Use of the Study Results 
The sponsor has the ownership of all data and results collected during this study. In 
consequence the sponsor or any third Party either appointed by the Sponsor or having 
concluded a specific agreement with the Sponsor, reserves the right to use the data of the 
present study, either in the form of case report forms (or copies of these), or in the form of a 
report, with or without comments and with or without analysis, in order to submit them to the 
health authorities of any country. 
The Investigator is committed to give his support to any requests for a patent or any property 
title based on, or illustrated with the results of the present Study for any country. 
19.6 
Publication 
The results of the trial will be published after complete data collection and evaluation. Partial 
or preliminary results can be published beforehand. Publication is to be initiated by the two 


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coordinating investigators in charge of the study with approval of partner if applicable. 
Any publication in the form of a lecture, poster or article must be basically approved by the 
Scientific Committee of LYSA. 
The authors will be proposed (according to the updated LYSA publication rules) by the 
coordinating investigators in charge of the study, and finally decided by the Steering 
Committee of LYSA. 
All study data and publications are the property of LYSA/LYSARC. 
19.7 
Insurance Compensation 
The sponsor certifies having taken out appropriate liability insurance policy which covers the 
Sponsor, the investigator and his co-workers and which is in accordance with the local laws 
and requirements. Specific statements will be contained in appendix where needed. 
A certificate of insurance will be provided to the investigator in countries in which this 
document is required. 
The Investigator(s) will remain responsible towards the Sponsor of any fault or misconduct 
regarding the performance of the Study. 
19.8 
Company Audits and Inspections by Regulatory Agencies 
For the purpose of ensuring compliance with good clinical practice and regulatory agency 
guidelines it may be necessary to conduct a site audit or an inspection. 
By signing this study, the investigator agrees to allow LYSARC and its representative, drug 
regulatory agencies (ANSM) and auditor(s) from Seattle Genetics, AMC or the NCI and 
regulatory authorities (FDA) to have direct access to his study records for review. These 
personnel, bound by professional secrecy, will not disclose any personal identity or personal 
medical information. 
These audits involve review of source documents supporting the adequacy and accuracy of 
data gathered in CRF, review of documentation required to be maintained, and checks on drug 
accountability. 
LYSARC will in all cases help the investigator prepare for an inspection by any regulatory 
agency. 
19.9 
Clinical study Report 
The sponsor will inform of the end of the trial the Competent Authorities and Ethics 
Committees during the 3 months following the end of the study. A publication, as a study report 
will be prepared under the responsibility of the sponsor, less than one year after the end of the 
study and forwarded to the Competent Authorities and Ethics Committees. 
19.10 Protocol Amendments 
It is specified that the appendices attached to this study and referred to in the main text of this 
study, form an integral part of the study. 
No changes or amendments to this study may be made by the investigator or by the sponsor 
after the study has been agreed to and signed by both parties unless such change(s) or 
amendment(s) have been fully discussed and agreed upon by the investigator and the 
LYSARC. 
Any change agreed upon will be recorded in writing, the written amendment will be signed by 
the investigator and by the sponsor and the signed amendment will be appended to this study. 
Approval/advice of amendments by Ethics Review Committee and Competent Authorities are 
required prior to their implementation, unless there are overriding safety reasons. 


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If the change or deviation increases risk to the study population, or adversely affects the 
validity of the clinical investigation or the subject's rights, full approval / advice must be 
obtained prior to implementation. For changes that do not involve increased risk or affect the 
validity of the investigation or the subject's rights, approval / advice may be obtained by 
expedited review, where applicable. 
In some instances, an amendment may require a change to a consent form. The investigator 
must receive approval/ advice of the revised consent form prior to implementation of the 
change. In addition, changes to the case report forms, if required, will be incorporated in the 
amendment. 
Prior to initiating the changes, study amendment must be submitted to regulatory agencies, 
where applicable, except under emergency conditions. 


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20.0 
REFERENCES 
1. Swerdlow SH, Campo E, Harris NL, et al. WHO Classification of Tumours of Haematopoietic 
and Lymphoid Tissues (ed. 4th). Lyon, France: IARC Press; 2008. 
2. Hodgkin T (1832). "On some morbid experiences of the absorbent glands and spleen". Med Chir 
Trans 17: 69–97. 
3. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin 2008: 57;43-66. 
4. Kuppers R, Rajewsky K, Zhao M et al. Hodgkin disease: Hodgkin and Reed-Sternberg cells 
picked from histological sections show clonal immunoglobulin gene rearrangements and 
appear to be derived from B cells at various stages of development. Proc Natl Acad Sci 
USA 1994; 91:10962. 
5. Hummel M, Ziemann K, Lammert H et al. Hodgkin’s disease with monoclonal and polyclonal 
populations of Reed-Sternberg cells. N Engl J Med 1995; 333:901. 
6. Kanzler H, Küppers R, Hansmann M-L et al. Hodgkin and Reed-Sternberg cells in Hodgkin’s 
disease represent the outgrowth of a dominant tumor clone derived from (crippled) 
germinal center B cells. J Exp Med 1996; 184:1495 
7. Marafioti T, Hummel M, Anagnostopoulos I et al. Origen of nodular lymphocyte-predominant 
Hodgkin’s disease from a clonal expansion of highly mutated germinal- center B cells. N 
Engl J Med 1997; 337:459. 
8. Carbone A, Gloghini A, Gaidano G et al. Expression status of BCL-6 and syndecan-1 
identifies distinct histogenetic subtypes of Hodgkin’s disease. Blood 1998; 92:2220. 
9. Shiels MS, Pfeiffer RM, Gail MH et al. Cancer burden in the HIV-infected population in the 
United States. J Natl Cancer Inst. 2011;103(9):753-62. 
10. Patel, P., D. L. Hanson, et al. Incidence of types of cancer among HIV-infected persons 
compared with the general population in the United States, 1992-2003. Ann Intern Med 
2008;148: 728-36. 
11. Levine A. HIV-associated Hodgkin’s disease. Hematol Oncol Clin North Am 1996; 10; 1135-48. 
12. Skinnider BF, Mak TW. The role of cytokines in classical Hodgkin lymphoma. Blood. 
2002;99:4283-4297. 
13. Levine AM. Hodgkin lymphoma: to the HAART of the matter. Blood 2006; 108; 3630. 
14. Biggar RJ, Jaffe ES, Goedert JJ et al. Hodgkin lymphoma and immunodeficiency in 
persons with HIV/AIDS. Blood 2006;108: 3786-91. 
15. Spina M, Carbone A, Gloghini A, Serraino D, Berretta M, Tirelli U. Hodgkin's Disease in 
Patients with HIV Infection. Adv Hematol. 2011;!doi:10.1155/2011/402682. 
16. 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 1998;19:1506-
14. 
17. Ambinder RF. Epstein-Barr virus and Hodgkin lymphoma. Hematology Am Soc Hematol 
Educ Program. 2007:204-9. 
18. Keegan TH, Glaser SL, and Clarke CA et al. Epstein-Barr virus as a marker of survival after 
Hodgkin's lymphoma: a population-based study. J Clin Oncol. 2005; 23: 7604-1. 
19. Carbone A, Gloghini A, Larocca LM et al. Human immunodeficiency virus-associated 
Hodgkin's disease derives from post-germinal center B cells. Blood. 1999; 93: 2319-26. 
20. Powles T and Bower M. HIV-associated Hodgkin’s Disease. Int J STD AIDS 2000; 11, 492-4. 
21. Gerard L, Galicier L, Boulanger E, et.al Improved survival in HIV-related Hodgkin's lymphoma 
since the introduction of highly active antiretroviral therapy. AIDS. 2003 Jan 3;17(1):81-7. 
22. Hentrich M, Maretta L, Chow KU et al. Highly active antiretroviral therapy (HAART) improves 


LYSARC 
 
AMC-085 
 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
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survival in HIV-associated Hodgkin's disease: results of a multicenter study. Ann Oncol. 
2006; 17: 914-9. 
23. Spina M, Gabarre J, Rossi G et al. Stanford V regimen and concomitant HAART in 59 patients 
with Hodgkin disease and HIV infection. Blood. 2002;100:1984-8. 
24. Xicoy B, Ribera JM et al. Results of treatment with doxorubicin, bleomycin, vinblastine and 
dacarbazine and highly active antiretroviral therapy in advanced stage, human 
immunodeficiency virus- related Hodgkin’s Lymphoma. Haematologica 2007; 92: 191-198. 
25. Spina M, Rossi G, Antinori A et al. VEBEP regimen and highly active antiretroviral therapy 
(HAART) in patients with HD and HIV Infection (HD-HIV). Blood 2005; 106:100a. 
26. Hartmann P, Rehwald U, Salzberger B et al. BEACOPP therapeutic regimen for patients with 
Hodgkin's disease and HIV infection. Ann Oncol. 2003;14 :1562-9. 
27. Levine A M, Li P, et al.. "Chemotherapy consisting of doxorubicin, bleomycin, vinblastine, and 
dacarbazine with granulocyte-colony-stimulating factor in HIV-infected patients with newly 
diagnosed Hodgkin's disease: a prospective, multi-institutional AIDS clinical trials group 
study (ACTG 149)." J Acquir Immune Defic Syndr. 2000;24(5): 444-50. 
28. Errante D, Gabarre J, Ridolfo AL et al. Hodgkin's disease in 35 patients with HIV infection: an 
experience with epirubicin, bleomycin, vinblastine and prednisone chemotherapy in 
combination with antiretroviral therapy and primary use of G-CSF. Ann Oncol. 1999;10:189-
95. 
29. Errante D, Tirelli U, Gastaldi R et al. Combined antineoplastic and antiretroviral therapy for 
patients with Hodgkin’s disease and human immunodeficiency virus infection: a prospective 
study of 17 patients. Cancer 1994;73: 437-444. 
30. Gastaldi R, Martino P, Gentile G et al. Hodgkin's disease in HIV-infected patients: report of 
eight cases usefully treated with doxorubicin, bleomycin, vinblastine and dacarbazine 
(ABVD) plus granulocyte colony- stimulating factor. Ann. of Oncol 2002; 13: 1158-1160. 
31. Tirelli U. Errante D, Vaccher E et al. Hodgkin's disease in 92 patients with HIV infection: The 
Italian experience. Ann Oncol 1992; 3: S69-72. 
32. Andrieu JM, Roithmann S, Tourani JM et al. Hodgkin's disease during HIV-I infection: The 
French registry experience. Ann Oncol 1993; 4: 635-41. 
33. Berenguer J, Miralles P et al. Characteristics and outcome of AIDS-related Hodgkin lymphoma 
before and after the introduction of highly active antiretroviral therapy. J Acquir Immune 
Defic Syndr 2008; 47: 422-8. 
34. Francisco JA, Cerveny CG, Meyer DL, et al. cAC10-vcMMAE, an anti-CD30–monomethyl 
auristatin E conjugate with potent and selective antitumor activity. Blood 2003; 102: 1458-
1465. 
35. Wahl AF, Klussman K, Thompson JD, Chen JH, Francisco LV, Risdon G, Chace DF, Siegall 
CB and Francisco JA (2002). The anti-CD30 monoclonal antibody SGN-30 promotes growth 
arrest and DNA fragmentation in vitro and affects antitumor activity in models of Hodgkin's 
disease. Cancer Res 62: 3736- 42. 
36. Younes A, Forero-Torres A, Bartlett NL, et al. Multiple complete responses in a phase 1 dose-
escalation study of the antibody-drug conjugate SGN-35 in patients with relapsed or 
refractory CD30-positive lymphomas. Blood (ASH Annual Meeting Abstracts) 2008. 
112:1006. 
37. Younes A, Bartlett NL, Leonard JP, et al. Brentuximab vedotin (SGN-35) for relapsed CD30-
positive lymphomas. N Engl J Med. 2010; 363: 1812-21 
38. Chen, Gopal A, Smith SE, Ansell SM, Rosenblatt JD, Klasa R, Connors JM, Engert A, Larsen 
EK, Kennedy D, Sievers E and Younes A. Results of a Pivotal Phase 2 Study of brentuximab 


LYSARC 
 
AMC-085 
 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
79 
Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma Blood (ASH 
Annual Meeting Abstracts) 2010 116: Abstract 283. 
39. Advani RH, Shustov AR, Brice P, et al. Brentuximab Vedotin (SGN-35) in Patients with 
Relapsed or Refractory Systemic Anaplastic Large Cell Lymphoma: A Phase 2 Study 
Update. American Society of Hematology 2011. Abstract 443. 
40. Forero-Torres A, Berryman RB, Advani RH et al. Prolonged Treatment with brentuximab 
Vedotin (SGN-35) in Patients with Relapsed or Refractory Hodgkin Lymphoma (HL) or 
Systemic Anaplastic Large Cell Lymphoma (sALCL). American Society of Hematology 
2011. Abstract 3711. 
41. Younes A, Connors J, Park S, et al. Frontline Therapy with brentuximab Vedotin Combined with 
ABVD or AVD in Patients with Newly Diagnosed Advanced Stage Hodgkin Lymphoma. 
American Society of Hematology 2011. Abstract 955. 
42. Hoskin PJ, Lowry L, Horwich A, et al. Randomized Comparison of the Stanford V Regimen and 
ABVD in the Treatment of Advanced Hodgkin’s Lymphoma: United Kingdom National 
Cancer Research Institute Lymphoma Group Study ISRCTN 64141244. J Clin Oncol. 2011 
Nov 10;29(32):4227-33. 
43. Ngeow J, Tan IB, Kanesvaran R, Tan HC, Tao M, Quek R, Lim ST. Prognostic impact of 
bleomycin- induced pneumonitis on the outcome of Hodgkin's lymphoma. Ann Hematol. 
2011 Jan;90(1):67-72. 
44. Pizzolo G, Vinante F, Morosato L, Nadali G, Chilosi M, Gandini, G, Sinicco A, Raiteri R, 
Semenzato G, Stein H, and Perona G. High serum level of the soluble form of CD30 
molecule in the early phase of HIV-1 infection as an independent predictor of progression to 
AIDS. AIDS 1994. 8: 741–745. 
45. Rizzardi GP, Barcellini W, Tambussi G, Lillo F, Malnati M, Perrin L, and Lazzarin A. Plasma 
levels of soluble CD30, tumour necrosis factor (TNF)- § and TNF receptors during primary 
HIV-1 infection: correlation with HIV-1 RNA and the clinical outcome. AIDS 1996. 10:45-
50. 
46. Pizzolo, G., Vinante, F., Nadali, G., Krampera, M., Morosato, L., Chilosi, M., Raiteri, R. and 
Sinicco, A., High serum level of soluble CD30 in acute primary HIV-1 infection. Clin. Exp. 
Immunol. 1997. 108: 251– 253. 
47. Maggi E, Annunziato F, Biagiotti R, Giudizi MG, Ravina A, Almerigogna F, Boiani N, Alderson 
M, Romagnani S. Activation of HIV expression by CD30 triggering in CD4 + T cells from 
HIV infected individuals. Immunity 1995; 3:251–255. 
48. Brew BJ, Davies NW, Cinque P, Clifford DB and Nath A. Progressive multifocal 
leukoencephalopathy and other forms of JC virus disease. Nat Rev Neurol 2010; 6: 667-79. 
49. Koralnik IJ, Schellingerhout D, Frosch MP. Case records of the Massachusetts General Hospital. 
Weekly clinicopathological exercises. Case 14-2004. A 66-year-old man with progressive 
neurologic deficits. N Engl J Med. 2004;350(18):1882. 
50. Cinque P, Koralnik IJ, Gerevini S, Miro JM, and Price RW. Progressive multifocal 
leukoencephalopathy in HIV-1 infection. Lancet Infect Dis. 2009 Oct;9(10):625-36. 
51. Engsig FN, Hansen AB, Omland LH et al. Incidence, clinical presentation, and outcome of 
progressive multifocal leukoencephalopathy in HIV-infected patients during the highly 
active antiretroviral therapy era: a nationwide cohort study. J Infect Dis. 2009;199(1):77. 
52. Khanna N, Elzi L, Mueller NJ et al. Incidence and outcome of progressive multifocal 
leukoencephalopathy over 20 years of the Swiss HIV Cohort Study. Clin Infect Dis. 2009 
May 15;48(10):1459-66. 
53. Major EO. Progressive multifocal leukoencephalopathy in patients on immunomodulatory 


LYSARC 
 
AMC-085 
 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
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therapies. Annu Rev Med. 2010;61:35-47. 
54. FDA Drug Safety Communication, New Boxed Warning and Contraindication for Adcetris 
(brentuximab vedotin) 1/13/2012. http://www.fda.gov/Drugs/DrugSafety/ucm287668.htm. 
55. Antoniou T and Tseng AL. Interactions Between Antiretrovirals and Antineoplastic Drugs. Clin 
Pharmacokinet 2005; 44: 111-145. 
56. Rubinstein PG, Braik T, Jain S et al. Ritonavir Based Highly Active Antiretroviral Therapy 
(HAART) Correlates with Early Neurotoxicity When Combined with ABVD Treated HIV 
Associated Hodgkin Lymphoma but Not Non-Hodgkin Lymphoma. A Retrospective Study. 
American Society of Hematology 2010. Abstract # 2807. 
57. Sandu S, Gupta S, Itokazu G et al. Suspension of Ritonavir and Zidovudine Prevents Adverse 
Events During the Treatment of HIV Associated Hodgkin Lymphoma. ASCO 2012, abstract 
#8085. 
58. Gallamini A, Hutchings M, Rigacci L, et al. Early interim 2-[18F]fluoro-2-deoxy-D-glucose 
positron emission tomography is prognostically superior to international prognostic score in 
advanced-stage Hodgkin's lymphoma: a report from a joint Italian-Danish study. J. Clin. 
Oncol. 25:3746-52, 2007. 
59. Hutchings M, Loft A, Hansen M, et. al FDG-PET after two cycles of chemotherapy predicts 
treatment failure and progression-free survival in Hodgkin lymphoma Blood, 1 January 
2006, Vol. 107, No. 1, pp. 52-59. 
60. Wedgwood A.R, Fanale A, Fayad L.E, et al. Rituximab + ABVD Improves Event-Free Survival 
(EFS) in Patients with Classical Hodgkin Lymphoma in All International Prognostic Score 
(IPS) Groups and in Patients Who Have PET Positive Disease after 2–3 Cycles of Therapy. 
Blood (ASH Annual Meeting Abstracts) 2007 110: Abstract 215. 
61. Brust D, Polis M, Davey R, et al. Fluorodeoxyglucose imaging in healthy subjects with HIV 
infection: impact of disease stage and therapy on pattern of nodal activation. AIDS 2006, 
Vol 20 No 7. 
62. Kelley T, Pohlman B, Elson P, et al. The ratio of FOXP3+ regulatory T cells to granzyme B+ 
cytotoxic T/NK cells predicts prognosis in classical Hodgkin lymphoma and is independent 
of bcl-2 and MAL expression. Am J Clin Pathol 128:958-65, 2007. 
63. Epeldegui M, Lee JY, Martinez AC, Widney DP, Magpantay L, Regidor D, Mitsuyasu R, 
Sparano JA, Ambinder RF and Martίnez-Maza O. Serum levels of several molecules 
associated with B cell activation and inflammation are elevated in AIDS-NHL and predict 
response to treatment. In preparation. 
64. Epeldegui, M. D. P. Widney, A. C. Martínez, D. Regidor, L. Magpantay, R. Mitsuyasu, J. A. 
Sparano, J. Y. Lee, R. F. Ambinder, O. Martínez-Maza. 2011. Serum levels of several 
molecules that are associated with B cell activation and inflammation are elevated in AIDS-
associated non-Hodgkin’s lymphoma (AIDS-NHL) and predict response to treatment. 
International Conference on Malignancies in AIDS and Opportunistic Infections (ICAMOI). 
Abstract. Bethesda, MD. 
65. Levin, L., E. C. Breen, B. Birmann, J. J. Kasperzyk, L. Magpantay, R. F. Ambinder, N. Mueller 
and O. Martίnez-Maza. Elevated serum levels of soluble CD30, IL-6 and IL-10 precede the 
diagnosis of Hodgkin lymphoma. In preparation. 
66. Levin, L., E. C. Breen, C. Kitchen, D. Widney, B. Kim B, A. Marrogi, R. Krampf, L. Magpantay, 
and O. Martínez-Maza. 2010. Elevated Serum Levels of CXCL13 Precede the Diagnosis of 
B Cell Non Hodgkin Lymphoma (NHL). AACR Special Conference on The Future of 
Molecular Epidemiology: New Tools, Biomarkers, and Opportunities. Abstract. Miami, FL. 
67. Yeung ML, Bennasser Y, LE SY, Jeang KT. siRNA, miRNA and HIV: promises and challenges. 


LYSARC 
 
AMC-085 
 
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Cell Res. 2005 ;15(11-12):935-46. 
68. Qi P, Han JX, Lu YQ, Wang C, Bu FF. Virus-encoded microRNAs: future therapeutic targets? 
Cell Mol Immunol. 2006;3(6):411-9. 
69. Visone R, Croce CM. MiRNAs and Cancer. Am J Pathol. 2009;174(4):1131-8. 
70. Bartel DP. MicroRNAs: target recognition and regulatory functions. Cell 2009; 136 (2): 215–
33. 
71. Bartel DP. MicroRNAs: genomics, biogenesis, mechanism, and function. Cell 2004; 116 (2): 
281–97. 
72. Bentwich I, Avniel A, Karov Y et al. Identification of hundreds of conserved and nonconserved 
human microRNAs. Nat. Genet. 2005; 37 (7): 766–70. 
73. Homo sapiens miRNAs in the miRBase at Manchester University. 
74. Lu J, Getz G, Miska EA, et al. MicroRNA expression profiles classify human cancers. Nature 
2005;435:834-838. 
75. Navarro A, Gaya A, and Martinez A et. al. MicroRNA expression profiling in classic Hodgkin 
lymphoma. Blood 2008; 111: 2825-2832 
76. Lok AS, McMahon BJ. Chronic hepatitis B: update 2009. Hepatology. 2009 Sep;50(3):1-36. 
77. 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. 
78. 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. 
79. Duggan DB, Petroni GR, Johnson JL, Glick JH, Fisher RI, Connors JM, Canellos GP and 
Peterson BA. Randomized comparison of ABVD and MOPP/ABV hybrid for the treatment 
of advanced Hodgkin's disease. report of an intergroup trial. J Clin Oncol; 2003 21: 607-14. 
80. Martin WG, Ristow KM, Habermann TM, Colgan JP, Witzig TE and Ansell SM. Bleomycin 
pulmonary toxicity has a negative impact on the outcome of patients with Hodgkin's 
lymphoma. J Clin Oncol; 2005 23: 7614-20. 
81. Hoskin PJ, Lowry L, Horwich A, Jack A, Mead B, Hancock BW, Smith P, Qian W, Patrick P, 
Popova B, Pettiti A, Cunningham D, Pettengell R, Sweetenham J, Linch D and Johnson PW. 
Randomized comparison of the Stanford V regimen and ABVD in the treatment of advanced 
Hodgkin’s Lymphoma: United Kingdom National Cancer Research Institute Lymphoma 
Group Study ISRCTN 64141244. J Clin Oncol 2009; 27: 5390-6. 
82. Glaser, S.L., et al., Population-based patterns of human immunodeficiency virus-related 
Hodgkin lymphoma in the Greater San Francisco Bay Area, 1988-1998. Cancer, 2003. 98(2): 
p. 300-9. 
83. Keegan, T.H., et al., Epstein-Barr virus as a marker of survival after Hodgkin's lymphoma: a 
population- based study. J Clin Oncol, 2005. 23(30): p. 7604-13. 
84. Hohaus, S., et al., The viral load of Epstein-Barr virus (EBV) DNA in peripheral blood predicts 
for biological and clinical characteristics in Hodgkin lymphoma. Clinical Cancer Research: 
an official journal of the American Association for Cancer Research, 2011. 17(9): p. 2885-
92. 
85. Gandhi, M.K., et al., Plasma Epstein-Barr virus (EBV) DNA is a biomarker for EBV-positive 
Hodgkin's lymphoma. Clinical cancer research : an official journal of the American 
Association for Cancer Research, 2006. 12(2): p. 460-4. 
86. Kanakry, J.A., Plasma viral DNA as a marker of tumor response in EBV(+) Hodgkin lymphoma 
in a phase III study (E2496). Journal of clinical oncology, 2012. 30. 


LYSARC 
 
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87. Chan, K.C., et al., Molecular characterization of circulating EBV DNA in the plasma of 
nasopharyngeal carcinoma and lymphoma patients. Cancer research, 2003. 63(9): p. 2028-
32. 
88. Lin, L., et al., Effects of chemotherapy in AIDS-associated non-Hodgkin's lymphoma on 
Kaposi's sarcoma herpesvirus DNA in blood. J Clin Oncol, 2009. 27(15): p. 2496-502. 
89. Shamay, M., et al., CpG methylation as a tool to characterize cell-free Kaposi sarcoma 
herpesvirus DNA. J Infect Dis, 2012. 205(7): p. 1095-9. 
90. Kasamon, Y.L., et al., Multicenter phase II study of rituximab-ABVD in classic Hodgkin 
lymphoma (cHL). ASCO Meeting Abstracts, 2011. 29(15_suppl): p. 8039. 
91. Meignan M, Barrington S, Itti E, Gallamini A, Haioun C, Polliack A. Report on the 4th 
International Workshop on Positron Emission Tomography in Lymphoma held in Menton, 
France, 3-5 October 2012. Leuk Lymphoma. 2013 Jun 14. [Epub ahead of print] 
92. Meignan M, Gallamini A, Meignan M, Gallamini A, Haioun C. Report on the First International 
Workshop on Interim-PET-Scan in Lymphoma. Leuk Lymphoma. 2009 Aug;50(8):1257-60. 


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21.0 
APPENDIXES 
21.1 
Appendix Study Design 
 


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21.2 
Appendix Schedule of Evaluations (study flow-chart) 
 
Treatment 
(W-2) Must be completed within 2 weeks prior to patient registration (D-7) To be performed within 7 days prior to first day of cycle 
(D-21) To be performed within 21 days prior to Cycle 1, Day 1 
(D-28) To be performed no more than 28 days before enrollment. 
(H-48) To be performed within 48 hours of day 1 and 15 of every cycle. 
Follow-up 
Date (weeks or months) 
Eligibility 
(Baseline) 6 
weeks before 
C1D1 
C1D1 C1D15 C2D1 C2D15 C2D22 
-28 
C3D1 C3D15 C4D1 C4D15 C5D1 C5D1
5 
C6D1 C6D15 
End of 
treatment 6 
-8 w after 
C6D15 
Early 
Treatment 
Discontinuatio
n 1 m after 
discontinuation 
Every 
3 m 2 y 
(+/-7d) 
Every 
6 m 3 y 
(+/-7d) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history and physical 
examination 
X 
X 
(h-48) 
 
X 
(h-48) 
 
 
X 
(h-48) 
 
X 
(h-48) 
 
X 
(h-48) 
 
X 
(h-48) 
 
X 
X 
X 
X 
FDG-PET/CT or FDG-PET + CT 
X (D-28) 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
CT scan with oral/IV contrast 
(d) To be done if the CT portion of 
the PET/CT is without contrast. 
X (d) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Every 6 
m 
X 
PFTs with volumes, spirometry, DLCO 
and pulse oximetry 
(b) To be performed only for patients 
with DLCO (corrected for hemoglobin) 
<70% during treatment until 
normalization. 
X 
 
 
 
 
 
X 
(d-7) 
 
 
 
X   
(D-7) 
 
 
 
X (b) 
 
 
 
MRI of brain with and without 
IV gadolinium contrast 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MUGA or echocardiogram 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Treatment 
(W-2) Must be completed within 2 weeks prior to patient registration (D-7) To be performed within 7 days prior to first day of cycle 
(D-21) To be performed within 21 days prior to Cycle 1, Day 1 
(D-28) To be performed no more than 28 days before enrollment. 
(H-48) To be performed within 48 hours of day 1 and 15 of every cycle. 
Follow-up 
Date (weeks or months) 
Eligibility 
(Baseline) 6 
weeks before 
C1D1 
C1D1 C1D15 C2D1 C2D15 C2D22 
-28 
C3D1 C3D15 C4D1 C4D15 C5D1 C5D1
5 
C6D1 C6D15 
End of 
treatment 6 
-8 w after 
C6D15 
Early 
Treatment 
Discontinuatio
n 1 m after 
discontinuation 
Every 
3 m 2 y 
(+/-7d) 
Every 
6 m 3 y 
(+/-7d) 
FACT-GOG-neurotoxicity 
questionnaire 
X 
X 
(h-48) 
 
X 
(h-48) 
 
 
X 
(h-48) 
 
X 
(h-48) 
 
X 
(h-48) 
 
X 
(h-48) 
 
 
 
 
 
Bone marrow biopsy 
(a) Does not have to be repeated if bone 
marrow involvement by lymphoma 
already documented after bone marrow 
biopsy more than 6 weeks prior to 
registration 
(if+) Only need to perform to confirm CR 
is positive at baseline (only once, within 8 
weeks of last treatment dose) 
X(a) 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (if +) 
 
 
 
Central pathology review 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Blood sampling for biological studies 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CBC with diff Results must be known 
prior to treatment 
Sedimentation rate (only at baseline) 
X (W-2) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
X 
X 
X 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
86 
 
Treatment 
(W-2) Must be completed within 2 weeks prior to patient registration (D-7) To be performed within 7 days prior to first day of cycle 
(D-21) To be performed within 21 days prior to Cycle 1, Day 1 
(D-28) To be performed no more than 28 days before enrollment. 
(H-48) To be performed within 48 hours of day 1 and 15 of every cycle. 
Follow-up 
Date (weeks or months) 
Eligibility 
(Baseline) 6 
weeks before 
C1D1 
C1D1 C1D15 C2D1 C2D15 C2D22 
-28 
C3D1 C3D15 C4D1 C4D15 C5D1 C5D1
5 
C6D1 C6D15 
End of 
treatment 6 
-8 w after 
C6D15 
Early 
Treatment 
Discontinuatio
n 1 m after 
discontinuation 
Every 
3 m 2 y 
(+/-7d) 
Every 
6 m 3 y 
(+/-7d) 
Serum chemistries: electrolytes (Na, K, 
Cl, bicarbonate, Ca, Mg, phosphorus), 
glucose, BUN, creatinine, total bilirubin, 
alkaline phosphatase (ALP), LDH, total 
protein, albumin, AST and ALT 
X (W-2) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
(h-48) 
X 
X 
X 
X 
CD4/CD8 cell count 
(e) to be performed at study completion 
and every 3 months for one year 
(f) Do not repeat if done within 1 
month from removal from 
treatment. 
X 
 
 
X 
(h-48) 
 
 
 
 
 
 
X 
(h-48) 
 
 
 
X(e) 
X(f) 
 
 
HIV-1 RNA viral load 
(g) to be performed at study completion 
and every 3 months for one year 
(h) Do not repeat if done within 1 month 
from removal from treatment. 
X (D-21) 
 
 
X 
(h-48) 
 
 
 
 
 
 
X 
(h-48) 
 
 
 
X (g) 
X(h) 
 
 
Hepatitis C antibody, Hepatitis B core 
antibody, Hepatitis B surface antigen 
(HBsAg), and Hepatitis B surface 
antibody 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
87 
 
Treatment 
(W-2) Must be completed within 2 weeks prior to patient registration (D-7) To be performed within 7 days prior to first day of cycle 
(D-21) To be performed within 21 days prior to Cycle 1, Day 1 
(D-28) To be performed no more than 28 days before enrollment. 
(H-48) To be performed within 48 hours of day 1 and 15 of every cycle. 
Follow-up 
Date (weeks or months) 
Eligibility 
(Baseline) 6 
weeks before 
C1D1 
C1D1 C1D15 C2D1 C2D15 C2D22 
-28 
C3D1 C3D15 C4D1 C4D15 C5D1 C5D1
5 
C6D1 C6D15 
End of 
treatment 6 
-8 w after 
C6D15 
Early 
Treatment 
Discontinuatio
n 1 m after 
discontinuation 
Every 
3 m 2 y 
(+/-7d) 
Every 
6 m 3 y 
(+/-7d) 
Serum pregnancy test 
X (D-7) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Administration of treatment 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
Adverse event 
Continuous report 
 
 
 
 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
88 
21.3 
Appendix Ann Arbor Staging 
• 
Stage I: 
o I: Involvement of a single lymph node region. 
o IE: Localized involvement of a single extralymphatic organ or site. 
• 
Stage II: 
o II: Involvement of 2 or more lymph node regions on the same side of the diaphragm. 
o IIE: Localized involvement of a single associated extralymphatic organ or site and its 
regional lymph nodes with or without other lymph node regions on the same side of the 
diaphragm. 
• 
Stage III: 
o III: Involvement of lymph node regions on both sides of the diaphragm. 
o IIIE: Involvement of lymph node regions on both sides of the diaphragm accompanied 
by localized involvement of an extralymphatic organ or site. 
o IIIS: Involvement of lymph node regions on both sides of the diaphragm accompanied 
by involvement of the spleen. 
o IIIS+E: Both IIIS+IIIE. 
• 
Stage IV: 
o IV: Disseminated (multifocal) involvement of 1 or more extralymphatic sites with or 
without associated lymph node involvement or isolated extralymphatic organ 
involvement with distant (non regional) nodal involvement. 
o IVE: Extranodal lymphoid malignancies arise in tissues separate from, but near, the 
major lymphatic aggregates. 
Source: American Joint Committee on Cancer. Non Hodgkin’s lymphoma. In: AJCC Staging 
Manual. 5th ed. Philadelphia, PA: Lippincott-Raven;1997:289-294. 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
89 
21.4 
Appendix Body Surface Area Calculation 
The algorithm to be used in this study is Mosteller formula (1987): 
BSA = √ [(Height (cm) x Weight (kg))/3600] 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
90 
21.5 
Appendix Performance Status Criteria 
Karnofsky Performance Scale 
ECOG Performance Status Scale 
Percent 
Description 
Grade 
Description 
100 
Normal, no complaints, no 
evidence of disease. 
0 
Normal activity. Fully active, able to 
carry on all pre-disease performance 
without restriction. 
90 
Able to carry on normal activity; 
minor signs or symptoms of 
disease. 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
1 
Symptoms, but ambulatory. 
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or sedentary 
nature (e.g., light housework, office 
work). 
70 
Cares for self, unable to carry  on 
normal activity or to do active 
work.
60 
Requires occasional assistance, but 
is able to care for most of his/her 
needs. 
2 
In bed <50% of the time. Ambulatory 
and capable of all self-care, but 
unable to carry out any work 
activities. Up and about more than 
50% of waking hours. 
50 
Requires considerable assistance 
and frequent medical care. 
40 
Disabled, requires special  care  
and assistance. 
3 
In bed >50% of the time. Capable of 
only limited self-care, confined to 
bed or chair more than 50% of 
waking hours. 
30 
Severely disabled, hospitalization 
indicated. Death not imminent. 
20 
Very sick, hospitalization 
indicated. Death not imminent. 
4 
100% bedridden. Completely 
disabled. Cannot carry on any self-
care. Totally confined to bed or 
chair. 
10 
Moribund, fatal processes 
progressing rapidly. 
0 
Dead. 
5 
Dead. 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
91 
21.6 
Appendix FACT-GOG-Neurotoxicity Questionnaire v4.0 
Veuillez indiquer votre réponse en entourant un seul chiffre par ligne et en tenant compte des 7 
derniers jours. 
AUTRES SUJETS D’INQUIÉTUDE 
 
 
 
 
 
 
 
 
Pas du tout 
Un peu 
Moyen-
nement 
Beau-coup 
Énormé-
ment 
 
 
 
 
 
NTX 
1 
J'ai les mains qui s'engourdissent 
ou qui picotent  
0 
1 
2 
3 
4 
NTX 
2 
J'ai les pieds qui s'engourdissent ou 
qui picotent  
0 
1 
2 
3 
4 
NTX 
3 
J'ai une gêne dans les mains  
0 
1 
2 
3 
4 
NTX 
4 
Je sens une gêne dans mes pieds  
0 
1 
2 
3 
4 
NTX 
5 
J’ai des douleurs aux articulations 
et/ou des cramps aux muscles  
0 
1 
2 
3 
4 
HI 
12 
Je ressens une faiblesse générale  
0 
1 
2 
3 
4 
NTX 
6 
J'ai du mal à entendre  
0 
1 
2 
3 
4 
NTX 
7 
J'ai les oreilles qui tintent ou qui 
bourdonnent  
0 
1 
2 
3 
4 
NTX 
8 
J’ai du mal à boutonner les 
vêtements  
0 
1 
2 
3 
4 
NTX 
9 
J’ai du mal à palper la forme de 
petits objects quand ils sont dans 
ma main  
0 
1 
2 
3 
4 
An 
6 
J’ai du mal à marcher  
0 
1 
2 
3 
4 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
92 
21.7 
Appendix Pathological Samples Review 
General principles and organization of the pathological review: 
The AMC-85 study requires a histological review of all cases included in the trial at diagnosis. 
The aims of the centralized histopathological review will be to confirm the diagnosis of 
Hodgkin lymphoma, according to the criteria of the updated WHO classification 2008 (S. 
Swerdlow et al.) for each patient in the AMC-085 study. Histological criteria of inclusion and 
exclusion have been detailed in the current protocol. 
The review process will be organized by the LYSA-Pathology institute, Hopital Henri Mondor, 
Créteil (LYSA-P). Therefore for each included patient, tumor tissue blocks - or only when not 
possible - unstained slides will have to be sent for analysis and confirmation of diagnosis to 
LYSA-P. 
Practical aspects of the LYSA review: 
1. 
Information on patient inclusion 
At patient randomization/inclusion, the investigator will be requested to fax to LYSARC 
registration center with the inclusion form a copy of the histopathological report on 
which the name and address of the pathologist having diagnosed the Hodgkin lymphoma 
will be easily identified as well as the bone marrow report when possible. 
The LYSARC registration center will transmit these documents to the LYSA-P. 
2. 
Sample request 
At reception of the pathological report and inclusion form, the LYSA-P will sent to the 
initial pathologist a letter requesting: 
• 
The paraffin block from the formalin fixed sample that was used to set the diagnosis 
and/ or 10 unstained Superfrost+ slides 
• 
A copy of the bone marrow pathological report if not sent previously 
• 
To notify the LYSA-P of the presence of frozen tissue 
3. 
Sample centralisation at LYSA-P 
All these requirements will be sent in prepaid envelope and centralized by the LYSA-P 
at the following address: 
LYSA-P, LYSA – AMC-085 study, 
Hôpital Henri Mondor 
51, avenue de Lattre de Tassigny, 94010 
Créteil France 
4. 
Sample review 
At sample reception, routinely stained sections will be performed and an appropriate 
panel of antibodies according to morphological aspects will be applied. When sufficient 
slides are available, a pathological review will be organized at the LYSA-P with the 
designated panel of pathologists for this study. All the cases will be reviewed by at least 
2 experts hematopathologists and a consensus diagnosis will be set and registered in the 
LYSA-P data base. This consensus diagnosis will then be sent to the clinical investigator 
and to the initial pathologist. For the need of the ancillary study, blocks will be kept 
temporarily to avoid a second request. Meanwhile, the block will be at the entire 
disposition of the initial anatomopathology laboratory under request if they need it. 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
93 
 
21.8 
Appendix Biological samples for further ancillary studies 
A)  
RATIONALE 
The AMC-085 study represents a unique opportunity to collect biological 
samples from patients with Hodgkin lymphoma and HIV at diagnosis that can 
be used to improve comprehension of the disease, better define the prognostic 
criteria in Hodgkin lymphoma and identify new factors that influence treatments 
results and outcome. These scientific studies will be performed as ancillary 
studies based on the AMC-085 protocol. 
B)  
TUMOR BIOPSY 
A tissue microarray as well as DNA and RNA extraction will be performed on 
each paraffin embedded tissue block received. 
C) 
BLOOD SAMPLE 
Specific informed consents must be signed before any sample procedure. 
Every collected samples will be part of a comprehensive collaborative studies. 
This may include genetic, proteomic, virological and immunology studies. 
The following sample will be collected at baseline, before treatment: 
• 30mL of blood on heparin lithium tubes 
• 10mL of blood on EDTA tubes 
LYSARC provides consumables for realisation of biological studies: tubes 
heparin lithium, labels, traceability form.  
LYSARC supports the transporting of biological sample until hospital Bicêtre: 
The day before blood sampling, contact the carrier to schedule the 
removing of samples. The day of blood sampling, complete the 
traceability form, and send the tubes and the form to Bicêtre hospital, at 
room temperature, by carrier. 
Address: CHU Bicetre, 
Laboratoire d'immnunologie,  
4ème étage pavillon Broca  
78 rue du Gal Leclerc, 
94275 LE KREMLIN BICETRE FRANCE 
D)  
CONTROL AND IDENTIFICATION OF THE BIOLOGICAL SAMPLES 
FROM THE BLOOD 
In order to organize the tracking of biological samples, the LYSARC asks the 
centres to complete a document “AMC- 085– traceability form (in investigator 
file). This document must be completed on site, shipped with the blood sample. 
The complete procedure will remain anonymous all along the biological 
analysis. Observations will be linked with the LYSA clinical database 
(registered to the CNIL) only after the end of the study. This database 
contains the main information about patients participating to the study 
including demographic data, baseline clinical evaluation, treatment, 
response to treatment and follow-up (relapse, death). 
 
 


LYSARC 
 
AMC-085 
EudraCT number: 2014-003678-18 Protocol version 6.0 dated 15/04/2019 
94 
 
21.9 
Appendix: Prohibited and use with caution medications that are p-glycoprotein 
and cyp3a4 inhibitors 
Strong CYP3A inhibitors and P-glycoprotein inhibitors must be discontinued 7 days prior to 
therapy. Moderate CYP3A4 inhibitors should be used with Caution but are not excluded. If 2 
moderate CYP3A4 inhibitors are used concurrently, one must be discontinued at least 7 days 
prior to chemotherapy. 
Because the lists of these agents are constantly changing, it is important to regularly consult a 
frequently-updated medical reference for a list of drugs to avoid or minimize use of. 
P-Glycoprotein Inhibitors 
Strong CYP 3A4 
Inhibitors 
Moderate CYP 3A4 
Inhibitors 
Antiretrovirals 
Lopinavir and ritonavir 
 
Other Agents 
Amiodarone 
Azithromycin 
Captopril 
Carvedilol 
Clarithromycin 
Conivaptan 
Cyclosporine 
Diltiazem 
Dronedarone 
Erythromycin 
Felodipine 
Itraconazole 
Ketoconazole 
Quercetin 
Quinidine 
Ranolazine 
Tacrolimus 
Verapamil 
Antiretrovirals 
Cobicistat 
Indinavir 
Nelfinavir 
Ritonavir 
Saquinavir 
 
Other Agents 
Boceprevir 
Clarithromycin 
Itraconazole 
Ketoconazole 
Mibefradil 
Nefazodone 
Posaconazole  
Suboxone 
Telithromycin 
Telaprevir 
Troleandomycin 
 
Antiretrovirals 
Atazanavir 
 
Other Agents 
Aprepitant 
Amprenavir 
Amiodarone 
Ciprofloxacin 
Dronedarone 
Erythromycin 
Diltiazem 
Fluconazole 
Fosamprenavir 
Grapefruit juice 
Seville orange juice 
Verapamil 
Voriconazole