Clinical trial NCT01775475
Conditions: AIDS-related Diffuse Large Cell Lymphoma AIDS-related Diffuse Mixed Cell Lymphoma AIDS-related Diffuse Small Cleaved Cell Lymphoma AIDS-related Immunoblastic Large Cell Lymphoma AIDS-related Lymphoblastic Lymphoma AIDS-related Peripheral/Systemic Lymphoma AIDS-related Small Noncleaved Cell Lymphoma Stage III AIDS-related Lymphoma Stage IV AIDS-related Lymphoma
Sponsor: AIDS Malignancy Consortium
Start date: 2016-09-15; Completion date: 2021-07-15
Enrollment: 7 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This randomized phase II trial studies how well intravenous (IV) chemotherapy or oral chemotherapy works in treating patients with previously untreated stage III-IV human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone, lomustine, etoposide, and procarbazine hydrochloride, work in different ways to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more cancer cells

Detailed description:
PRIMARY OBJECTIVES:

I. To compare the efficacy of standard cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) and an oral chemotherapy regimen for acquired immune deficiency syndrome (AIDS)-related (AR)-non-Hodgkin lymphoma (NHL) in sub-Saharan Africa with respect to overall survival (OS).

SECONDARY OBJECTIVES:

I. To compare the objectives response rate (ORR) of persons randomized to CHOP and oral chemotherapy.

II. To compare the progression free survival (PFS) of persons randomized to CHOP and oral chemotherapy.

III. To compare the safety and tolerance of persons randomized to CHOP and oral chemotherapy.

TERTIARY OBJECTIVES:

I. To describe the rates of completion of therapy of persons randomized to CHOP and oral chemotherapy.

II. To describe adherence to chemotherapy of persons randomized to CHOP and oral chemotherapy.

III. To describe adherence to antiretroviral therapy of persons randomized to CHOP and oral chemotherapy.

IV. To describe the effects of therapy on HIV control, as measured by cluster of differentiation (CD)4 counts and HIV viral load.

V. To investigate correlates of survival.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive CHOP chemotherapy comprising cyclophosphamide intravenously (IV) on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone orally (PO) on days 1-5. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive lomustine PO once daily (QD) on day 1 (courses 1 and 3 only), etoposide PO QD on days 1-3, cyclophosphamide PO QD on days 22-26, and procarbazine hydrochloride PO QD on days 22-26. Treatment repeats every 6 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 12, 18, and 24 months.

Arms: arm 1: Patients receive CHOP chemotherapy comprising cyclophosphamide IV on day 1, doxorubicin hydrochloride IV on day 1, vincristine sulfate IV on day 1, and prednisone PO on days 1-5. Treatment repeats every 3 weeks for up to 6 courses in the absence of disease progression or unacceptable toxicity. arm 2: Patients receive lomustine PO QD on day 1 (courses 1 and 3 only), etoposide PO QD on days 1-3, cyclophosphamide PO QD on days 22-26, and procarbazine hydrochloride PO QD on days 22-26. Treatment repeats every 6 weeks for up to 3 courses in the absence of disease progression or unacceptable toxicity.
Interventions: intervention 1: cyclophosphamide intervention 2: doxorubicin hydrochloride intervention 3: vincristine sulfate intervention 4: prednisone intervention 5: lomustine intervention 6: etoposide intervention 7: cyclophosphamide intervention 8: procarbazine hydrochloride intervention 9: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given IV intervention 2: Given IV intervention 3: Given IV intervention 4: Given PO intervention 5: Given PO intervention 6: Given PO intervention 7: Given PO intervention 8: Given PO intervention 9: Correlative studies

Protocol documents:
Prot_SAP_000.pdf: 
AMC #068 (Version 8.0) 03DEC2019 
i 
NCI Version Date 03DEC2019 
SUMMARY OF CHANGES 
Randomized, Phase II Trial of CHOP vs. Oral Chemotherapy with Concomitant 
Antiretroviral Therapy in Patients with HIV-associated Lymphoma in Sub-Saharan Africa 
Version 8.0 
 
NCI Protocol #: AMC-068 
Local Protocol #: AMC-068 
 
NCI Version Date: 03DEC2019 
Protocol Date: 03DEC2019 
 
Due to early study closure on 30NOV2018 and completion of study therapy, no changes were 
made in response to the disapproval letters for protocol versions 6 and 7. 
 
I. 
Scientific and Substantive Changes: 
# 
Section 
Description of Changes 
1. 
1.3 
3.3 
4.4 
4.5 
Appendix I 
These sections were modified to include information on early study closure and to 
reduce total follow-up to 2 years, as the protocol team believes sufficient data will be 
collected during the first 2 years of follow-up to complete study analysis. Additionally, 
the clinical evaluations section was reorganized to clarify the procedures for 2 year-
follow up. Timelines and windows for these follow-up assessments were modified to 
refer to the treatment discontinuation visit, including in the schedule of evaluation in 
Appendix I. 
 
II. 
Administrative and Editorial Changes: 
# 
Section 
Description of Changes 
2. 
Global 
Version number and version date were updated to version 8.0 dated 03DEC2019. 
3. 
Global 
The protocol was modified to update the CTCAE version from 4.0 to 5.0. 
4. 
Cover Page 
Protocol 
Roster 
These sections were updated for current protocol team members and contact 
information. The site pathologist roster was removed to accurately reflect essential 
protocol team members and their roles.  
5. 
Appendix IV 
The AMC Data and Safety Management Plan has been updated from v5 to v6. 
 


AMC #068 (Version 8.0) 03DEC2019 
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AMC PROTOCOL #068: 
Randomized, Phase II Trial of CHOP vs. Oral Chemotherapy 
with Concomitant Antiretroviral Therapy in Patients with HIV-
associated Lymphoma in Sub-Saharan Africa 
A Trial of the AIDS Malignancy Clinical Trials Consortium 
(AMC) 
 
Sponsored by: 
Supported by: 
National Cancer Institute 
Office of HIV and AIDS Malignancy (OHAM) 
 
NCT Registration Number: 
NCT01775475 
 
Protocol Chair: 
R. Matthew Strother, MD (IVR-48877) 
 
Protocol Co-Chairs: 
Susan E. Krown, MD (IVR-20879) 
Ariela Noy, MD (IVR-28244) 
 
Version 8.0 
NCI Version Date: 03DEC2019 


AMC #068 (Version 8.0) 03DEC2019 
 
 
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AMC PROTOCOL SIGNATURE PAGE 
 
I,           , Principal Investigator at site     , agree to conduct and follow this protocol: AMC Protocol 
#068 – Randomized, phase II trial of CHOP vs. oral chemotherapy with concomitant 
antiretroviral therapy in patients with HIV-associated Lymphoma in sub-Saharan Africa, 
(Version 8.0, 03DEC2019, as written according to AMC, NCI, and FDA guidelines. I understand 
that no deviations from the above protocol eligibility criteria or waivers for protocol deviations 
will be permitted. 
 
_________________________________ 
_____________________ 
 
Signature 
Date (dd/mm/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 
ABBREVIATIONS LIST ............................................................................................................. 6 
SITES PARTICIPATING IN THE STUDY .............................................................................. 9 
PROTOCOL ROSTER .............................................................................................................. 10 
PROTOCOL SYNOPSIS ........................................................................................................... 12 
PROTOCOL SCHEMA ............................................................................................................. 14 
1.0 BACKGROUND AND RATIONALE ............................................................................. 15 
1.1 AIDS-Related Non-Hodgkin’s Lymphoma (AR-NHL) ............................................. 15 
1.2 Rationale ..................................................................................................................... 16 
1.3 Study Design ............................................................................................................... 17 
1.4 Correlative Study Background .................................................................................... 17 
2.0 STUDY OBJECTIVES ...................................................................................................... 19 
2.1 Objectives ................................................................................................................... 19 
3.0 PARTICIPANT SELECTION ......................................................................................... 20 
3.1 Inclusion Criteria ........................................................................................................ 20 
3.2 Exclusion Criteria ....................................................................................................... 22 
3.3 Number of Participants to be Enrolled........................................................................ 22 
3.4 Accrual Targets ........................................................................................................... 23 
3.5 Study Enrollment Procedures ..................................................................................... 23 
3.6 Required Pathology Material and Data ....................................................................... 24 
4.0 CLINICAL AND LABORATORY EVALUATIONS .................................................... 25 
4.1 Baseline Evaluations ................................................................................................... 25 
4.2 Evaluations During Treatment .................................................................................... 26 
4.3 Evaluations at the Completion of Chemotherapy ....................................................... 27 
4.4 Follow-up Evaluations ................................................................................................ 28 
4.5 Final Evaluations, Off Study....................................................................................... 29 
4.6 Procedures in the Event of Contraceptive Failure ...................................................... 29 
4.7 Procedures in the Event of On-Study Breastfeeding or Pregnancy ............................ 29 


 
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5.0 TREATMENT PLAN ........................................................................................................ 31 
5.1 Study Drugs ................................................................................................................ 31 
5.2 Drug Orders, Transfers, Returns, and Accountability ................................................ 36 
5.3 Dosing ......................................................................................................................... 36 
5.4 Dosing Modifications for Hematologic Toxicities ..................................................... 38 
5.5 Dosing Modifications for Other Toxicities ................................................................. 41 
5.6 Duration of Treatment................................................................................................. 43 
5.7 Concomitant Medication(s) and Diet .......................................................................... 44 
5.8 Treatment Compliance ................................................................................................ 45 
6.0 REPORTING OF ADVERSE EVENTS .......................................................................... 46 
6.1 Classification of AEs by Severity and Relationship to Study Drug Administration .. 46 
6.2 Expedited AE Reporting Procedures .......................................................................... 48 
6.3 Routine AE Reporting................................................................................................. 50 
6.4 Secondary Malignancy................................................................................................ 51 
6.5 Second Malignancy ..................................................................................................... 51 
7.0 CRITERIA FOR DISCONTINUATION ........................................................................ 52 
7.1 Permanent Treatment Discontinuation ....................................................................... 52 
7.2 Premature Study Discontinuation ............................................................................... 52 
8.0 EVALUATION OF RESPONSE ...................................................................................... 53 
8.1 Definition of Response ............................................................................................... 53 
9.0 DATA COLLECTION AND MONITORING ................................................................ 56 
9.1 Records to Be Kept ..................................................................................................... 56 
9.2 CRF Instructions ......................................................................................................... 56 
9.3 Data Quality ................................................................................................................ 56 
9.4 Clinical Site Monitoring and Record Availability ...................................................... 56 
10.0 STATISTICAL CONSIDERATIONS ............................................................................. 57 
10.1 Study Design ............................................................................................................... 57 
10.2 Statistical Analyses of Clinical Outcomes .................................................................. 57 
10.3 Proposed Sample Size ................................................................................................. 57 
10.4 Lost to Follow-Up and Trial Futility .......................................................................... 58 
11.0 ETHICAL AND REGULATORY CONSIDERATIONS .............................................. 59 
11.1 Ethical Committee or Institutional Review Board (IRB) Review and Informed Consent
..................................................................................................................................... 59 


 
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11.2 Participant Confidentiality .......................................................................................... 59 
11.3 Study Discontinuation ................................................................................................. 59 
11.4 Women and Minorities ............................................................................................... 59 
11.5 NIH Guidance Regarding Post-Trial Access .............................................................. 60 
12.0 PUBLICATION OF RESEARCH FINDINGS ............................................................... 61 
13.0 BIOHAZARD CONTAINMENT ..................................................................................... 62 
14.0 REFERENCES ................................................................................................................... 63 
APPENDIX I: SCHEDULE OF PATIENT ASSESSMENT(S) AND EVALUATION(S) ... 64 
APPENDIX II: ECOG PERFORMANCE SCALE ................................................................. 66 
APPENDIX III: INITIAL PATHOLOGY REVIEW AND EXTERNAL QUALITY 
ASSURANCE AND HANDLING OF TISSUES ..................................................................... 67 
APPENDIX IV: AMC DATA AND SAFETY MONITORING PLAN ................................. 69 
APPENDIX V: AMC-068 STUDY DRUG DIARY (ORAL CHEMOTHERAPY REGIMEN)
 
72 
APPENDIX VI: AMC-068 STUDY DRUG DIARY (CHOP REGIMEN) ............................ 75 


 
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ABBREVIATIONS LIST 
 
CTEP-AERS 
CTEP Adverse Event Reporting System 
ADL 
Activities of daily living 
AE 
Adverse event 
AIDS 
Acquired Immune Deficiency Syndrome 
AMC 
AIDS Malignancy Clinical Trials Consortium 
AML 
Acute myelocytic leukemia 
AR-NHL 
AIDS-Related Non Hodgkin’s Lymphoma 
ART 
Antiretroviral therapy 
AZT 
Zidovudine 
C 
Celsius  
CBC 
Complete blood count 
CCNU 
Lomustine 
cCR 
Clinical complete response 
CDC 
U.S. Centers for Disease Control and Prevention 
CDUS 
Clinical Data Update System 
CFR 
U.S. Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence interval 
CNS 
Central nervous system 
CR 
Complete response 
CRF 
Case report form 
CT 
Computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTX 
Cyclophosphamide 
DARF 
NCI Drug Accountability Record Form 
DNA 
Deoxyribonucleic acid 
DSMP 
Data and Safety Monitoring Plan 
ECOG 
Eastern Cooperative Oncology Group 


 
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EFS 
Event free survival 
EQA 
External quality assurance 
F 
Fahrenheit  
FDA 
U.S. Food and Drug Administration 
G-CSF 
Granulocyte colony-stimulating factor 
IATA 
International Air Transport Association 
ICH 
International Conference on Harmonization 
ICU 
Intensive care unit 
IEC 
Institutional ethics committee 
IRB 
Institutional review board 
IV 
Intravenous  
HGB 
Hemoglobin 
HIV 
Human Immunodeficiency Virus 
HR 
Hazard ratio 
LDH 
Lactate dehydrogenase 
LTFU 
Loss-to-follow-up 
LLT 
Lower Level Term 
LVEF 
Left ventricular ejection fraction 
Max 
Maximum 
MDS 
Myelodysplastic syndrome 
MedDRA 
Medical Dictionary for Regulatory Activities  
MOP 
Manual of Procedures 
 NHL 
Non Hodgkin’s Lymphoma 
 NCI 
U.S. National Cancer Institute 
ODMC 
Operations and Data Management Center 
OHAM 
Office of HIV and AIDS Malignancy 
OHRP 
Office for Human Research Protections 
ORR 
Objective response rate 
OS 
Overall survival 
PCP 
Pneumocystis pneumonia 
PCR 
Polymerase chain reaction 


 
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PD 
Progressive disease 
PFS 
Progression free survival 
PI 
Principal investigator 
PLTs 
Platelets 
PR 
Partial response 
Proc 
Procarbazine 
PS 
Performance status 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SD 
Stable disease 
SGOT 
Aspartate transaminase 
SGPT 
Alanine transaminase 
SOC 
System organ class 
SPD 
Sum of perpendicular diameters  
TB 
Tuberculosis 
ULN 
Upper limit of normal 
VP-16 
Etoposide 
WBC 
White blood cells 
WHO 
World Health Organization 


 
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SITES PARTICIPATING IN THE STUDY 
 
This protocol will be open for participant enrollment at the AMC core sites in Africa named in the 
protocol roster, as approved by the AMC Executive Committee and the protocol leadership for 
participation.  


 
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PROTOCOL ROSTER 
 
Protocol Chair: 
R. Matthew Strother, MD 
Clinical Senior Lecturer 
University of Otago 
Medical Oncologist 
Canterbury Regional Cancer & Blood Service 
Private Bag 4710, Christchurch 8140 New 
Zealand 
Tel: +64 03 364 0230 
Mobile: +64 027 703 3247 
Email: matthew.strother@cdhb.health.nz 
Statistician: 
Jeannette Y. Lee, PhD 
AMC Statistical Center 
University of Arkansas for Medical Sciences 
4301 W. Markham, #781 
Little Rock, Arkansas 72205-7199 
Tel: (501) 526-6712 
Fax: (501) 526-6729 
Email: JYLee@uams.edu 
Protocol Co-Chairs: 
Susan Krown, MD 
AIDS Malignancy Consortium 
P.O. Box 1051 
Planetarium Station 
127 West 83rd Street 
New York, NY 10024 
Email: krowns@mskcc.org 
 
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 & Data Management Center 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD  20850 
Tel: (301) 251-1161 
Fax: (240) 238-2842 
Email: amipm@emmes.com 
 
AMC Study Pathologist: 
Ethel Cesarman, MD, PhD 
Dept. of Pathology and Lab Medicine 
Weill Cornell Medical College 
1300 York Avenue, Room C410 
New York, NY 10065 
Tel: (212) 746-8838 
Fax: (212) 746-4483 
Email: ecesarm@med.cornell.edu 
 
AMC Medical Monitor: 
Ashraf El Fiky, MD 
The Emmes Company, LLC 
401 N. Washington Street, Suite 700 
Rockville, MD  20850 
Tel: (301) 251-1161 
Fax: (240) 238-2842 
Email: amipm@emmes.com 
 


 
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Protocol Team: 
Jackson Orem, MBChB 
Uganda Cancer Institute 
P.O. Box 3935  
Kampala, Uganda 
Tel: +256 414 540605/680467 
Mobile: +256 782 320543 
Fax: +256 414 540410 
Email: jacksonorem@yahoo.co.uk 
 
Webster Kadzatsa MD, MMed   
University of Zimbabwe College of Health 
Sciences 
Radiotherapy and Oncology 
Department of Radiology 
Mazowe Street 
P.O. Box A 178 
Avondale, Harare, Zimbabwe 
Tel:+263712432770 
Fax: +2634706627 
Email: webkad@yahoo.co.uk 
 
Ntokozo Ndlovu, MB ChB, MMed 
University of Zimbabwe College of Health 
Sciences 
Mazowe Street 
P.O. Box A 178 
Avondale, Harare, Zimbabwe 
Tel: +263 4 860032 
Email: nndlovu@mweb.co.zw 
 
Naftali Busakhala, MBChB, MMed 
Moi University School of Medicine, 
Department of Hematology and Oncology 
P.O. BOX 4606 
Eldoret 30100, Kenya 
Tel: +254 722496933 
Email: nbusakhala@yahoo.com 
 
Evangeline Njiru 
Moi University School of Medicine, 
Department of Hematology and Oncology  
P.O. Box 4606 
Eldoret 30100, Kenya 
Tel: +254 722624353 
Email: oyungueva@yahoo.com 
 
Bongani Kaimila, MBBS, MSc 
UNC Project Malawi  
Tidziwe Centre 
100 Mzimba Road, 
Kamuzu Central Hospital 
Private Bag A-104 
Lilongwe 
Malawi 
 
Satish Gopal, MD, MPH 
UNC Project Tidziwe Centre 
100 Mzimba Road 
Kamuzu Central Hospital 
Private Bag A-104 
Lilongwe, Malawi 
Tel: +265-26-517-50610 
Email: gopal@med.unc.edu 


 
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PROTOCOL SYNOPSIS 
 
TITLE: 
Randomized, phase II trial of CHOP vs. oral chemotherapy with concomitant 
antiretroviral therapy in patients with HIV-associated Lymphoma in sub-
Saharan Africa 
DESIGN: 
Open-label, randomized parallel phase II study 
DURATION: 
48 months (24 months for recruitment and 24 months for follow-up) 
SAMPLE SIZE: 
90 evaluable participants (45 participants per arm) 
STUDY 
POPULATION: 
Eligible participants will be 18 years of age or older with documented HIV 
infection, and biopsy-proven, previously untreated, measurable systemic 
diffuse large B-cell lymphoma (DLBCL) 
PRIMARY 
OBJECTIVE: 
To compare the efficacy of standard CHOP and an oral chemotherapy 
regimen for DLBCL in Sub-Saharan Africa with respect to overall survival 
(OS). 
SECONDARY AND 
EXPLORATORY 
OBJECTIVES: 
Secondary Objectives 
1. To compare the objective response rate (ORR) of persons randomized  to 
CHOP and oral chemotherapy 
2. To compare the progression free survival (PFS) of persons randomized to 
CHOP and oral chemotherapy 
3. To compare the safety and tolerance of persons randomized to CHOP and 
oral chemotherapy.   
Exploratory Objectives 
1. To describe the rates of completion of therapy of persons randomized to 
CHOP and oral chemotherapy 
2. To describe adherence to chemotherapy of persons randomized to CHOP 
and oral chemotherapy 
3. To describe adherence to antiretroviral therapy of persons randomized to 
CHOP and oral chemotherapy 
4. To describe the effects of therapy on HIV control, as measured by CD4 
counts and HIV viral load 
5. To investigate correlates of survival. 
TREATMENT 
REGIMEN: 
Patients will be randomized to one of two treatment arms: either standard, 
intravenously delivered CHOP, delivered over six 3-week cycles or oral 
chemotherapy delivered over three 6-week cycles. 
Formal assessment of objective response (complete response [CR]/partial 
response [PR]/stable disease [SD]) will be performed following cycle 6 for 


 
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CHOP and following cycle three for the oral regimen, and the patient will then 
be followed for relapse and survival. Patients found to have progressive 
disease (PD) at any time will come off study and receive the local standard of 
care treatment for their disease. 
 
Regimen A*: 
Cyclophosphamide 
750 mg/m2  IV Day 1, each cycle 
Doxorubicin 
50 mg/m2  IV Day 1, each cycle 
Vincristine 
1.4 mg/m2  IV Day 1, each cycle (max 2.0 mg)  
Prednisone 
100 mg  orally Day 1-5, each cycle 
 
* Please see 5.3.2 for dosing modifications for poor risk patients. 
Regimen B: All chemotherapy drugs are administered orally.  For CCNU, the 
dose should be rounded to nearest 10 mg; and for each of the other drugs 
rounded to nearest 50 mg or 25 mg, depending on how supplied (e.g., for 
calculated dose of 175 may administer 150 mg alternating with 200 mg, if 
only 50 mg tabs/caps available). 
Lomustine (CCNU) 
50 mg/m2 Day 1, cycles 1 and 3 only 
Etoposide (VP-16) 
100 mg/m2 Day 1-3, each cycle 
Cyclophosphamide (CTX) 
100 mg/m2 Day 22-26, each cycle 
Procarbazine (Proc.) 
100 mg/m2 Day 22-26, each cycle 
 
Regimen A: CHOP 
Cycle 
1 
2 
3 
4 
5 
6 
Restage and 
follow 
(CR, PR, SD) 
Day 
1 
2-5 
1 
2-5 
1 
2-5 
1 
2-5 
1 
2-5 
1 
2-5 
CTX 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Dox 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Vinc 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
Pred 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Regimen B: Oral Regimen 
 
 
Cycle 
 
1 (D1) 
Day 42 Cycle 
1 Complete 
2 (D43) 
Day 84 Cycle 
2 Complete 
 
3 (D85) 
Restage 
and follow 
(CR, PR, 
SD) 
Day 
1 
2-3 
22-26 
1-2-3 
22-26 
1 
2-3 
22-26 
CCNU 
X 
 
 
 
 
X 
 
 
VP-16 
X 
X 
 
X 
 
X 
X 
 
CTX 
 
 
X 
 
X 
 
 
X 
Proc. 
 
 
X 
 
X 
 
 
X 


 
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PROTOCOL SCHEMA 
 
 
Eligible Participants: 
HIV+ persons with previously untreated, stage III/IV 
Randomization, Stratified by: 
• Risk Stratum: 
o Poor risk: CD4+ lymphocyte count <100 OR ECOG PS 2 or 3 
o Good risk: CD4+ lymphocyte count ≥100 AND ECOG PS 0 or 1 
CHOP 
Cycle 1-6 
Oral Chemotherapy 
Cycle 1-3 
Tumor 
Measurement 
Follow for OS 
Up to Month 24 


 
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1.0 
BACKGROUND AND RATIONALE 
1.1 
AIDS-Related Non-Hodgkin’s Lymphoma (AR-NHL) 
Approximately 10% of the world population lives in sub-Saharan Africa, but the region is 
home to approximately 68% of the world population living with HIV1. Most countries in 
this region have an HIV prevalence of at least 10% with a number of countries having a 
prevalence that exceeds 20%2. As the AIDS pandemic advances, the burden of related 
neoplastic disease is increasing in developing nations3,4. While under-developed cancer 
registries in sub-Saharan Africa bar a definitive statement being made regarding increases 
in incidence and prevalence in Africa, it is felt that AIDS-Related Non-Hodgkin’s 
Lymphoma (AR-NHL) has rising incidence in this setting.  Investigators involved in this 
study have previously published data that outcomes of AR-NHL are worse than NHL in 
seronegative patients5.  Unfortunately, building on this observation is difficult, as there 
have been few published data on the tolerance and outcomes of treatment for HIV-
associated non-Hodgkin lymphoma (NHL) in sub-Saharan Africa or on the most effective 
treatment regimen(s) in the varied clinical settings that exist within the region. Although 
all of the AMC African trial sites cite CHOP as a “standard of care” for initial treatment of 
HIV-associated NHL, only one, the Uganda Cancer institute (UCI), has published 
information on treatment outcomes. 
The most comprehensive accounting of newly diagnosed NHL, from the UCI and recently 
published by Bateganya et al6, remains limited; between 2004 and 2008 only 51 HIV-
infected patients were identified. Although CHOP chemotherapy was administered to 
approximately two-thirds of all patients, the estimated median survival, even among HIV-
seronegative individuals, was less than 1 year and the authors found no evidence that 
receipt of chemotherapy improved survival.  HIV-positive patients receiving antiretroviral 
therapy had survival rates approximating those of HIV-negative persons, but the adjusted 
hazard of death was significantly elevated among HIV-positive patients not receiving 
antiretroviral therapy [adjusted hazard ratio (HR) 8.99, P < 0.001] compared with HIV-
negative patients. An updated and as yet unpublished analysis (P. Imani and C. Casper, 
Personal Communication, January 2012) showed that of the 37 HIV+ patients in this study 
who received CHOP chemotherapy, 34 received at least 70% of the standard dose. 
However, only 4 of 34 patients received at least 6 cycles of chemotherapy. The estimated 
median survival for all HIV+ patients who received CHOP was approximately 6 months, 
and only one patient was known to be alive at 2 years. Interpreting the reason for the poor 
outcome for both HIV-infected and HIV-uninfected individuals is complicated by a high 
loss to follow-up rate and lack of information on therapy-related complications and causes 
of death7, not to mention issues related to the purity and potency of locally-sourced 
chemotherapeutic agents. 
Except for a single meeting abstract, published data from the other AMC African trial sites 
in Eldoret, Kenya, Harare, Zimbabwe, and Johannesburg, South Africa, are not available, 
but investigators at the sites have provided personal observations. The AMC PI in Eldoret 
stated that while full-dose CHOP is the standard, most patients require dosage reductions 
because of toxicity (Naftali Busakhala, Moi University, Personal Communication). CHOP 
is not given in satellite clinics within the Eldoret clinical network because timely blood 
counts are not available (M. Strother, Indiana University, Personal Communication). Drs. 
Kadzatsa and Ndlovu, from the AMC site in Harare, presented a retrospective analysis of 


 
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their experience in adults with NHL treated from January 2004 to December 2007 at the 
14th National Congress of the South African Oncology Societies held in Cape Town in 
February 2009. Of 127 patients eligible for the study, HIV results were known in only 
67/127 (52.8%) and of these, 55 were positive and 12 were negative. Twenty-five of the 
HIV-positive patients were already on antiretroviral treatment at presentation. High grade 
histology was found in 93/127 patients and was significantly associated with HIV+ 
serology (p<0.001). Clinical stage III was the most common disease stage. Extra-nodal 
disease was found in 29/127 (23%) patients, all of whom were HIV positive. Thirty-two 
patients were considered too ill for active cancer treatment. Of these 32 patients, 20 had an 
unknown HIV status, 10 were positive and 2 negative. Radiotherapy was offered to 33/127 
(26%) patients, 14/127 as a first line treatment. Chemotherapy was offered to 72/127 
patients. Of these, 61 patients had chemotherapy administered with 24/61 patients 
completing 6 cycles and 23/61 receiving less than 3 cycles. Data on response rates, 
response duration and survival were not available.  The investigators noted that prior to the 
widespread availability of antiretroviral therapy (ART) the number of treatment cycles was 
deliberately truncated in many HIV+ patients.  Although data on their experience since the 
widespread roll-out of ART in Zimbabwe (post-2007) are not available, the Zimbabwean 
investigators expressed the opinion that among HIV+ patients receiving concomitant ART, 
most are now able to complete chemotherapy, but data on response rates, response 
durations, or survival are not available. Although there are no published data from the 
University of Witwatersrand in Johannesburg, Dr. Adam Nosworthy, the oncologist 
providing treatment for HIV+ patients with NHL, has noted that at their center, lymphoma 
patients “all have very good outcomes” and remarked that “we are fortunate enough to 
have access to all supportive care including ICU support, growth factors, unlimited 
antibiotic usage and isolation facilities” which are not available at other African centers 
(A. Nosworthy, Personal Communication). 
1.2 
Rationale 
Although the available data on the performance of CHOP in HIV+ patients at AMC sites 
in sub-Saharan Africa are too scant to draw firm conclusions, what little data are available 
suggest that there are factors that may limit CHOP’s optimal activity in resource-
constrained settings. Additionally, studies of cytotoxic systemic therapy for AIDS-
associated and other virus-associated tumors in similar settings report mortality rates 
ranging between 20-66% and the median survival duration for AIDS-related Burkitt’s 
lymphoma is 15 weeks3,5,8,9. Prospective studies are needed to identify factors that have led 
to poorer than expected outcomes in NHL to standard CHOP-based approaches in 
resource-constrained settings and to determine whether these factors can be overcome.  
Concurrent with this effort, we will assess strategies to facilitate safe and effective delivery 
of standard chemotherapy, as well as explore potential alternatives developed specifically 
to avoid the limitations of effective cancer care delivery in resource-constrained settings.   
It is in this context that we propose to test an oral chemotherapy regimen in a randomized, 
phase II study. The regimen we propose to test in parallel with CHOP consists of four 
drugs, lomustine, etoposide, cyclophosphamide, and procarbazine, which were chosen for 
their single-agent activity in NHL, their ability to cross the blood-brain barrier (lomustine 
and procarbazine), and the in vitro antitumor synergy between etoposide, 
cyclophosphamide and nitrosoureas.  In a pilot study in 49 HIV+ NHL patients conducted 


 
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in Kampala, Uganda and Nairobi, Kenya before the widespread availability of ART10, two 
cycles of oral therapy over 12 weeks (intended to approximate 4 cycles of a standard IV 
regimen) induced objective responses in 78% of patients, with median EFS and OS of 7.9 
(95% CI, 3.3-13.0) and 12.3 (95% CI, 4.9-32.4) months, respectively; 33% of patients 
survived 5 years.  Only 18 patients (37%) had access to ART, 63% had poor performance 
status, and 69% had advanced stage disease.  Treatment was well tolerated, with only 4 
episodes of febrile neutropenia and three treatment-related deaths (6%).  Building on these 
promising pilot data, it seems reasonable to pursue the investigation of an oral regimen that 
extends treatment to 3 cycles (approximating 6 cycles of a standard IV regimen) and that 
ensures receipt of ART in all patients. 
The current proposal is justified given the limited outcome data regarding administration 
of IV therapy that is standard-of-care in high resource settings. Although it is technically 
feasible to administer IV therapy, other factors, such as differences in adherence, a limited 
ability to manage adverse events, or exposure to nosocomial pathogens such as tuberculosis 
may diminish the efficacy of CHOP in a resource-limited setting and render it less effective 
than an oral therapy.  Conducting a randomized, phase II trial should help to identify some 
of these issues and point the way forward toward the development of future trials.   
1.3 
Study Design 
This is a randomized phase II trial for HIV-associated diffuse large B-cell lymphoma 
(DLBCL) to compare CHOP and an oral chemotherapy regimen in terms of efficacy and 
tolerability. 
Population 
HIV-positive adults with measurable, advanced stage (stage III/IV) systemic DLBCL who 
have not received prior NHL treatment.  
Randomization 
Randomization will be performed by the AMC Operations and Data Management Center 
(ODMC) at the time of participant registration in AdvantageEDC. Stratification factors 
will include: 
1. CD4+ lymphocyte count < 100 OR ECOG PS 2 or 3 (poor risk stratum), vs. CD4+ 
lymphocyte count ≥100 AND ECOG PS 0 or 1 (good risk stratum). 
2. By country/trial site. 
All participants will be randomized. However, sites will be permitted to enroll study 
participants into both risk strata, or may elect to enroll participants in only the poor-risk 
stratum. Sites electing to enroll and randomize only participants in the poor-risk stratum 
will treat good risk patients according to their local standard of care. 
On 30 November 2018, the study was closed to further accrual because of slow enrollment. 
Participants on study at the time of study closure to accrual will continue to be followed 
for up to 2 years following treatment discontinuation. 
1.4 
Correlative Study Background 
Previous work with this oral combination chemotherapy in AR-NHL has shown the 
chemotherapy regimen did not adversely affect the underlying HIV infection11. This is 


 
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consistent with other results that have failed to show an effect of anti-neoplastic 
chemotherapy on virologic control of HIV12. However, given the study setting, in which 
many programs have limited options of ART, it is particularly relevant to determine the 
effect of the treatment of AR-NHL on HIV control; therefore, we will follow HIV viral 
loads, along with assessments of ART adherence while participants are on protocol. 


 
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2.0 
STUDY OBJECTIVES 
2.1 
Objectives 
2.1.1 Primary Objective 
To compare the efficacy of standard CHOP and an oral chemotherapy regimen for 
HIV-associated DLBCL in Sub-Saharan Africa with respect to overall survival 
(OS). 
2.1.2 Secondary Objectives 
2.1.2.1 To compare the objective response rate (ORR) of persons randomized to 
CHOP and oral chemotherapy. 
2.1.2.2 To compare the progression free survival (PFS) of persons randomized to 
CHOP and oral chemotherapy. 
2.1.2.3 To compare the safety and tolerance of persons randomized to CHOP and 
oral chemotherapy. 
2.1.3 Exploratory Objectives 
2.1.3.1 To describe the rates of completion of therapy of persons randomized to 
CHOP and oral chemotherapy. 
2.1.3.2 To describe adherence to chemotherapy of persons randomized to CHOP 
and oral chemotherapy. 
2.1.3.3 To describe adherence to antiretroviral therapy of persons randomized to 
CHOP and oral chemotherapy. 
2.1.3.4 To describe the effects of therapy on HIV control, as measured by CD4 
counts and HIV viral load. 
2.1.3.5 To investigate correlates of survival. 


 
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3.0 
PARTICIPANT SELECTION 
All protocol participants must meet 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. 
3.1 
Inclusion Criteria 
3.1.1 Ability to understand and the willingness to provide informed consent to 
participate. 
3.1.2 Adults, 18 years of age or older. Date of birth and age should be determined based 
on the best possible information or source documentation available.  
3.1.3 HIV-1 infection, documented by any licensed rapid HIV test or HIV enzyme or 
chemiluminescence immunoassay (E/CIA) test kit at any time prior to study entry 
and confirmed by a licensed Western blot or a second antibody test by a method 
other than the initial rapid HIV and/or E/CIA, or confirmed by HIV-1 antigen or 
plasma HIV-1 RNA viral load > 1,000 copies/mL. 
NOTE: The term “licensed” refers to a U.S. FDA-approved kit or for sites located 
in countries other than the United States, a kit that has been certified or licensed by 
an oversight body within that country and validated internally.  
WHO (World Health Organization) and CDC (Centers for Disease Control and 
Prevention) guidelines mandate that confirmation of the initial test result must use 
a test that is different from the one used for the initial assessment. A reactive initial 
rapid test should be confirmed by either another type of rapid assay or an E/CIA 
that is based on a different antigen preparation and/or different test principle (e.g., 
indirect versus competitive), or a Western blot or a plasma HIV-1 RNA viral load. 
3.1.4 Biopsy-proven, systemic DLBCL with a proliferation rate ≤90%, that has been 
confirmed 
by 
an 
AMC-approved 
site 
pathologist 
using 
H&E 
and 
immunohistochemical stains as defined in Appendix III. If a hard copy of the 
pathology report is unavailable at the time of enrollment into the Screening 
Segment, a verbal report by the pathologist confirming the diagnosis must be 
documented in the medical chart. A hardcopy of the pathology report must be 
available prior to randomization (enrollment into the Treatment Segment). Note: 
Measurable disease is not an entry requirement. See section 8.0 for response 
assessments with and without measurable disease. 
3.1.5 Pathology slides from tumor tissue obtained by surgical excision or core biopsy 
must be reviewed by the designated site pathologist, or backup pathologist, prior to 
study entry. Confirmation of the diagnosis must be documented by the AMC-
approved pathologist prior to study entry. Please reference the AMC-068 MOP for 
further instructions on documenting the diagnosis. 
The site pathologist for NHL must be approved through the AMC’s EQA process. 
3.1.6  Participants must have fifteen blank (unstained) slides or a diagnostic tissue block 
must be available for external quality assurance by the AMC Core Pathology 
Laboratory (see Appendix III for instructions on preparation and submission of 


 
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materials for external quality assurance). 
 
3.1.7 ECOG performance status of 0 - 3 within 7 days of enrollment (Appendix II). 
3.1.8 Participants must have an estimated life expectancy of > 6 weeks.  
3.1.9 The following acceptable end organ function/laboratory parameters within 7 days 
prior to enrollment: 
• Hematologic (Participants may enroll with lower hematologic values, if bone 
marrow involvement is documented. In this case, patients should be transfused 
to hemoglobin ≥ 8 g/dL): 
o WBC ≥ 3,000 cells/µL (3.0 x 109 L) or absolute granulocytes ≥ 1500 
cells/μL (1.5 x 109 L); 
o Platelets ≥ 100,000 cells/μL (75 x 109 L); and, 
o Hemoglobin ≥ 8 g/dL (5.0 mmol/L) 
• Renal – estimated creatinine clearance of >50 ml/min (0.84 mL/s) by the 
Cockcroft-Gault equation; and  
• Hepatic 
o Total bilirubin ≤ 1.5 times the institutional upper limit of normal (ULN), 
unless elevated secondary to lymphomatous involvement of liver or biliary 
system, or due to other HIV medications (e.g., indinavir, tenofovir, or 
atazanavir). If secondary to lymphomatous involvement, an initial upper 
limit of total bilirubin 5 mg/dL (85.5 μM/L) should be utilized - for direct 
bilirubin > 1.2 mg/dL (20.5 μM/L) see section 5.5.2 for the initial dose of 
CHOP drug adjustment 
o AST/ALT < 2.5 times the institutional ULN (unless elevated secondary to 
lymphomatous involvement of the liver, in which case the AST/ALT must 
be ≤ 5 times the institutional ULN) 
3.1.10 Participants must have a lumbar puncture with negative cerebral spinal fluid 
cytology within 4 weeks prior to enrollment.  
3.1.11 All participants must be prescribed combination antiretroviral therapy with the goal 
of virological suppression using an acceptable regimen that adheres to national 
guidelines for treatment of HIV infection. Non-suppressed, treatment experienced 
patients, defined as patients with a viral load > 400 copies/mL who have been on 
antiretroviral therapy for more than 4 months can be enrolled if an alternative ART 
regimen is available that includes at least two ART drugs that, in the opinion of the 
site investigator, are expected to have activity based on genotypic testing (if 
available) and treatment history. Patients are not allowed to receive zidovudine 
(AZT) as part of concurrent chemotherapy and ART regimen, since it is 
myelosuppressive. Zidovudine may be discontinued and substituted as clinically 
indicated prior to or at the time of enrollment. 
3.1.12 Participants of childbearing potential, defined as a sexually mature woman who: 1) 
has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been 
naturally postmenopausal for at least 24 consecutive months (i.e., has had menses 
at any time in the preceding 24 consecutive months), must have a pregnancy test 


 
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within 7 days prior to enrollment and agree to use an effective form of contraception 
(e.g., barrier contraception, highly effective hormonal contraception). 
3.1.13 Participants must, in the opinion of the investigator, be capable of complying with 
the protocol. 
3.1.14 Participants must be able to take oral medications. 
3.1.15 Participants must have a CD4 count performed within 30 days of enrollment. 
3.2 
Exclusion Criteria 
3.2.1 Inability to provide informed consent. 
3.2.2 Participants who received any lymphoma directed chemotherapy or radiotherapy 
with the exception of a single dose of intrathecal chemotherapy given at the time of 
the diagnostic lumbar puncture (spinal tap.) Patients who received chemotherapy 
or radiotherapy for Kaposi’s sarcoma > 2 years prior to study enrollment are 
allowed as long as the prior treatment did not include doxorubicin in its non-
liposomal form. Prior exposure to liposomal doxorubicin is allowed. Prior exposure 
to intrathecal therapy given as prophylaxis within 30 days is allowed.  
3.2.3 Participants who received greater than 10 days of corticosteroids in doses greater 
than physiologic replacement in the preceding 30 days prior to enrollment. 
Physiologic dosing of steroid is 4-5 mg/m2/day prednisone, 0.03-0.15 mg/kg/day 
dexamethasone, or 0.5-0.75 mg/kg/day hydrocortisone.  Contact the AMC Protocol 
Team for physiologic dosing limits for other corticosteroids. 
3.2.4 Participants with evidence for CNS lymphoma on neurological exam and/or with 
radiographic evidence (if radiographic studies are done) of CNS lymphoma 
(inclusive of parenchymal, vitreal, or leptomeningeal involvement). 
3.2.5 Participants with active infection(s) for which they are receiving drug treatment 
unless the clinical status is judged to be stable and survival is estimated to be at 
least 6 weeks. 
3.2.6 A medical or psychiatric illness that precludes ability to give informed consent or 
is likely to interfere with the ability to comply with the protocol stipulations. 
3.2.7 Participants with circumstances that will not permit completion of the study or 
required follow-up. For instance, if travel to and from treatment site is an issue. 
3.2.8 Pregnant or breastfeeding 
3.2.9 Inability to swallow oral medications 
3.2.10 Participants with known congestive heart failure (CHF). If known, patients with 
left ventricular ejection fraction (LVEF)  <40% are excluded.  
3.3 
Number of Participants to be Enrolled 
The study was planned to enroll 90 evaluable participants (45 on each treatment arm). The 
study was terminated on 30NOV2018 after enrolling 7 participants. For the purposes of 
this study evaluable participants are those defined as participants who initiate study 
treatment. Participants who are enrolled and fail to initiate study treatment will be replaced. 


 
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3.4 
Accrual Targets 
Accrual Targets 
Ethnic Category 
Sex/Gender 
Female 
 
Male 
 
Total 
Hispanic or Latino 
0 
+ 
0 
= 
0 
Not Hispanic or Latino 
45 
+ 
45 
= 
45 
Ethnic Category: Total of all 
subjects 
45 (A1) 
+ 
45 (B1) 
= 
90 (C1) 
Racial Category 
 
American Indian or Alaskan Native 
0 
+ 
0 
= 
0 
Asian 
0 
+ 
0 
= 
0 
Black or African American 
45 
+ 
45 
= 
90 
Native Hawaiian or other Pacific 
Islander 
0 
+ 
0 
= 
0 
White 
0 
+ 
0 
= 
0 
Racial Category: Total of all 
subjects 
45 (A2) 
+ 
45 (B2) 
= 
90 (C2) 
 
(A1 = A2) 
 
(B1 = B2) 
 
(C1 = C2) 
3.4.1 Accrual Rate 
It is estimated that accrual will be 3-4 patients/month for duration of 24 months to 
obtain a sample size of 90 evaluable total patients. 
3.5 
Study Enrollment Procedures  
This study will be available for enrollment at the African AMC sites. Sites must have this 
protocol approved by their Institutional Review Boards (IRB), national regulatory 
authority (where required) and be registered with the AMC Operations and Data 
Management Center (ODMC) before they may enroll participants. Protocol registration 
instructions and forms will be made available on the AMC Operations website 
(www.amcoperations.com). Participating sites may not order study drugs until protocol 
registration with the AMC ODMC is complete. 
3.5.1 Registration for Screening 
After an informed consent form has been signed by the participant, the participant 
must be registered for screening (AMC-068, Screening Segment) on-line via the 
AMC AdvantageEDCSM Internet Data Entry System. After successful registration 
into the screening segment, the participant will receive a nine-digit participant ID 
and will then enter the screening process (Screening and Pre-entry visits). 
Participants will be enrolled on-line via the AMC Internet Data Entry System no 
more than 4 weeks prior to the initiation of treatment. Once the eligibility checklist 
is submitted, a system-generated confirmation will be sent to the site staff, AMC 
ODMC, and Protocol Chair upon successful registration.  
Please reference the AMC-068 MOP for additional details regarding the required 
tests prior to enrollment in the screening segment. 


 
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If the on-line system is inaccessible for Screening Registration (Screening 
Segment), 
the 
site 
should 
notify 
the 
AMC 
ODMC 
via 
email 
at 
amipm@emmes.com or via phone at 1-301-251-1161 for further instructions. 
Please refer to the AMC-068 MOP for additional instructions. 
3.5.2 Enrollment and Randomization 
After a written pathology report confirming the lymphoma diagnosis is available, 
the participating site will complete the protocol-specific eligibility checklist and 
enroll the participant into the AMC-068 Treatment Segment on-line via the AMC 
AdvantageEDC
SM Internet Data Entry System. The participating site will ensure the 
participant meets all eligibility criteria prior to completing the protocol-specific 
eligibility checklist. Participants will be enrolled on-line via the AMC Internet Data 
Entry System 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 will be sent to the site staff, 
AMC ODMC, and Protocol Chair with the participant’s randomization assignment 
upon successful registration.  
If the on-line system is inaccessible for Randomization Registration (Treatment 
Segment), 
the 
site 
should 
notify 
the 
AMC 
ODMC 
via 
email 
at 
amipm@emmes.com or via phone at 301-251-1161 for further instructions. 
3.6 
Required Pathology Material and Data 
Local pathology must be performed according to local standard procedures to confirm the 
diagnosis of non-Hodgkin’s lymphoma. The local pathology review must be done prior to 
enrollment to confirm participant eligibility. Appropriate pathology reports from the 
participating institution are required to be maintained as source documents.  
An external quality assurance will be performed according to Appendix III. The purpose 
of the external quality assurance is to provide a consistent review and confirmation of the 
diagnosis and histology of DLBCL for all study participants, and to build diagnostic 
pathologic capacity at the participating institutions. This requirement applies to all cases, 
regardless of the country in which the participant is enrolled. 


 
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4.0 
CLINICAL AND LABORATORY EVALUATIONS 
Please see Appendix I, Schedule of Evaluations, for a tabular schedule. 
The designated study personnel at each site will explain the study to the participant. The 
informed consent document will be given/read to the participant in the local language(s) 
(this will be English or a language understandable to the participant and/or his/her 
representative), and a copy given to the participant. Once a participant’s questions have 
been answered the participant will sign the informed consent document if the participant 
wishes to participate.  
All patients will undergo thorough physical examination with assessment of involved sites 
of disease including thorough tumor measurement (including assessment of extranodal 
sites of disease that can be determined on physical examination), bone marrow aspiration 
biopsy, and cerebrospinal fluid analysis to exclude leptomeningeal disease. If lumbar 
puncture is to be performed there should be no CNS mass/lesion by CT scan or suggested 
by clinical exam. On-study staging chest radiograph, abdominal ultrasound and CT scans 
of the chest, abdomen and pelvis (the latter if available and can be done within the time 
period for study entry) are required. 
Response criteria will be aligned with conventional response criteria for lymphoma (36, 
37), outlined in section 8.0. Clinical CR will be allowed in situations where radiographic 
studies were done at the time of initial on-study evaluation and cannot be repeated due to 
costs or other reasons. 
4.1 
Baseline Evaluations 
4.1.1 Medical history, history of drug allergies, history of current and past anti-retroviral 
regimens, if available, review of concomitant medications; and history of any prior 
AIDS-defining conditions. Date of the initial lymphoma diagnosis is required with 
a copy of the pathology report. The presence or absence of systemic “B” symptoms 
should be noted, as well as other symptoms of NHL. 
4.1.2 Physical exam including performance status, vital signs (height, weight, pulse, 
blood pressure, temperature, and body surface area), a neurologic exam and tumor 
measurements must be assessed within 48 hours of initiating therapy. Tumor 
measurements refers either to bi-dimensional (long axis and short axis) 
measurement on CT imaging or physical measurement (long axis and short axis) of 
palpable disease. Patients must not have clinical signs of CNS involvement by 
neurologic exam at time of enrollment. 
4.1.3 All baseline blood work should be done within 1 week (7 days) prior to treatment 
unless otherwise specified, and will suffice as Day 1 pretreatment laboratory tests. 
Results from baseline blood work must be clinically appropriate for participant to 
receive treatment. NOTE: If laboratory tests performed to determine eligibility has 
been performed within the timeframe required for baseline, they do not need to be 
repeated.   
4.1.4 Complete blood count (CBC) with differential and platelet count. 
4.1.5 Electrolyte panel (sodium, potassium,  chloride) with creatinine. 
4.1.6 Serum chemistries to include: SGOT (AST) or SGPT (ALT); total bilirubin; 


 
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albumin; uric acid; and lactate dehydrogenase (LDH). 
4.1.7 Women of child bearing potential must have a negative urine pregnancy test within 
48 hours prior to Day 1 and Day 22 for all cycles of treatment in the oral regimen 
and prior to Day 1 for all cycles of the CHOP regimen. 
4.1.8 Chest radiograph, abdominal ultrasound and CT scan of chest, abdomen and pelvis 
must be done within 4 weeks prior to initiation of therapy. Imaging within 2 weeks 
prior to the initiation of therapy is preferred. 
4.1.9 Bone marrow core biopsy, with or without aspiration, will be performed in all 
patients at baseline. Bilateral biopsies are encouraged, but not required. This should 
be done within 4 weeks of the first treatment, although results need not be reported 
before treatment. If the bone marrow is initially involved with lymphoma, it must 
be repeated in patients thought to have clinical CR at the time of restaging or 
treatment completion.  
4.1.10 HIV-1 plasma RNA viral load is to be performed within 1 week prior to treatment. 
HIV-1 RNA plasma level will be measured by RNA PCR. (Results need not be 
reported before treatment.) 
4.1.11 A lumbar puncture with cell count, total protein, cytology and flow cytometry 
(where available) must be completed within 4 weeks prior to enrollment. Results 
are required prior to study enrollment.  
4.2 
Evaluations During Treatment 
The time frames for evaluations exclude the assessments performed at baseline (refer to 
section 4.1). Except as noted in the Schedule of Evaluations, Appendix I, evaluations 
during treatment must be performed on Cycle 1, Days 1* and 22, Cycle 2 Days 1 and 22, 
and Cycle 3 Days 1 and 22 for participants on the oral regimen and on Cycle 1, Day 1*, 
Cycle 2, Day 1, Cycle 3, Day 1, Cycle 4, Day 1, Cycle 5, Day 1, and Cycle 6, Day 1 for 
participants receiving IV CHOP). 
*Cycle 1, Day 1 can be combined with the baseline/eligibility assessments if they are 
completed within the allowable window. Cycle 1, Day 1 labs and assessments must be 
performed within 7 days prior to treatment initiation, with the exception of imaging.  
Imaging is encouraged to be done as closely as possible prior to Cycle 1, Day 1, but must 
be performed within 28 days prior to Cycle 1 Day 1.   
At any time if progression of disease has been unequivocally documented on the basis of 
physical exam findings, the participant will be considered off study therapy and should be 
followed for survival only. 
If progression of disease by physical exam is suspected but not confirmed,  the investigator 
can either perform a radiographic assessment to confirm the response status or can continue 
therapy and evaluate prospectively. 
4.2.1 Physical examination (including weight) and clinical tumor measurements are to 
be performed within the 48 hours prior to Day 1 (oral regimen and IV CHOP) and 
Day 22 (oral regimen only) of each chemotherapy cycle. 
4.2.2 CBC, differential, and platelet counts are to be performed within the 48 hours prior 


 
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to Day 1 (oral regimen and IV CHOP) and Day 22 (oral regimen only) of each 
chemotherapy cycle. 
4.2.3 Serum creatinine and total bilirubin are to be performed within the 48 hours prior 
to Day 1 (oral regimen and IV CHOP) and Day 22 (oral regimen only) of each 
chemotherapy cycle. 
4.2.4 Electrolyte panel; SGOT (AST) or SGPT (ALT); albumin; uric acid; and lactate 
dehydrogenase (LDH) are performed within the 48 hours prior to Day 1 (oral 
regimen and IV CHOP) and Day 22 (oral regimen only) of each chemotherapy 
cycle. 
4.2.5 Women of child bearing potential must have a negative urine pregnancy test within 
48 hours prior to Day 1 and Day 22 of each chemotherapy cycle prior to treatment. 
4.2.6 ART adherence assessment. See Appendix I, Schedule of Evaluations for required 
time points. Sites are encouraged to do this immediately prior to study drug 
administration. Please see the AMC-068 MOP for additional details.)   
4.2.7 Review of interim medical history including concomitant medications and adverse 
events. 
4.2.8 Oral study drug adherence assessment consisting of a review of returned bottles, 
pill count, participant interview and review of the study drug diary (where 
appropriate). See Appendix I, Schedule of Evaluations for required time points. 
4.3 
Evaluations at the Completion of Chemotherapy 
Unless otherwise noted, all evaluations will be performed +/- 7 days of completing the final 
cycle of chemotherapy (completion of the cycle includes the days of the cycle with no 
treatment). All participants must have these assessments at the completion of 
chemotherapy, regardless of the reason for treatment discontinuation. Participants 
discontinuing treatment due to toxicity should be followed until the toxicity resolves or 
through the end of study follow-up. 
4.3.1 The following laboratory tests are required: CBC with differential and platelet 
count; electrolyte panel and creatinine; SGOT (AST) or SGPT (ALT); total 
bilirubin; albumin; uric acid; and lactate dehydrogenase (LDH). 
4.3.2 CD4+ lymphocyte count. 
4.3.3 HIV-1 RNA plasma level.  
4.3.4 Complete re-staging will be performed within the 4 weeks following completion of 
chemotherapy. Imaging studies, including abdominal ultrasound and CT scans, 
which showed evidence of disease at baseline, are to be repeated at this time. When 
clinically indicated, fine needle aspiration or open biopsy confirmation should be 
performed to reconcile equivocal disease status. If the participant has clearly 
progressed based on clinical examination, it is not necessary to conduct imaging 
studies at this visit. 
If a biopsy is performed for assessment of tumor recurrence or tumor persistence, 
pathology slides from tumor tissue obtained by surgical excision or core biopsy 
must be submitted for external quality assurance by the AMC Core Pathology 


 
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Laboratory (see Appendix III for instructions on preparation and submission of 
materials for external quality assurance). Fifteen blank (unstained) slides or a 
diagnostic tissue block must be submitted. 
4.3.5 If pre-treatment bone marrow biopsy showed lymphoma, a repeat bone marrow 
biopsy will be performed for re-staging following the completion of chemotherapy 
in participants thought to be in a clinical CR. 
4.3.6 ART adherence assessment 
4.3.7  Oral study drug adherence assessment consisting of a review of returned bottles, 
pill count, participant interview and review of the study drug diary (where 
appropriate). 
4.4 
Follow-up Evaluations 
Participants must be followed for 2 years or until death, whichever occurs first. All follow-
up time points for post-treatment evaluations should be calculated in reference to the 
treatment discontinuation visit. Participants are to be followed at 3 and 6 months (+/-14 
days) after the treatment discontinuation visit and then every 6 months for a total of 2 years 
(at 12, 18, and 24 months, +/- 28 days) with documentation of clinical and disease status 
(e.g., continuing in remission, relapse, or progression of disease), and performance status 
by exam. Restaging assessments such as imaging and bone marrow biopsy are at the 
discretion of the treating physician.  
4.4.1 For participants who have not progressed, the following assessments are required 
at 3, 6, 12, 18, and 24 months unless otherwise noted. 
• 
CD4+ lymphocyte count 
• 
HIV-1 RNA plasma viral load 
• 
Physical examination (including vitals and ECOG PS score), including 
neurological examination 
• 
Review of interim medical history, including adverse events and concomitant 
medications. Only adverse events that are possibly, probably, or definitely 
related to a study drug and those specified in Section 6.0 must be reported. 
Only concomitant medications administered to treat reportable adverse events 
and second line therapies for DLBCL must be reported 
• 
CT imaging will be repeated at 6, 12, 18, and 24 months. Other imaging 
modalities can be employed off-study, as appropriate and at the discretion of 
the treating physician, at other time points. If the participant has clearly 
progressed based on clinical examination, it is not necessary to conduct 
imaging studies at this visit. 
• 
Biopsy confirmation of relapse is required, if clinically feasible, if it occurs 
within the first 2 years of completing treatment. If a biopsy is performed for 
assessment of tumor recurrence or tumor persistence, pathology slides from 
tumor tissue obtained by surgical excision or core biopsy must be submitted 
for external quality assurance by the AMC Core Pathology Laboratory (see 
Appendix III for instructions on preparation and submission of materials for 


 
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external quality assurance). Fifteen blank (unstained) slides or a diagnostic 
tissue block must be submitted. 
4.4.2 Second line therapy is not provided as part of the protocol.  If participants receive 
additional treatment, the treatment regimens should be documented during the 2-
year follow-up period. Adverse event information regarding second-line therapies 
will not be collected. Participants will be followed only for vital status, adverse 
events related to study treatment, and a recording of the second-line and subsequent 
regimens which fall within the 2-year window following completion of protocol 
treatment. 
4.4.3 Participants who have progressed either on study or during the 2-year follow-up 
will be followed for overall survival, Grade 2 and greater adverse events related to 
study treatment, and additional treatment regimens only, for the duration or 
remainder of follow-up. This can be done by phone, mail or other contact. 
4.4.4 Participants who received the oral regimen who show disease progression, or who 
subsequently show relapse after a prior response, should be offered CHOP or a 
CHOP-like regimen off study if medically appropriate. If the participant is not 
offered CHOP, the reason for not doing so must be documented in the source. If 
the participant is offered CHOP and does not receive it, the reason must be 
documented in the source.  
4.4.5 Participants are followed for OS as primary endpoint. Causes of death need to be 
documented and categorized as either progressive HIV disease/AIDS; progressive 
lymphoma; or death from other causes. 
4.5 
Final Evaluations, Off Study 
4.5.1 The participant is considered off-study (a) upon reaching two years of follow-up 
from discontinuation of treatment, or (b) death, or (c) the participant withdraws 
consent, or (d) is lost to or refuses follow-up. Lost to follow-up will be defined for 
this purposes of this study as 12 months of inability to contact or determine the 
participant’s vital status, in spite of at least 3 documented attempts to contact the 
participant. The final study visit evaluation will include clinical and disease status 
(e.g., continuing in remission, relapse or progressive disease and residual treatment-
related toxicity). 
4.6 
Procedures in the Event of Contraceptive Failure 
In the event of contraceptive failure, the use of an emergency contraceptive is an option. A 
levonorgestrel-only emergency contraceptive (i.e., Plan B) is preferred to minimize the 
occurrence of nausea, which may interfere with adherence to protocol medications. 
Combined ethinyl estradiol/levonorgestrel emergency contraceptive is, however, an 
acceptable option if a levonorgestrel-only emergency contraceptive is unavailable. 
Emergency contraceptives will not be provided by the AMC.  
4.7 
Procedures in the Event of On-Study Breastfeeding or Pregnancy 
Female participants who become pregnant or initiate breastfeeding while on protocol 
treatment must immediately discontinue protocol treatment. Participants will continue to 
be followed for the remainder of the study visit schedule and procedures. AMC-068 will 


 
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not provide perinatal care for women. Women who become pregnant will be referred to 
local clinics and/or other research studies for prenatal and postpartum care.  
Pregnancy reporting and outcomes will be documented by completion of the appropriate 
eCRFs. 


 
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5.0 
TREATMENT PLAN  
5.1 
Study Drugs 
5.1.1 CHOP (IV) 
5.1.1.1 Cyclophosphamide 
Cyclophosphamide is an alkylating agent and is cell cycle nonspecific. It 
causes cross-linking of DNA and is the most active single agent in the 
treatment of non-Hodgkin’s lymphoma.  
• Common side effects and toxicity: 
o Nausea and vomiting 
o Myelosuppression 
o Alopecia 
o Sterility and testicular atrophy are common in men and amenorrhea 
is seen in women. 
o Hemorrhagic cystitis is caused by metabolites of cyclophosphamide 
excreted through the urine. Bladder irritation can be reduced by 
adequate hydration.  
• Please refer to the approved package insert for complete prescribing and 
toxicity information. 
• Source of study medication: Study medication will be provided by the 
AMC. 
• Study medication formulation: 500 mg vial lypholized powder 
• See the AMC-068 MOP for preparation instructions.   
• Storage and stability: Store at or below 25°C (77°F). 
5.1.1.2 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. 
• Special precautions: Doxorubicin is given intravenously and is a 
vesicant causing severe local necrosis at the site of injection if 
extravasation occurs.  
• Common side effects and toxicity: 
o Myelosuppression 
o Nausea and vomiting 
o Alopecia 
o Stomatitis, which is dose related and may be severe  
o 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.  
• Please refer to the approved package insert for complete prescribing and 
toxicity information. 
• Source of study medication: Study medication will be provided by the 
AMC. 


 
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• Study medication formulation: 50 mg/25 ml vial 
• Storage and stability: Store unreconstituted vial at controlled room 
temperature, 15°C to 30°C (59°F to 86°F). Protect from light. Retain in 
carton until time of use. Discard unused portion.  
5.1.1.3 Vincristine Sulfate 
Vincristine sulfate is a vinca alkaloid from the plant Cantharanthus roseus. 
It acts by binding to or crystallizing microtubular proteins of the mitotic 
spindle. It is a cell cycle phase specific agent and can also affect DNA-
directed RNA polymerase. It has a triphasic half-life and primary 
elimination is by the liver into the bile and feces.  
• Common side effects and toxicity: 
o The major and dose-limiting side effect of vincristine is 
neurotoxicity. The main manifestation is a mixed sensorimotor 
peripheral neuropathy.  
o Reduction or loss of deep tendon reflexes, paresthesias, weakness, 
myalgias and motor disturbances may occur.  
o Autonomic toxicity also occurs which may cause constipation, 
obstipation, abdominal cramps and ileus.  
o Mild myelosuppressive effects  
o Special precautions: Vincristine is given intravenously and is a 
vesicant causing severe local necrosis at the site of injection if 
extravasation occurs.  
• Please refer to the approved package insert for complete prescribing and 
toxicity information.  
• Source of study medication: Study medication will be provided by the 
AMC. 
• Study medication formulation: 1 mg/ 1 mL vial 
• Storage and stability: Store refrigerated between 2°C - 8°C (36°F - 
46°F). Discard unused solution. Protect from light. Store upright. 
5.1.1.4 Prednisone 
Prednisone is a corticosteroid and its mechanism of action as a cytotoxic 
agent is not clearly understood.  
• Common side effects and toxicity 
o Short-term use produces minimal side effects but prolonged use is 
associated 
with 
hypertension, 
hyperglycemia, 
myopathy, 
osteoporosis, pancreatitis, and immunosuppression. Alterations in 
mood and insomnia are common acute side effects.  
• Please refer to the approved package insert for complete prescribing and 
toxicity information. 
• Source of study medication: Study medication will be provided by the 
AMC. 
• Study medication formulation: 50 mg tablets 
• Storage and stability: Store at controlled room temperature between 20° 


 
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to 25°C (68° to 77°F) 
5.1.2 Oral Regimen 
5.1.2.1 Lomustine 
• Other name(s) and abbreviation: CeeNU, CCNU 
• Mechanism of action: Alkylation and carbamylation by lomustine 
metabolites interfere with the synthesis and function of DNA, RNA and 
proteins. 
• Metabolism and excretion: lipid soluble and easily enters the CNS. 
Rapidly metabolized into toxic products. Fifty percent of products in 
blood are bound to plasma protein. Most of the intact drug and 
metabolites are excreted in urine. Some products have an entero-hepatic 
cycle, 
• Usual dosage and schedule: 100-130 mg/m2 orally every 6 to 8 weeks 
(lower dose used for patients with compromised bone marrow function). 
• Special precautions: Because of delayed myelosuppression (3-6 weeks), 
do not treat more than every 6 weeks. Await return of normal platelet 
and granulocyte counts before repeating therapy. 
• Common side effects and toxicity: 
o Myelosuppression – universal and dose-limiting. Leukopenia and 
thrombocytopenia are delayed 3 to 6 weeks after therapy begins and 
may be cumulative with successive doses. 
o Nausea and vomiting – may begin 3 to 6 hours after oral dose and 
may last up to 24 hours. 
o Stomatitis and alopecia are rare. 
o Additional side effects – confusion, lethargy and ataxia are rare. 
Mild hepatoxicity is infrequent. Secondary neoplasia is possible. 
• Source of study medication: Study medication will be provided by the 
AMC. 
• Study medication formulation: 10 mg capsules 
• Storage and stability: Store at room temperature in well closed 
containers. Avoid excessive heat (over 40° C or 104° F). 
5.1.2.2 Cyclophosphamide 
• Other name(s) and abbreviation: Cytoxan, CTX 
• Mechanism of action: metabolism of cyclophosphamide by hepatic 
microsomal enzymes produces active alkylating metabolites. Primary 
effect is alkylation of DNA with resultant inhibition of DNA synthesis. 
• Metabolism and excretion: The native drug is inactive and must be 
activated by the hepatic microsomal oxidase system. Drugs that induce 
microsomal enzymes (e.g., barbiturates, griseofulvin) may enhance 
toxicity, liver disease may decrease toxicity. Native drug is not protein 
bound, but active metabolites are 50% bound. Active metabolites are 
excreted in the urine. 
• Usual dosage and schedule: 1000-1500 mg/m2 intravenously every 3 to 


 
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4 weeks; 60-120 mg/m2 orally daily; and 100 mg/m2 daily for 2 weeks 
with a repeat cycle every 4 weeks. 
• Special precautions: Adequate fluid hydration, oral or intravenous, must 
be maintained and have patient empty bladder several times daily to 
diminish 
likelihood 
of 
hemorrhagic 
cystitis. 
Metabolites 
of 
cyclophosphamide are injurious to bladder urothelium. 
• Common side effects and toxicity:  
o Myelosuppression – is dose-limiting. Platelets are relatively spared. 
Granulocyte nadir is about 10-14 days after IV dose with recovery 
by day 21. 
o Nausea and vomiting are seen frequently with large intravenous 
doses; less commonly after oral doses. Symptoms begin several 
hours after treatment and usually subside by the next day. 
o Reversible alopecia is common. Skin and nails may become darker. 
Mucositis is uncommon. 
o Bladder – hemorrhagic or non-hemorrhagic cystitis may occur in 5-
10% of patients treated. It is usually reversible on discontinuation of 
the drug, but it may persist and lead to fibrosis or death. Frequency 
is diminished by ample fluid intake and voiding of the bladder. 
o Additional side effects – immunosuppression, amenorrhea, and 
azoospermia are common. Inhibition of antidiuretic hormone is only 
of significance with very large doses. Interstitial pulmonary fibrosis 
is rare. Secondary neoplasia is possible. 
• Source of study medication: Study medication will be provided by the 
AMC. 
• Study medication formulation: 50 tablets 
• Storage and stability: Storage at or below 77°F (25°C) is recommended; 
this product will withstand brief exposure to temperatures up to 86°F 
(30°C) but should be protected from temperatures above 86°F (30°C). 
5.1.2.3 Etoposide 
• Other name(s) and abbreviation: Vepesid, epipodophyllotoxin, VP-
16-213, VP-16  
• Mechanism of action: Induce DNA strand breaks by inhibition of 
topoisomerase II, a DNA reparative enzyme.  
• Metabolism and excretion: Highly bound to plasma protein with a 
terminal half-life of 11.5 hours. Excreted in bile and urine as intact and 
degraded drug. 
• Usual dosage and schedule: When given intravenously, 100-125 mg/m2 
daily (day 1-3, day 1-5), or intermittently (days 1, 3, 5). Oral dose is 
doubled (200 mg/m2/d) and given in a divided dose, if total dose is 400 
mg or greater. 
• Special precautions: cause hypotension if given rapidly by intravenous 
injection. 
• Common side effects and toxicity:  
o Myelosuppression – leukopenia in particular, is dose-limiting. Nadir 


 
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usually observed at 16 days with recovery by day 20 to 22. 
o Nausea and Vomiting – are usually minor problems in one-third of 
patients. 
o Alopecia is common and stomatitis rare. 
o Additional side effects – severe allergic reactions including 
bronchospasm, wheezing, and anaphylaxis are rare. Chemical 
phlebitis is uncommon but caution is advised to avoid extravasation 
when drug is given intravenously. Secondary neoplasia is possible. 
• Source of study medication: Study medication will be provided by the 
AMC or a pharmaceutical sponsor. 
• Study medication formulation: 50 mg soft gelatin capsule 
• Storage and stability: Store between 2°C – 8°C (36°F – 46°F). Do not 
freeze. After dispensing to participants, etoposide may be stored for up 
to 30 days at room temperature. 
5.1.2.4 Procarbazine 
• Other name(s) and abbreviation: Natulane,methylhydrazine, Proc. 
(for protocol purposes)  
• Mechanism of action: Causes formation of free hydroxyl radicals and 
thus mimics the effect of ionizing radiation. Depolymerizes DNA. 
Inhibits DNA, RNA and protein synthesis. 
• Metabolism and excretion: Readily enters the CSF. Degraded in the 
liver to inactive compounds. Inactive products are excreted in the urine.  
• Usual dosage and schedule: 100 mg/m2 orally for 7 to 14 days every 4 
weeks when given in combination with other drugs. Procarbazine is a 
monoamine oxidase inhibitor and has various drug interactions. The 
clinical incidence of these interactions is low 
• Special precautions: May cause disulfiram-like reactions in patients 
consuming alcohol. May cause additive depression with CNS 
depressants. May interact with sympathomimetic amines causing 
hypersensitive crises. 
• Common side effects and toxicity:  
o Myelosuppression – pancytopenia is dose-limiting. 
o Nausea and vomiting are frequent during first few days until 
tolerance develops. 
o Stomatitis and diarrhea are uncommon. Alopecia, pruritus and drug 
rash are also uncommon. 
o CNS effects – include paresthesias, neuropathies, headache, 
dizziness, depression, apprehension, nervousness, insomnia, 
nightmares, hallucinations, ataxia, confusion, convulsions and 
coma. These have all been reported with variable frequency. 
• Additional side effects – visual disturbances and postural hypotension 
are rare. Secondary neoplasia is possible. 
• Source of study medication: Study medication will be provided by the 
AMC or a pharmaceutical sponsor. 
• Study medication formulation: 50 mg capsules 


 
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• Storage and stability: Store below 40°C (104°F), preferably between 15 
and 30°C (59 and 86 °F), in a tight, light-resistant container. 
5.2 
Drug Orders, Transfers, Returns, and Accountability 
The Investigator, or a responsible party designated by the Investigator, must maintain a 
careful record of the inventory and disposition of all drugs received using the NCI Drug 
Accountability Record Form (DARF) (available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the Pharmaceutical Management Branch at 301-
496-5725). The DARFs document the drug delivery date to the site, inventory at the site, 
use by each study participant, and disposal of the drug (if applicable). A site-specific 
accountability record, either manual or electronic, may be used if it includes all the 
information required on the NCI Investigational Drug Accountability Record and if the 
paper printout is identical to the NCI accountability record. A separate DARF is required 
for each protocol using the same agent. The investigator will ensure that the drugs are used 
only in accordance with this protocol. 
Drug will be shipped through a third party vendor. Instructions for drug ordering are 
available on the AMC website (www.amcoperations.com). 
5.2.1 Drug Dispensing 
The clinic pharmacist or an alternative qualified person at each participating AMC 
site will be responsible for dispensing study medication. The total amount of drug 
necessary for a single cycle of treatment (prednisone for CHOP regimen) or a 3 to 
5 day supply (oral regimen) will be dispensed to the subject at the beginning of the 
cycle (CHOP regimen) or Day 1 and Day 22 (oral regimen), with instructions on 
the number of capsules to be taken at each dose.  
Oral agents will be provided in bulk supply bottles. Since oral study agents are not 
subject-specific, site pharmacists must dispense agent from opened bulk supply 
bottles (break bottles) before opening a new bulk agent supply bottle to avoid 
unnecessary drug wastage. A new bottle may be opened prior to exhausting the 
supply in an open bottle if the agent in the open bottle is expired or the open bottle 
has not been stored in accordance with the package insert. 
5.3 
Dosing 
5.3.1 CHOP 
Intravenous chemotherapy medication is given on the following schedule: 
Cyclophosphamide 
750 mg/m2 IV Day 1, each cycle 
Doxorubicin 
50 mg/m2 IV Day 1, each cycle 
Vincristine 
1.4 mg/m2 IV Day 1, each cycle (max, 2.0 mg) 
Prednisone 
100 mg orally Day 1-5, each cycle 
*Total six 3-week cycles 
A cycle of therapy is 3 weeks. A total of six 3-week cycles of therapy will be 
administered (18 weeks). Vincristine should be rounded to the nearest 0.1 mg. All 
other drug doses are rounded to the nearest milligram dosage. Doses of 


 
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chemotherapy must be recalculated and adjusted if the participant’s weight changes 
greater than 10% from baseline or the prior dose. Otherwise doses may be adjusted 
in accordance with institutional guidelines. 
5.3.2 Modification of Initial Intravenous Chemotherapy Medication 
Poor risk patients, defined as those with PS 2-3 or CD4 < 100 or WBC or HGB, or 
PLTS below the institution normal range, and randomized to CHOP, will be treated 
in cycles 1 and 2 with a reduced dose CHOP, as follows:  
Two, 3-week (21 day) cycles of the following regimen:  
Cyclophosphamide 
375 mg/m2 IV Day 1, each cycle 
Doxorubicin 
25 mg/m2 IV Day 1, each cycle 
Vincristine 
1.4 mg/m2 IV Day 1, each cycle (max, 2.0 mg) 
Prednisone 
100 mg orally Day 1-5, each cycle 
After 2 cycles, patients without major adverse events, defined as no new Grade 3 
toxicities attributed to treatment, will have CHOP doses escalated to standard doses 
for cycle 3. Patients with any new Grade 3 toxicities will continue on the reduced-
dose regimen for a total of 6 cycles. This approach represents a consensus approach 
that is consistent with the AMC African sites’ current practice. 
5.3.3 Oral Chemotherapy 
Oral chemotherapy medication is given on the following schedule: 
Lomustine (CCNU): 
50 mg/m2 once daily  
Day 1, cycle 1 and cycle 3 
only 
Etoposide (VP-16): 
100 mg/m2once daily 
Day 1-3 of each cycle*  
Cyclophosphamide (CTX) 100 mg/m2 once daily 
Day 22-26 of each cycle*  
Procarbazine (Proc): 
100 mg/m2 once daily 
Day 22-26 of each cycle*  
*Total three 6-week cycles 
A cycle of therapy is 6 weeks. A total of three 6-week cycles of therapy will be 
administered (18 weeks). Starting drug and modified drug doses are rounded to 
accommodate pill size. Lomustine is rounded to the nearest 10 mg increment. All 
other oral drugs (etoposide, cyclophosphamide, and procarbazine) are rounded to 
the nearest 25 or 50 mg increment, as available. Rounding should be to the nearest 
available tablet or capsule size.  
If the calculated dose is exactly half way between two available pill sizes, the initial 
dose should be rounded to the next higher value (e.g., if the calculated dose is 75 
mg, and only 50 mg capsules are available, the initial dose would be 100 mg).  
If rounding is part of a dose reduction (i.e. for toxicity), rounding should be 
performed to result in a decrease in the dose of the modified drug (e.g., if the 
reduced dose is calculated at 75 mg, and only 50 mg capsules are available, the 
administered dose should be 50 mg).  


 
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Please see MOP for additional examples. Doses of chemotherapy must be 
recalculated and adjusted if the participant’s weight changes greater than 10% from 
baseline or the prior dose. Otherwise doses may be adjusted in accordance with 
institutional guidelines. 
5.4 
Dosing Modifications for Hematologic Toxicities 
Intravenous and oral chemotherapy dosing will be guided by blood counts performed 
within 48 hours of the scheduled day initiating of chemotherapy administration (day 1 of 
each cycle for CHOP and days 1 and 22 for the oral regimen). The exception to this is 
Cycle 1, Day 1, which allows  blood counts to be performed within 7 days of dosing.  
All participants will receive chemotherapy provided the post-nadir ANC is ≥ 1,000/µL and 
the post-nadir platelet count is ≥ 50,000/µL. Specific dosage requirements are detailed 
below. 
G-CSF may be used if it is locally available, however, it will not be provided by the study. 
If dose modifications are required for toxicity, the participant must receive a reduced 
dose for all subsequent cycles. 
5.4.1 Oral Chemotherapy Modifications if G-CSF is Not Available 
Dose modifications for the oral regimen will be made according to the table below: 
If ANC > 1500/mm3 and platelets > 75,000/mm3 prior to Day 
1 of cycle 2 or any cycle thereafter, or Day 22 of any cycle:  
Treat at full dose 
If ANC is 1000/mm3 to 1499/mm3 and/or platelets are 
50,000/mm3 to 74,999/mm3 prior to Day 1 of cycle 2 or any 
cycle thereafter, or Day 22 of any cycle: 
Reduce all oral drug doses by 
50% of the original dose 
If ANC is <1000 mm3 and/or platelets are < 50,000/mm3 prior 
to Day 1 of cycle 2 or any cycle thereafter, or Day 22 of any 
cycle: 
Hold treatment for up to 3 
weeks to allow for recovery.*  
• If treatment held, weekly CBCs are recommended to monitor count recovery. 
If, after ≤3 weeks, the ANC is ≥1000/mm3 and the platelet count is 
≥50,000/mm3, treatment may resume at a 50% dose reduction for all drugs. If 
the ANC remains <1000/mm3 and/or the platelet count remains <50,000/mm3 
for >3 weeks after the scheduled start of treatment (day 1 or day 22 of each 
cycle), study treatment will be permanently discontinued. 
• Once the doses of oral drugs have been reduced by 50%, subsequent treatment 
cycles may be given at this dose if the ANC is ≥1000/mm3 and the platelet count 
is ≥50,000/mm3 within 48 hours of the scheduled treatment. 
• Once the doses of oral drugs have been reduced by 50%, if the ANC is 
<1000/mm3 and/or the platelet count is <50,000/mm3 within 48 hours of a 
scheduled treatment, study treatment will be permanently discontinued.  
• G-CSF may be administered per the site standard. G-CSF must be discontinued 
at least 24 hours before chemotherapy administration and should not be 
resumed less than 48 hours after the last dose of chemotherapy in each cycle. 
5.4.2  Oral Regimen Modifications if G-CSF is Available 
Dose modifications are required if either the ANC or the platelet counts meet the 


 
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criteria for modification. If different modification criteria are met based on the 
blood counts, please follow the more stringent dose modification plan. Dose 
modifications for the oral regimen will be made according to the table below: 
ANC Dose Modification Criteria 
If ANC is > 1000/mm3 prior to Day 1 of 
cycle 2 or any cycle thereafter, or Day 22 of 
any cycle: 
Treat at full dose 
If ANC is < 1000/mm3 administer G-CSF 
as per site standard and delay treatment by 
7 days.  
If, after 7 days, the ANC is > 1000/mm3, treatment may 
be continued at full dose with G-CSF administered per 
site standard for all remaining cycle.  
If the ANC is 500/mm3 – 999/mm3 after 7 days, 
treatment may resume at a 50% dose reduction for all 
oral drug doses, with G-CSF administered per site 
standard for all remaining cycles. 
If the ANC is < 500 mm3 after 7 days, study treatment 
will be permanently discontinued. 
• G-CSF must be discontinued at least 24 hours before chemotherapy 
administration and should not be resumed less than 48 hours after the last dose 
of chemotherapy in each segment of the treatment cycle. 
• Once the doses of the oral regimen have been reduced by 50%, subsequent 
treatment cycles may be given at this dose if the ANC is ≥500/mm3 within 48 
hours of the scheduled treatment. 
• Once the doses of the oral regimen have been reduced by 50%, if the ANC is 
<500/mm3 and/or within 48 hours of a scheduled treatment, study treatment will 
be permanently discontinued.  
Platelet Dose Modification Criteria 
If platelets > 75,000/mm3 prior to Day 1 of 
cycle 2 or any cycle thereafter, or Day 22 of 
any cycle: thereafter: 
Treat at full dose 
If platelets are 50,000/mm3 to 74,999/mm3: 
Reduce all oral agents by 50% of the original dose 
If platelets are < 50,000/mm3: 
Hold treatment for up to 3 weeks to allow for recovery.*  
• If platelets <50,000/mm3, treatment will be held for up to 3 weeks. Weekly 
CBCs are recommended to monitor count recovery. If, after ≤3 weeks, the 
platelet count is ≥50,000/mm3, treatment may resume at a 50% dose reduction 
for all oral agents. If the platelet count remains <50,000/mm3 for >3 weeks after 
the scheduled start of the cycle, study treatment will be permanently 
discontinued. 
• Once the doses of the oral agents have been reduced by 50%, subsequent 
treatment cycles may be given at this dose if the platelet count is ≥50,000/mm3 
within 48 hours of the scheduled treatment. 
• Once the doses of oral agents have been reduced by 50%, if the platelet count 
is <50,000/mm3 within 48 hours of a scheduled treatment, study treatment will 
be permanently discontinued.  


 
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5.4.3 CHOP Modifications if G-CSF is Not Available 
Dose modifications for the CHOP regimen will be made according to the table 
below: 
If ANC > 1500/mm3 and platelets > 75,000/mm3 prior to Day 
1 of Cycle 2 and any cycle thereafter:  
Treat at full dose 
If ANC is 1000/mm3 to 1499/mm3 and/or platelets are 
50,000/mm3 to 74,999/mm3 prior to Day 1 of Cycle 2 and any 
cycle thereafter: 
Reduce all cyclophosphamide 
and doxorubicin doses by 50% 
of the original dose 
If ANC is <1000 mm3 and/or platelets are < 50,000/mm3 
prior to Day 1 of Cycle 2 and any cycle thereafter: 
Hold treatment for up to 3 
weeks to allow for recovery.*  
• If ANC <1000/mm3 and/or platelets <50,000/mm3, treatment will be held for 
up to 3 weeks. Weekly CBCs are recommended to monitor count recovery. If, 
after ≤3 weeks, the ANC is ≥ 1000/mm3 and the platelet count is ≥50,000/mm3, 
treatment may resume at a 50% dose reduction for cyclophosphamide and 
doxorubicin. If the ANC remains <1000/mm3 and/or the platelet count remains 
<50,000/mm3 for >3 weeks after the scheduled start of the cycle, study 
treatment will be permanently discontinued. 
• Once the doses of cyclophosphamide and doxorubicin have been reduced by 
50%, subsequent treatment cycles may be given at this dose if the ANC is 
≥1000/mm3 and the platelet count is ≥50,000/mm3 within 48 hours of the 
scheduled treatment. 
• Once the doses of cyclophosphamide and doxorubicin have been reduced by 
50%, if the ANC is <1000/mm3 and/or the platelet count is <50,000/mm3 within 
48 hours of a scheduled treatment, study treatment will be permanently 
discontinued.  
5.4.4 CHOP Modifications if G-CSF is Available 
Dose modifications are required if either the ANC or the platelet counts meet the 
criteria for modification. If different modification criteria are met based on the 
blood counts, please follow the more stringent dose modification plan. Dose 
modifications for the CHOP regimen will be made according to the table below: 
ANC Dose Modification Criteria 
If ANC > 1000/mm3 prior to Day 1 of 
Cycle 2 and any cycle thereafter:  
Treat at full dose 
If ANC is < 1000/mm3 administer G-
CSF as per site standard and delay 
treatment by 7 days.  
If, after 7 days, the ANC is > 1000/mm3, treatment 
may be continued at full dose with G-CSF 
administered per site standard for all remaining 
cycle. 
If the ANC is 500/mm3 – 999/mm3 after 7 days, 
treatment may resume at a 50% dose reduction for 
cyclophosphamide and doxorubicin, with G-CSF 
administered per site standard for all remaining 
cycles. 


 
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If the ANC is < 500 mm3 after 7 days, study 
treatment will be permanently discontinued. 
• G-CSF must be discontinued at least 24 hours before chemotherapy 
administration and should not be resumed less than 48 hours after the last dose 
of chemotherapy in each cycle. 
• Once the doses of cyclophosphamide and doxorubicin have been reduced by 
50%, subsequent treatment cycles may be given at this dose if the ANC is 
≥500/mm3 within 48 hours of the scheduled treatment. 
• Once the doses of cyclophosphamide and doxorubicin have been reduced by 
50%, if the ANC is <500/mm3 and/or within 48 hours of a scheduled treatment, 
study treatment will be permanently discontinued.  
Platelet Dose Modification Criteria 
If platelets > 75,000/mm3 prior to Day 1 of 
Cycle 2 and any cycle thereafter: 
Treat at full dose 
If platelets are 50,000/mm3 to 74,999/mm3: 
Reduce all cyclophosphamide and doxorubicin 
doses by 50% of the original dose 
If platelets are < 50,000/mm3: 
Hold treatment for up to 3 weeks to allow for 
recovery.*  
• If platelets <50,000/mm3, treatment will be held for up to 3 weeks. Weekly 
CBCs are recommended to monitor count recovery. If, after ≤3 weeks, the 
platelet count is ≥50,000/mm3, treatment may resume at a 50% dose reduction 
for cyclophosphamide and doxorubicin. If the platelet count remains 
<50,000/mm3 for >3 weeks after the scheduled start of the cycle, study 
treatment will be permanently discontinued. 
• Once the doses of cyclophosphamide and doxorubicin have been reduced by 
50%, subsequent treatment cycles may be given at this dose if the platelet count 
is ≥50,000/mm3 within 48 hours of the scheduled treatment. 
• Once the doses of cyclophosphamide and doxorubicin have been reduced by 
50%, if the platelet count is <50,000/mm3 within 48 hours of a scheduled 
treatment, study treatment will be permanently discontinued.  
5.5 
Dosing Modifications for Other Toxicities 
Any dose reduction for treatment related toxicities will be permanent. All subsequent 
treatment cycles must be given at the reduced dose.  
5.5.1 Oral Chemotherapy Dose Modifications 
5.5.1.1 Hemorrhagic cystitis: If this occurs, a 50% dose reduction in 
cyclophosphamide is to be made for the next cycle of therapy, provided the 
patient has recovered from this event. A treatment delay of up to 3 weeks is 
permissible. If this occurs again, eliminate the cyclophosphamide from the 
chemotherapy regimen. 
5.5.1.2 Procarbazine skin rash/allergy: Procarbazine allergy is manifested by a 


 
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generalized rash and must be differentiated from drug reactions secondary 
to other agents or a related problem due to underlying immunodeficiency. 
If procarbazine rash occurs, eliminate procarbazine from the chemotherapy 
regimen. 
5.5.1.3 Nausea and Vomiting: Nausea and vomiting should be managed according 
to standard practice as outlined in the published American Society of 
Clinical Oncology (ASCO) guidance “Preventing and Treating Nausea and 
Vomiting Caused by Cancer Treatment.” Briefly, antiemetic agents 
including, but not limited  
to, 5HT-3 antagonists, aprepitant, lorazepam, 
diphenhydramine, or phenothiazines may be considered. 
5.5.1.4 Renal toxicity: Dose modifications are recommended for etoposide in 
participants with reduced creatinine clearance. A 25% reduction in 
etoposide dose is recommended if the calculated creatinine clearance is 
between 15 and 50 mL/min, and a 50% reduction is recommended if the 
calculated creatinine clearance is below 15 mL/min.   
5.5.1.5 Other–Non-Hematologic Toxicities: All drugs will be withheld for a Grade 
3 or higher non-hematologic toxicities other than those specified above. A 
treatment delay of up to 3 weeks is permissible. If after 3 weeks the toxicity 
does not resolve to ≤ Grade 1, the patient is to discontinue study treatment. 
If the toxicity resolves to ≤ Grade 1 within 3 weeks, treatment may be 
resumed at a 50% dosage reduction for all drugs. If Grade 3 or higher non-
hematologic toxicity recurs at the reduced dose, the patient is to discontinue 
study treatment.  
5.5.2 CHOP Modifications 
5.5.2.1 Hepatic toxicity: All drugs will be withheld for a direct serum bilirubin of 
>5.0 mg/dL. A treatment delay of up to 3 weeks is permissible at which 
point a determination is to be made as to whether the hepatic dysfunction is 
secondary to progressive NHL or toxicity. If after 3 weeks the serum 
bilirubin remains >5.0 mg/dl, the patient is to discontinue study treatment.  
Direct Bilirubin 
Agent (s) 
Reduction 
1.2-3.0 mg/dL 
Doxorubicin 
50% based on full dose initially or 
previous dose for cycles 2-6 
>3.0-5.0 mg/dL 
Vincristine 
50% based on full dose initially or 
previous dose for cycles 2-6 
Doxorubicin 
75% based on full dose initially or 
previous dose for cycles 2-6 
• If direct bilirubin >5.0 mg/dl, doxorubicin and vincristine should not be 
administered. 
• No 
dosage 
adjustment 
is 
required 
for 
isolated 
indirect 
hyperbilirubinemia associated with the use of indinavir, tenofovir, or 
atazanavir. 
5.5.2.2 Renal toxicity: All drugs will be withheld for a serum creatinine >3.0 


 
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mg/dL. A treatment delay of up to 3 weeks is permissible at which point a 
determination is made as to whether the renal dysfunction is secondary to 
progressive NHL or toxicity. If the participant is receiving tenofovir, the 
tenofovir dose can either be adjusted based on the creatinine clearance or 
stopped and an alternative NRTI substituted. If the creatinine returns to 
normal, chemotherapy may be resumed. If after 3 weeks despite these 
maneuvers, the serum creatinine remains >3.0 mg/dl, the patient is to 
discontinue study treatment. 
5.5.2.3 Hemorrhagic cystitis: If this occurs, a 50% dose reduction in 
cyclophosphamide is to be made for the next cycle of therapy, provided the 
patient has recovered from this event. A treatment delay of up to 3 weeks is 
permissible. If this occurs again, eliminate the cyclophosphamide from the 
chemotherapy regimen. 
5.5.2.4 Cardiac toxicity: If clinical findings suggesting congestive heart failure are 
present, doxorubicin will be discontinued and evaluation by MUGA or 
echocardiogram should be performed. 
5.5.2.5 Neurological 
Neurotoxicity 
Vincristine Dose 
Moderate paresthesias (inability 
to button)  
No change  
Inability to walk on heels or 
obstipation  
25% reduction  
Ambulation difficulties  
No vincristine 
5.5.2.6 Nausea and Vomiting: Nausea and vomiting should be managed according 
to standard practice as outlined in the published American Society of 
Clinical Oncology (ASCO) guidance “Preventing and Treating Nausea and 
Vomiting Caused by Cancer Treatment.” Briefly, antiemetic agents 
including, but not limited to, 5HT-3 antagonists, aprepitant, lorazepam, 
diphenhydramine, or phenothiazines may be considered. 
5.5.3 Antiretroviral Modifications 
Tenofovir and Emtricitabine: Participants with reduced creatinine clearance who 
are receiving tenofovir (TDF) and/or emtricitabine (FTC) as part of their ART 
regimen should have the doses of these drugs modified. Please see the TDF/FTC, 
TDF and FTC package inserts for dosage adjustment recommendations. 
5.6 
Duration of Treatment 
5.6.1 All participants shall be removed from treatment upon documentation of PD, 
unacceptable toxicity as defined by the dose modification guidelines, or at the 
discretion of the treating physician (See section 8.0). 
5.6.2 Total duration of chemotherapy prescribed in this protocol is 18 weeks of therapy 
(as either six 3-week cycles of CHOP, or three 6-week cycles of oral 
chemotherapy). Patients are to be restaged following completion of therapy. Tumor 


 
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response and clinical safety/toxicity status are assessed by international criteria and 
the NCI Common Terminology Criteria for Adverse Events (Version 5.0) (11-13) 
Categories of objective response (described in section 8.0) include CR/cCR and 
PR, SD, and PD.  
5.6.3 All patients with PD at any point are to be removed from study treatment. They will 
continue to be followed for overall survival. Patients developing CNS involvement 
(i.e., lymphomatous meningitis, vitreal involvement, parenchymal metastasis, or 
epidural spinal cord compression) will be considered to have PD. Patients 
experiencing persistent or unusual toxicity as outlined in sections 5.4 and 5.5 will 
also be removed from treatment. 
5.6.4 All supportive therapy measures consistent with optimal patient care will be given 
throughout the duration of the study, including, if appropriate, to the standard of 
care in the country where the participant is enrolled, blood transfusions, G-CSF and 
antibiotics. There is no prescribed second-line or ‘salvage’ chemotherapy regimen 
for patients with PD. Subsequent chemotherapy regimen(s) for second-line 
treatment and tumor response should be documented, if possible. Adverse event 
information regarding second-line therapies will not be collected. Participants will 
be followed only for vital status and a recording of the second-line and subsequent 
regimens which fall within the two year window following completion of first line 
therapy. 
5.7 
Concomitant Medication(s) and Diet 
5.7.1 Required and Permitted Medications 
• All participants must be prescribed combination antiretroviral therapy with the 
goal of virological suppression using an acceptable regimen that adheres to 
national guidelines for treatment of HIV infection. Participants can already be 
on a regimen and remain on that regimen during treatment on this protocol. 
Participants can begin ART on the day of enrolling in this study to meet 
eligibility criteria. The prescribed ART regimen at the time of enrollment 
cannot contain zidovudine (AZT) 
• The antiretroviral regimen must be recorded in the case report form at baseline. 
Any changes to the participant’s ART regimen must be recorded through 12 
month follow-up. 
• There will be no specific prescribed antiemetic regimen, although use of 
antiemetics is recommended, if available, during this protocol. Antiemetics are 
prescribed by the treating physician team. Pre-hydration and allopurinol are not 
required but are permitted and encouraged, if appropriate to avoid tumor lysis 
syndrome. Patients should be encouraged to increase oral fluid intake during 
the period of cyclophosphamide administration. 
• PCP prophylaxis must be administered for the duration of treatment using drugs 
available in the participant’s country of enrollment unless medically 
contraindicated.  
• Other prophylactic interventions are prescribed at the discretion of the treating 
physician. Routine TB prophylaxis should not be given; however, patients 
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during the study at the discretion of the treating physician. 
• CNS prophylaxis is recommended, where feasible, in patients who meet the 
following criteria: lymphomatous involvement of bone marrow, testes, sinuses, 
or epidural regions. One of the following regimens is recommended: IT 
liposomal cytarabine (Depocyt®), IT cytarabine, or IT methotrexate. The 
specific regimen will be at the discretion of the primary oncologist but should 
include 4-6 doses of therapy.  IT chemotherapy will not be provided by the 
study.  
5.7.2 Prohibited Medications 
Zidovudine (AZT) in the absence of G-CSF administration is known to be 
myelosuppressive, which may adversely impact the dose intensity of the 
chemotherapy regimens prescribed in this protocol. As most of the patients who are 
enrolled in this study will not have access to G-CSF support, AZT is not permitted 
as an ART agent during concurrent chemotherapy. 
5.7.3 Diet: There are no specific dietary recommendations or restrictions. 
5.7.4 Medications Reported in the eCRF: All concomitant medications must be reported 
in the source documents. However, only antiretroviral medications, PCP 
prophylactic medications, TB prophylactic medications, opportunistic infection 
prophylactic medications, antineoplastic agents other than study drugs, and 
systemic corticosteroids other than those administered as part of CHOP must be 
reported in the eCRF. 
5.8 
Treatment Compliance 
5.8.1 Intravenous medications will be administered as per study protocol. The oral 
component of CHOP (prednisone) will be dispensed at the start of each cycle of 
therapy. 
5.8.2 Oral chemotherapy medications will be dispensed on Days 1 and 22 (every 3 
weeks) of each cycle of therapy for three 6-week cycles. 
5.8.3 Patients will be required to bring their study medication bottles with them to 
subsequent follow-up visits to document that oral medications have been taken (i.e., 
Days 1 and 22 of each cycle or every 3 weeks). Site personnel must collect the 
bottles, perform a pill count, compliance interview and review the completed 
participant diary.  
5.8.4 Site personnel should present literate participants with the appropriate oral study 
drug diary based upon the study regimen (Appendix V). The diary should be 
completed by the participant to the best of his/her ability and returned to the site for 
review. The diary should be used to verify the pill count to determine medication 
compliance. Failure of the participant to properly complete or return the diary will 
not be considered a protocol deviation. 


 
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6.0 
REPORTING OF ADVERSE EVENTS  
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial. The 
following list of 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). 
This study will utilize the Common Terminology Criteria for Adverse Event (CTCAE) 
version 5.0 for adverse event reporting. A copy of the CTCAE version 5.0 can be 
downloaded 
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 CTCAE version 5.0. The 
document “NCI Guidelines: Adverse Event Reporting Requirements for NCI 
Investigational Agents clearly outlines reporting criteria. 
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. 
6.1 
Classification of AEs by Severity and Relationship to Study Drug Administration 
6.1.1 Common Terminology Criteria for Adverse Events (CTCAE) is designed as an 
instrument to be used to document AEs identified through a combination of clinical 
and laboratory evaluation. CTCAE is NOT a tool to assist with data extraction from 
source documents without the direct participation and supervision of clinical 
investigators. AE grading and assignment of attribution require documentation by 
medical personnel who are directly involved in the clinical care of protocol 
participants. 
6.1.2 Each CTCAE term in the current version is a unique representation of a specific 
event used for medical documentation and scientific analysis and is a single 
MedDRA Lowest Level Term (LLT). Grade is an essential element of the 
Guidelines and, in general, relates to severity for the purposes of regulatory 
reporting to NCI as follows: 
Grade 
Description 
0 
No AE (or within normal limits). 
1 
Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated. 
2 
Moderate; minimal, local, or noninvasive intervention (e.g., packing, cautery) 
indicated; limiting age-appropriate instrumental activities of daily living (ADL). 
3 
Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting self-care ADL. 
4 
Life-threatening consequences; urgent intervention indicated. 
5 
Death related to AE. 
NOTE: A severe AE, as defined by the above grading scale, is NOT the same as serious AE, which 
is defined in section 2.1.22 of the NCI Guidelines (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
 
 


 
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6.1.3 Adverse Event 
Any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug related. Therefore, an AE can be ANY unfavorable 
and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal (investigational) product, 
whether or not considered related to the medicinal (investigational) product 
(attribution of unrelated, unlikely, possible, probable, or definite). (International 
Conference of Harmonization [ICH] E2A, E6). 
6.1.4 Life-Threatening Adverse Event 
Any AE that places the participant, in view of the Investigator, at immediate risk of 
death from the reaction. It does NOT include an AE that, had it occurred in a more 
severe form, might have caused death (FDA 21 CFR 312.32, ICH E2A). 
6.1.5 Serious Adverse Event (SAE) 
Any adverse drug event (experience) occurring at any dose that results in ANY of 
the following outcomes: 
• Death. 
• A life-threatening adverse drug experience. 
• Inpatient hospitalization or prolongation of existing hospitalization (for >24 
hours). 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions. 
• A congenital anomaly/birth defect. 
• Important Medical Events (IME) that may not result in death, be life 
threatening, or require hospitalization may be considered a serious adverse drug 
experience when, based upon medical judgment, they may jeopardize the 
participant 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). 
Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events that result in an inpatient hospital stay equal to 
or greater than 24 hours must be reported regardless of the requirements for Phase 
of study, expected or unexpected, and attribution. Hospitalization is used as an 
indicator of the seriousness of the AE and should ONLY be used for situations 
where the AE truly fits this definition and NOT for hospitalizations associated with 
less serious events. For example, a hospital visit where a patient is admitted for 
observation or minor treatment such as hydration and released in less than 24 hours 
should not be reported, but do report an admission for a myocardial infarction. 
6.1.6 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 


 
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CTCAE continues to use the term ‘toxicity’ because of familiarity. 
6.1.7 Expectedness (Unexpected Adverse Event) 
An unexpected AE is any AE, the specificity or severity of which is not consistent 
with the known side effects or toxicities described in the drug package insert or the 
Instructions for Use or other such documents. Additionally the ICH E2A defines an 
unexpected adverse drug reaction as an AE, the nature and severity of which is not 
consistent with the applicable product information (for example, Investigator’s 
Brochure for investigational agent).  
6.1.8 CTEP Adverse Event Reporting System (CTEP-AERS)  
An electronic system for expedited submission of AE reports. Available at 
https://eapps-ctep.nci.nih.gov/ctepaers/. A username and password are not required 
for this system. 
6.1.9 Attribution 
An assessment of the relationship between the AE and the medical intervention. 
CTCAE does not define an AE as necessarily “caused by a therapeutic 
intervention.” After naming and grading the event, the clinical investigator must 
assign an attribution to the AE using the following attribution categories: 
Relationship 
Attribution 
Description 
Unrelated 
to 
investigational 
agent/intervention1 
 
Unrelated 
The AE is clearly NOT related to the 
intervention 
Unlikely 
The AE is doubtfully related to the 
intervention 
Related 
to 
investigational 
agent/intervention1 
Possible 
The AE may be related to the intervention 
Probable 
 
The AE is likely related to the intervention 
Definite 
The AE is clearly related to the intervention 
NOTE: AEs listed as “possibly, probably, or definitely” related to the investigational 
agent/intervention in CTEP-AERS are considered to have a suspected “reasonable causal 
relationship” to the investigational agent/intervention (ICH E2A). For routine, CDUS adverse event 
reporting purposes, “Attribution” defines the relationship between the adverse event and the 
investigational agent(s)/intervention as defined in Clinical Data Update System (CDUS) 
Instructions 
and 
Guidelines 
that 
can 
be 
found 
at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/cdus_ig_3r5.pdf. 
6.2 
Expedited AE Reporting Procedures 
6.2.1 Expedited AE reporting for this study must use CTEP-AERS, 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. 
 
 


 
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Commercial Agent Studies: Expedited Reporting Requirements for Adverse Events that 
Occur in a Non-IND/IDE trial within 30 Days of the Last Administration of a Commercial 
Agent1 
 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 participant 
and may require medical or surgical intervention to prevent one of the outcomes listed in this definition. (FDA, 
21 CFR 312.32; ICH E2A and ICH E6).  
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI via 
CTEP-AERS within the timeframes detailed in the table below.  
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting 
in 
Hospitalization ≥ 24 hrs  
10 Calendar Days 
24-Hours /  
5 Calendar Days 
Not resulting in  
Hospitalization ≥ 24 hrs  
Not required 
10 Calendar 
Days 
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 4, and Grade 5 AEs 
Expedited 10 calendar day reports for: 
• Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• Grade 3 adverse events 
Effective Date: May 5, 2011 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted above. Attribution to treatment or other cause must be 
provided. 


 
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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.  
6.2.2 Expedited AE reporting timelines defined: 
“24 hours; 5 calendar days”– The Investigator must initially report the AE via 
CTEP-AERS, according to the procedures outlined in section 6.2, within 24 hours 
of learning of the event, and followed by a complete AE report submitted via CTEP-
AERS within 5 calendar days of the initial 24-hour report. Use the NCI protocol 
number and protocol-specific participant ID assigned during trial registration on all 
reports. In the rare event when Internet connectivity is disrupted, a 24-hour 
notification is to be made to NCI by telephone at: 1-301-897-7497, or 1-301-897-
7402 for CIP studies. An electronic report MUST be submitted immediately upon 
re-establishment of internet connection. 
“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. Use the NCI 
protocol number and protocol-specific participant ID assigned during trial 
registration on all reports. 
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 AE reporting 
exclusions. 
Any event that results in persistent or significant disabilities/incapacities, 
congenital anomalies, or birth defects must be reported via CTEP-AERS according 
to the guidelines as described above. 
6.2.3 CTEP-AERS is programmed for automatic electronic distribution of reports to the 
following individuals: Study Coordinator of the Lead Organization, Principal 
Investigator, and the local treating physician. CTEP-AERS provides a copy feature 
for other e-mail recipients. 
6.2.4 Each participating institution will be responsible for submitting adverse event 
reports to the appropriate national regulatory authorities in the country. All adverse 
events that require expedited reporting to national regulatory authorities as a serious 
adverse events must be reported via CTEP-AERS. 
6.3 
Routine AE Reporting 
All AEs reported through CTEP-AERS must also be reported in routine study data 
submissions using the Adverse Event electronic case report form. Routine reporting using 
the Adverse Events electronic case report form is required for all Grade 2 AEs and higher, 
regardless of attribution, for adverse events that occur within 30 days of the last 
administration of investigational agent.  Routine reporting using the Adverse Events 


 
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electronic case report form is only required for adverse events that are possibly, probably, 
or definitely related to investigational agent(s) for adverse events that occur more than 30 
days after the last administration of investigational agent(s).  All adverse events must be 
assessed by a study investigator and documented in the medical record. 
Adverse event information regarding second-line therapies will not be collected. 
Participants will be followed only for vital status, adverse events related to study treatment, 
and a recording of the second-line and subsequent regimens which fall within the two year 
window following completion of first line therapy. 
6.4 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation or chemotherapy). A secondary 
malignancy is not considered a metastasis of the initial neoplasm. 
CTEP requires all secondary malignancies that occur following treatment with an agent 
under an NCI IND/IDE be reported via CTEP-AERS. Three options are available to 
describe the event: 
• Leukemia secondary to oncology chemotherapy (e.g., acute myelocytic leukemia 
[AML]) 
• Myelodysplastic syndrome (MDS) 
• Treatment-related secondary malignancy 
Any malignancy possibly related to cancer treatment (including AML/MDS) should also 
be reported via the routine reporting mechanism (via AdvantageEDCSM in the Adverse 
Event Form). 
6.5 
Second Malignancy 
A second malignancy is one unrelated to the treatment of a prior malignancy (and is NOT 
a metastasis from the initial malignancy). Second malignancies require ONLY routine 
adverse event reporting (via AdvantageEDCSM in the Adverse Event Form). 


 
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7.0 
CRITERIA FOR DISCONTINUATION  
7.1 
Permanent Treatment Discontinuation 
7.1.1 Specified drug-related toxicity. Please see criteria for discontinuation due to drug 
toxicities as has been clearly outlined in sections 5.4 and 5.5. 
7.1.2 Requirement for prohibited concomitant medications (see section 5.7.2). 
7.1.3 Completion of treatment as defined in the protocol. 
7.1.4 Request by participant to terminate treatment. 
7.1.5 Clinical reasons believed life threatening or no longer in the best interest of the 
participant by the site investigator, such as pregnancy or breastfeeding, even if not 
addressed in the toxicity section of the protocol.  
7.1.6 As outlined in 5.6.1, and as defined in 8.1.2.6, all patients with PD at any point are 
to discontinue study treatment. Patients developing CNS metastases (i.e., 
lymphomatous meningitis, vitreal involvement, parenchymal metastasis, or 
epidural spinal cord compression) will be considered to have progressive disease. 
7.1.7 Chemotherapy will be discontinued during pregnancy and breastfeeding. 
7.1.8 Window for missed chemotherapy visit for any reason (graded AE, missed 
appointment) is 3 weeks. The patient can come back “late” only up to 3 weeks.  If 
the participant discontinues treatment due to toxicity, the toxicity should be 
followed until resolution or the toxicity level returns to baseline. 
7.1.9 Request by the investigator if s/he thinks the participant to be at significant risk of 
failing to comply with the provisions of the protocol as to cause harm to self 
7.1.10 A participant returns to the study center late (> 7 days) for two 
consecutive chemotherapy visits for reasons other than protocol-mandated 
treatment delay for an AE. Every effort will be made to follow the participant for 
the primary outcome measure.  
7.1.11 The participant is not adherent with the oral regimen. Non-adherence is defined as 
missing > 20% of the prescribed oral doses in a 42 day cycle. Adherence should be 
determined based on the pill count and participant report. A completed diary can 
also be used as a supplemental tool to determine adherence. Please consult with 
Protocol Chair(s) for questions related to drug adherence. 
7.2 
Premature Study Discontinuation 
7.2.1 Request by the participant to withdraw. 
7.2.2 Request by the protocol chairs, AMC, IRB, NCI, OHRP, local government 
agencies, or pharmaceutical sponsors. 


 
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8.0 
EVALUATION OF RESPONSE 
Response assessment will be based on response definitions of the 2014 International 
Conference on Malignant Lymphoma Imaging Working Group (i.e. Lugano 
Classification)13. Only CT based response assessment will be used.  CT/PET evaluation, 
which is not readily available in many places in Africa, will not be used to assess response. 
Traditional tumor response assessment allows evaluation of measureable disease on 
physical examination and requires that all studies performed at baseline be repeated to 
document complete or partial response (CR or PR) 12, 13. 
Additionally, patients with residual lymphadenopathy less than 3 cm that remains stable 
for > 3 months, and in the opinion of the investigator could be attributable to residual HIV-
related lymphadenopathy may also be considered to have a CR/cCR (41). When feasible, 
fine needle aspiration or open biopsy confirmation will be performed when clinically 
indicated to reconcile equivocal disease status. See definitions of 2014 International 
Conference on Malignant Lymphoma Imaging Working Group below13.  
Unless the participant has clearly progressed based on clinical criteria, final CT scans to 
confirm PE findings of response should be performed at the end of treatment. This should 
be done 6-8 weeks post-treatment.  
8.1 
Definition of Response 
8.1.1 Definitions of Measurability 
• 
Patients without bi-dimensionally measureable disease are eligible for this 
study and can be assessed for all response categories except partial response 
(PR) as shown below.  
• 
Patients with bi-dimensionally measurable disease will have serial disease 
assessments defined below.  
o 
Bi-dimensionally measureable disease is malignant disease 
measurable in two dimensions by ruler or calipers with surface area 
determined by multiplying the longest diameter by the greatest 
perpendicular diameter. Measurements must be made by the same 
method, consistently, and preferably by the same observer. 
Malignant disease with sharply defined borders visualized by plain 
radiography (x-ray) or ultrasonography (sonogram) is considered 
measurable. Repeat studies should be performed at the same pre-
therapy site(s) of malignant disease. 
o 
Six target lesions will be identified. Preferably these will be on a CT 
scan, but physical findings may be substituted if necessary. 
8.1.2 Definition of Response 
8.1.2.1 Complete Response (CR) 
• 
Complete response is dated from the time all lesions disappeared. 
Complete disappearance (resolution) of all detectable lesions, and 
all disease related symptoms, if present before therapy, and 
normalization of biochemical abnormalities definitely assigned to 
NHL (e.g., lactate dehydrogenase [LDH]).  


 
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• 
Lymph nodes and nodal masses must have regressed to normal size 
(≤1.5cm for nodes >1.5cm before therapy) and in nodes 1.1-1.5cm 
prior to therapy a decrease to < 1cm or by >75% in sum of the 
products of the greatest diameters (SPD). 
• 
A bone marrow involved by lymphoma before treatment must be 
cleared on repeat bone marrow aspirate and/or biopsy of the same 
site.  
• 
Radiographic or ultrasound resolution of all abnormalities attributed 
to lymphoma from pre-treatment imaging. 
8.1.2.2 CR/Clinical CR (cCR) 
• 
Clinical CR (cCR) was utilized in the initial report of the dose-
modified oral chemotherapy trial11. It includes those patients who 
fulfill all the criteria in section 8.1.3, but with the following 
exception and features:  
• 
In the event radiographic studies cannot be repeated to ascertain 
disease status from baseline, unconfirmed or clinical CR can be 
assigned provided a thorough assessment of findings on physical 
examination 
is 
documented. 
In 
this 
scenario, 
complete 
disappearance on physical exam of clinically detectable disease is 
allowed. 
• 
All patients with known bone marrow involvement must have a 
repeat negative bone marrow aspiration biopsy to have a CR or cCR. 
• 
Findings on physical examination with assignment of clinical 
complete response must be reviewed and confirmed by an 
independent end point review team.  
8.1.2.3 Partial Response (PR) 
• 
A 50% or greater decrease of all tumors as measured by the sum of 
the products of the 2 largest perpendicular diameters (SPD) of all 
measurable lesions, but not complete resolution of all disease.  
• 
No new sites of disease. 
• 
No increase in size of other areas of tumor involvement. 
8.1.2.4 Stable Disease (SD) 
• 
Neither meets the criteria for a CR or PR (see above) nor meets the 
criteria for progressive disease (see below). 
8.1.2.5 Relapsed Disease (from CR, cCR) 
• 
Appearance of any new lesions after complete response or clinical 
complete response. 
8.1.2.6 Progressive Disease (PD, non-responders) 
• 
Greater than 50% increase from nadir in the SPD of any previously 
identified abnormal node; OR 
• 
Appearance of new lesions (unless these lesions appear prior to 


 
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completion of the first 3 weeks of therapy). 


 
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9.0 
DATA COLLECTION AND MONITORING 
9.1 
Records to Be Kept 
CRFs will be provided for each participant via the AMC AdvantageEDCSM Internet Data 
Entry System upon enrollment. Data will be recorded on the CRFs using the unique 
participant identification number assigned at registration. Participants must not be 
identified by name, initials, birthdates, name codes, or any other personally identifying 
numbers or codes on any study documents that are transmitted outside of the site. Sample 
CRFs will be available on the AMC ODMC website (www.amcoperations.com). 
9.2 
CRF Instructions 
Instructions concerning the recording of study data on CRFs will be provided by the AMC 
ODMC. 
9.3 
Data Quality 
It is the responsibility of the AMC ODMC to assure the quality of data for the study. This 
role extends from protocol development to generation of the final study database. 
9.4 
Clinical Site Monitoring and Record Availability 
This protocol has a Data and Safety Monitoring Plan (DSMP) that adheres to the master 
AMC Data and Safety Monitoring Plan for international trials (see Appendix IV). 


 
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10.0 
STATISTICAL CONSIDERATIONS  
10.1 
Study Design 
Randomized, phase II trial of CHOP vs. oral chemotherapy with concomitant antiretroviral 
therapy in patients with HIV-associated Diffuse Large B Cell Lymphoma in sub-Saharan 
Africa. 
10.2 
Statistical Analyses of Clinical Outcomes 
The log-rank test will be used to compare the two treatment arms with respect to overall 
survival. The one-sided 0.20 significance level will be used for this comparison. 
Proportional hazards models will be used to evaluate the association between covariates 
(e.g. CD4 count and HIV viral load) and overall survival. 
The overall response rate will be estimated for each of the treatment arms using the 
binomial proportion and its 95% confidence interval. The two arms will be compared with 
respect to overall response rate using Fisher’s exact test. The log-rank test will be used to 
compare the two treatment arms with respect to progression-free survival.  
For each treatment arm, the frequency and severity of adverse events will be summarized. 
For adverse events that occur in more than 5% of either arm, the two treatment arms will 
be compared with respect to the proportion of patients who experience that adverse event 
using Fisher’s exact test. Similarly, the proportion of patients who complete treatment will 
be compared using Fisher’s exact test.  
Fisher’s exact test will be used to compare the two treatment arms with respect to the 
proportions of patients who complete therapy. Patients will report whether they have 
missed any ARV medications since the last visit to assess adherence. Oral study drug 
adherence assessment consists of a review of returned bottles, pill count, and participant 
interview; patients who take >90% of their study medication during a given cycle will be 
classified as adherent for that cycle. General estimating equations for binary data will be 
used to compare treatment arms and to evaluate the effect of duration of therapy on ARV 
and oral study drug adherence adjusting for intrapatient variation.  Effects of therapy on 
HIV control will be measured as the change from baseline to off-treatment level in CD4 
count and HIV load. The Wilcoxon rank sum test will be used to compare the two treatment 
arms with respect to changes in CD4 count and HIV load. The proportional hazards model 
will be used to evaluate the association of covariates on overall survival and progression-
free survival. 
10.3 
Proposed Sample Size 
The objective of this study is to compare CHOP and an oral regimen with respect to overall 
survival. Using the log-rank test, 45 patients per treatment arm will be sufficient to test the 
null hypothesis that the two arms do not differ with respect to overall survival with the 
alternative hypothesis that the median overall survival duration is 18 months for CHOP 
and 12 months for the oral regimen at the one-sided 0.20 significance level with power of 
0.81, assuming that overall survival duration is exponentially distributed, the accrual period 
is 24 months and the minimum follow-up duration is 24 months. The projected overall 
survival duration for CHOP is based on the median overall survival duration reported in 
AMC-010 for patients treated with CHOP (Kaplan L et al, Blood 2005; 106:1538-43). 


 
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10.4 
Lost to Follow-Up and Trial Futility 
The loss-to-follow-up (LTFU) rate will be calculated as Poisson rate. Each patient’s 
follow-up duration will be defined as the time elapsed from the date of randomization to 
the date of data cut-off for calculation of the LTFU rate. The LTFU rate will be estimated 
as the number of study participants for whom vital status is unknown and is not expected 
to be observed divided by the sum of the follow-up duration for all patients on the study. 
The LTFU rate will be estimated 12 months and 24 months after the enrollment starts on 
the study. If the lower bound of the 95% Poisson confidence interval of the LTFU rate is > 
15 per 100 person-years, then the study team will consider termination of the study due to 
the high LTFU rate. 


 
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11.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
11.1 
Ethical Committee or Institutional Review Board (IRB) Review and Informed 
Consent 
The principles of informed consent described in OHRP regulations (45 CFR Part 46) must 
be followed. IRB approval of the protocol and the informed consent form must be given in 
writing. 
The 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. Records of all study review and approval 
documents must be kept on file by the Investigator and are participant to inspection during 
or after completion of the study. AEs must be reported to the IRB. 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. 
This protocol and the informed consent document and any subsequent modifications will 
be reviewed and approved by the ethics or IRB committees responsible for oversight of the 
study. A signed consent form will be obtained from the participant (or parent, legal 
guardian, or person with power of attorney for participants who cannot consent for 
themselves, such as those below the legal age of consent). The consent form will describe 
the purpose of the study, the procedures to be followed, and the risks and benefits of 
participation. A copy of the consent form will be given to the participant, parent, or legal 
guardian, and this fact will be documented in the participant’s record. 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by CTEP and the Investigator before implementation. Amendments 
significantly affecting the safety of participants, the scope of the investigation or the 
scientific quality of the study, require additional approval by the IRB/IEC/REB and 
national regulatory body approval depending upon the local regulations. A copy of the 
written approval of the IRB/IEC/REB and the national regulatory body (if applicable), must 
be sent to the ODMC. 
11.2 
Participant Confidentiality 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified by coded number only to maintain participant confidentiality. All records 
will be kept locked. All computer entry and networking programs will be done with coded 
numbers only. Clinical information will not be released without written permission of the 
participant, except as necessary for monitoring by the AMC Operations Center, the IRB, 
the NCI, the OHRP, or designee. 
11.3 
Study Discontinuation 
The study may be discontinued at any time by the Ethical Committee/IRB, the NCI, the 
Office of Human Research Protections (OHRP), or other government agencies as part of 
their duties to ensure that research participants are protected. 
11.4 
Women and Minorities 


 
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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 ensure that the participation of minority 
participants reflects the percentage representation of these populations in their geographic 
region. As such, it is expected that the representation of participants on this trial will reflect 
the constitution of the respective populations. 
11.5 
NIH Guidance Regarding Post-Trial Access 
For protocols conducted in developing countries, the National Institutes of Health (NIH) 
has 
a 
guidance 
document 
regarding 
post-trial 
access 
available 
at: 
http://grants.nih.gov/grants/policy/anitretroviral/guidance.doc. Participating centers 
by virtue of their selection to join this AMC international trial are required to make 
arrangements through national drug procurement, NGO, or other clinical drug access 
programs in their country to provide post-trial access to ART. This is stated in the informed 
consent document. Additionally, the AMC will commit to develop successor clinical trials 
for the treatment of AIDS-related lymphoma in Africa if this trial yields results that warrant 
further study of the investigational agents. 


 
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12.0 
PUBLICATION OF RESEARCH FINDINGS 
Publication of the results of this trial will be governed by AMC policies.  


 
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13.0 
BIOHAZARD CONTAINMENT 
As the transmission of HIV and other blood-borne pathogens can occur through contact 
with contaminated needles, blood, and blood products, appropriate blood and secretion 
precautions will be employed by all personnel in the drawing of blood and shipping and 
handling of all specimens for this study, as currently recommended by the Centers for 
Disease Control (CDC) and Prevention and the National Institutes of Health (NIH). 
All dangerous goods materials, including diagnostic specimens and infectious substances, 
must be transported according to the instructions detailed in the International Air Transport 
Association (IATA) Dangerous Goods Regulations. 


 
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14.0 
REFERENCES 
1. Anon. Global Report: UNAIDS Report on the Global AIDS Epidemic: 2010. 2010. Available 
at: http://www.unhcr.org/refworld/docid/4cfca9c62.html. Accessed July 31, 2012. 
2. Anon. The Global HIV/AIDS pandemic, 2006. MMWR Morb. Mortal. Wkly. Rep. 
2006;55(31):841–844. 
3. Orem J, Otieno MW, Remick SC. AIDS-associated cancer in developing nations. Curr Opin 
Oncol. 2004;16(5):468–476. 
4. Wakabi W. Kenya and Uganda grapple with Burkitt lymphoma. Lancet Oncol. 2008;9(4):319. 
5. Otieno MW, Remick SC, Whalen C. Adult Burkitt’s lymphoma in patients with and without 
human immunodeficiency virus infection in Kenya. Int. J. Cancer. 2001;92(5):687–691. 
6. Bateganya MH, Stanaway J, Brentlinger PE, et al. Predictors of Survival After a Diagnosis of 
Non-Hodgkin Lymphoma in a Resource-Limited Setting: A Retrospective Study on the 
Impact of HIV Infection and Its Treatment. JAIDS Journal of Acquired Immune 
Deficiency Syndromes. 2011;56(4):312–319. 
7. Krown SE. Cancer in Resource-Limited Settings. JAIDS Journal of Acquired Immune 
Deficiency Syndromes. 2011;56(4):297–299. 
8. Hesseling P, Broadhead R, Mansvelt E, et al. The 2000 Burkitt lymphoma trial in Malawi. 
Pediatr Blood Cancer. 2005;44(3):245–250. 
9. Hesseling PB, Broadhead R, Molyneux E, et al. Malawi pilot study of Burkitt lymphoma 
treatment. Med. Pediatr. Oncol. 2003;41(6):532–540. 
10. Mwanda WO, Orem J, Fu P, et al. Dose-Modified Oral Chemotherapy in the Treatment of 
AIDS-Related 
Non-Hodgkin’s 
Lymphoma 
in 
East 
Africa. 
J 
Clin 
Oncol. 
2009;27(21):3480–3488. 
11. Remick SC, McSharry JJ, Wolf BC, et al. Novel oral combination chemotherapy in the 
treatment of intermediate-grade and high-grade AIDS-related non-Hodgkin’s lymphoma. 
JCO. 1993;11(9):1691–1702. 
12. Little RF, Pittaluga S, Grant N, et al. Highly effective treatment of acquired immunodeficiency 
syndrome-related lymphoma with dose-adjusted EPOCH: impact of antiretroviral therapy 
suspension and tumor biology. Blood. 2003;101(12):4653–4659. 
13. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. 
J. Clin. Oncol. 2007;25(5):579–586. 


 
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APPENDIX I: SCHEDULE OF PATIENT ASSESSMENT(S) AND 
EVALUATION(S) 
Parameter(s) 
Baseline 
Cycle 1 
Day 1 
Cycle 1 
Day 22 
(oral) 
Cycle 2, 
D1 
(oral) 
Cycle 2, 
D22 
(oral) 
Cycle 3, 
D1  
(oral) 
Cycle 3, 
D22 
(oral) 
Off-
Treatment 
Day 128 
Follow-up 
until off-
study: 3M, 
6M, 12M, 
18M, 24M 3 
Cycle 2, 
Day 1 
(CHOP) 
Cycle 3, 
Day 1 
(CHOP) 
Cycle 4, 
Day 1 
(CHOP) 
Cycle 5, 
Day 1 
(CHOP) 
Cycle 6, 
Day 1 
(CHOP) 
History & 
Physical Exam 
including 
neurological 
exam1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
x1 
Review of interim 
medical history, 
adverse events, 
and concomitant 
medications 
 
x 
x 
x 
x 
x 
x 
x 
x 
Tumor 
measurements1,2 
x1 
x2 
x2 
x2 
x2 
x2 
x2 
x1,2 
x1,2 
CBC, diff. & 
plts.4 
x1,4 
x4 
x4 
x4 
x4 
x4 
x4 
x4 
 
Serum creatinine 
and total 
bilirubin5 
x1,5 
x5 
x5 
x5 
x5 
x5 
x5 
x5 
 
Electrolytes and 
serum 
chemistries6  
x1,6 
x6 
x6 
x6 
x6 
x6 
x6 
x6 
 
Chest x-ray2 
x2 
 
 
 
 
 
 
x2 
 
Abdomen & 
pelvic sonogram 
and CT scan2 
x2 
 
 
 
 
 
 
x2 
 
Bone marrow 
aspiration/ 
biopsy7 
x7 
 
 
 
 
 
 
x7 
 
Lumbar puncture 
x10 
 
 
 
 
 
 
 
 
CD4 lymphocyte 
count, HIV-1 
plasma RNA and 
viral load8  
x1,9 
 
 
 
 
 
 
x8 
x8 
Tumor biopsy 
x 
 
 
 
 
 
 
 
 
 
Urine pregnancy 
test 
x 
x 
x 
x 
x 
x 
x 
 
 
ART Adherence 
Assessment 
 
 
x 
x 
x 
x 
x 
x 
 
Oral Study Drug 
Adherence 
Assessment 
 
x 
x 
x 
x 
x 
x 
x 
 
1. 
Baseline history and physical exam (including neurological exam) must be assessed within 48 hours of initiating therapy and 
may count as history and physical exam requirement for Day 1, cycle 1. Subsequent history and physical exams are performed 
within the 48 hours prior to Days 1 and 22 of each cycle of chemotherapy, at time of treatment completion (Day 128), and at 
specified time points following discontinuation of chemotherapy.  Blood work of CBC, differential, platelet count, electrolyte 


 
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panel (sodium, potassium, chloride) with creatinine and serum chemistries including SGOT (AST) or SGPT (ALT), total 
bilirubin, albumin, uric acid and LDH must be done within 7 days prior to treatment and will suffice as Day 1 pretreatment 
laboratories. 
2. 
Baseline assessments of tumor measurements, sonograms, CT scans or X-rays used to document measurable/evaluable disease 
should be done within 4 weeks prior to initiation of therapy. Imaging studies performed within 2 weeks of treatment initiation 
are preferable. Lesions on physical examination must be assessed within 48 hours of initiating therapy. Complete restaging 
including tumor measurements, is performed upon completion of cycle 3 of therapy. Imaging studies which showed evidence 
of disease at baseline must be repeated at time of re-staging (following cycle 3). Unless the participant has progressed either 
during treatment or during post treatment follow-up, CT imaging will be repeated at the 6, 12, 18, and 24 month follow-up 
visits.  
3. 
Upon treatment completion, patients are followed at time points 3, 6, 12, 18 and 24 months following the treatment 
discontinuation visit (unless loss to follow up or death). Clinical status will be documented by exam and appropriate imaging 
modality at the discretion of the treating physician. Participants who have progressed either during study treatment or during 
post-treatment follow-up will be followed for vital status, adverse events related to study treatment, and for new treatment 
regimens ONLY, for the duration or remainder of follow-up. 
4.  Complete blood count (CBC), differential, and platelet counts are performed within the 48 hours prior to Day 1 and Day 22 
of each period of chemotherapy administration, and at treatment completion. It is advisable, but not required, to obtain nadir 
blood counts on Day 15 and Day 36. 
5. 
Serum creatinine and total bilirubin are performed within the 48 hours prior to Day 1 and Day 22 of each cycle of chemotherapy 
(three 6-week cycles total) and at treatment completion.  
6. 
Electrolyte panel and serum chemistries are performed within the 48 hours prior to Day 1 and Day 22 of each cycle of 
chemotherapy (three 6-week cycles total) and at treatment completion: SGOT (AST) or SGPT (ALT), albumin, uric acid and 
lactate dehydrogenase (LDH).  
7.  Bone marrow biopsy - This is performed in all patients at baseline, and must be repeated in patients thought to have clinical 
complete response if bone marrow was initially involved.  
8.  CD4 lymphocyte count and HIV-1 plasma RNA (i.e., viral load determination) - These studies are to be performed at Baseline; 
and after cycle 3 at completion of treatment (Day 128). Viral load will be measured by HIV plasma RNA PCR. In addition, 
the antiretroviral regimen must be recorded in the source documents at time of on-study and any changes recorded as well. 
Furthermore, unless the participant progressed either during treatment or during post treatment follow-up, CD4 lymphocyte 
count and viral load determination will be performed at one 3 month time point after completing cycle 3 and then at 6 month 
intervals (i.e. at months 3, 6, 12, 18 and 24) until patient off-study (death or completion of 2 years of follow-up).  
9. 
The baseline CD4 count must be collected within 30 days prior to enrollment on to the Treatment Segment.  
10. A lumbar puncture must be completed within 4 weeks prior to enrollment. 


 
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APPENDIX II: ECOG PERFORMANCE SCALE 
Grade 
Descriptions 
0 
Normal activity. Fully active, able to carry out all pre-disease performance 
without restriction. 
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 
house work or office work).  
2 
In bed < 50% of the time. Ambulatory and capable of all self care, but unable to 
carry out work activities. Up and about for more than 50% of waking hours. 
3 
In bed >50% of the time. Capable of only limited self care. Confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden. Completely disabled. Cannot carry on any self care. Totally 
confined to bed or chair. 
5 
Dead 
 


 
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APPENDIX III: INITIAL PATHOLOGY REVIEW AND EXTERNAL QUALITY 
ASSURANCE AND HANDLING OF TISSUES 
 
Diagnostic Pathology 
Initial pathologic diagnosis will be performed by an approved pathologist at the site, and a report 
confirming a diagnosis of DLBCL will be issued and signed by an approved pathologist prior to a 
patient entering the trial. This diagnosis will be based on: 
a) H&E showing a lymphoma with large cell morphology 
b) CD20 or Pax5 immunohistochemistry showing loss of normal architecture, and that the large 
cells are of B cell origin. 
c) Ki67 to evaluate the percentage of proliferating large cells. Cases with a proliferation rate of 
>90% will be excluded from the trial. 
These parameters limit the trial to inclusion of patients with the 2008-WHO-defined DLBCL. It 
excludes Burkitt and Burkitt-like lymphoma and all other subtypes of non-Hodgkin’s lymphoma. 
Additional immunostains performed at the site are allowed but not required, and should be 
described in the pathology report.  
Drs. Cesarman, Ely or Tam will be available for consultation on any cases where the site 
pathologist has questions about the diagnosis or eligibility. In this case, microscopic images of 
diagnostic areas will be emailed to ecesarm@med.cornell.edu, wtam@med.cornell.edu, and 
sae2001@med.cornell.edu. A record of cases excluded from the trial will be kept for eventual 
review. Case review conferences will be held on a regular basis via conference calls.  
Handling of Tissues for External Quality Assurance 
The appointed pathologist at each site will collect the tissues from each patient entered into the 
protocol. Either a formalin-fixed, paraffin embedded (FFPE) tissue block, or 15 unstained tissue 
slides must be made available for centralized pathology review, to be completed upon termination 
of the trial. A copy of the local pathology report must be submitted with the tissue block or slides 
for central pathology review. 
Tissues for external quality assurance pathology review must be batched at each site, and shipped 
via express mail, every six months to the AMC External Quality Assurance Laboratory at:  
Sharon Barouk, MA 
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, NY 10065 USA 
Phone: (212) 746-6357 
Fax: (212) 746- 8173  
Email: shb2016@med.cornell.edu 
 


 
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The Weill Cornell Laboratory will destroy residual materials, when a block was submitted  upon 
completion of the pathology review. For sites that request return of the slides and/or blocks, all the 
materials will be returned by the laboratory to the clinical site. 
Each sample must be labeled using a Sharpie pen, or other waterproof, permanent marker with the 
following information: 
Protocol #: AMC-068 
9 digit Patient #  
Date of collection  
Specimen type: Tissue (tissue block) or Tissue (unstained slide) 
Specimen purpose: External quality assurance 
*Note: if unstained slides are collected, only one specimen label should be used for each set and 
applied to the bag or slide holder in which the slides are kept. The number of slides will need to 
be entered into the AMC’s specimen tracking system, GlobalTraceSM. 
Specimen Accessioning 
Upon receipt at Weill Cornell Medical College, each specimen from AMC will receive an 
Immunopathology Laboratory accession number which will be sequential with the other specimens 
received. This will avoid delays in processing. Specimens belonging to AMC will be so stated 
under “Clinical Information”, and therefore can be easily identified and tracked. A report will be 
issued by Dr. Tam or Dr. Ely within a month of receipt, with a diagnosis based on the microscopic 
review of H&E-stained sections, results of immunohistochemistry, in situ hybridization (EBER) 
and molecular or cytogenetic analysis (if requested or considered informative for final diagnosis),. 
All the reports will be sent by FAX to the AMC ODMC as well as to the submitting physician and 
pathologist, and hard copies will follow. 
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. 
Pathology Review 
Specimens received from AMC will undergo histopathologic diagnosis and classification, 
immunostaining and molecular analysis. Pathologic evaluation will be performed by  
Dr. Tam or Dr. Ely; all interesting, atypical and unusual cases will also be reviewed by  
Drs. Orazzi and/or Knowles. Specifically, cases will be processed as follows: 
1. H&E 
3. Ten immunostains (CD20, CD3, BCL6, BCL2, Mum, CD10, PRDM1, Ki67, p53, LANA) 
4.  In situ hybridization (EBER) 
5. FISH (cMYC, BLC6, BCL2). 
6. Pathologist interpretation. 


 
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APPENDIX IV: AMC DATA AND SAFETY MONITORING PLAN 
Version 6.0  March 17, 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 pilot or 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 


 
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Monitor, and Group Statistician determine whether these criteria have been met. 
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 


 
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the protocol requirements, and assuring compliance with reporting to the local IRB. Protocol 
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 preventive 
action plan to correct deficiencies. 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 V: AMC-068 STUDY DRUG DIARY (ORAL CHEMOTHERAPY 
REGIMEN) 
AMC-068 Oral Regimen Study Drug Administration Instruction Sheet 
 
Site Staff: Please complete the study drug instruction worksheet below. Circle the picture of the 
agent the participant should take. 
 
Please take your study drugs as follows: 
 
Drug Name: _____________________________ 
Please take __________ pills for __________ days.  
You should take this medication on (day and date):  
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
 
 
Drug Name: _____________________________ 
Please take __________ pills for __________ days.  
You should take this medication on (day and date):  
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 


 
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AMC-068 Oral Regimen Drug Diary 
 
The following fields are to be completed by the site staff before the diary is given to the study participant. 
 
Participant Number: ________________________________ 
Treatment Cycle: ________________________________ 
Date Agent Dispensed: ____________________________ 
Number of Lomustine pills/day: ___________________ 
Number of Etoposide pills/day: ____________________ 
 
Participants: The study investigator or nurse will tell you how many pills to take. Please write the date you took each drug and how 
many pills you took. 
 
 
Day 1 
Day 2 
Day 3 
Date 
 
 
 
 
Medication (name) 
Medication (photo) 
Number of  
Tablets Taken 
Number of  
Tablets Taken 
Number of  
Tablets Taken 
 
Lomustine (CCNU) 
 
 
 
 
 
 
Etoposide (VP-16) 
 
 
 
 
 


 
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AMC-068 Oral Regimen Drug Diary 
 
The following fields are to be completed by the site staff before the diary is given to the study participant  
 
Participant Number: _________________________________ 
Treatment Cycle: _________________________________ 
Date Agent Dispensed: ____________________________ 
Number of Cyclophosphamide pills/day: ___________________ 
Number of Procarbazine pills/day: ____________________ 
 
Participants: The study investigator or nurse will tell you have many pills to take. Please write the date you took each drug and how 
many pills you took. 
 
 
Day 22 
Day 23 
Day 24 
Day 25 
Day 26 
Date 
 
 
 
 
 
 
Medication (name) 
Medication 
(photo) 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
 
Cyclophosphamide (CTX) 
 
 
 
 
 
 
 
 
Procarbazine (Proc.) 
 
 
 
 
 
 
 
 


 
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APPENDIX VI: AMC-068 STUDY DRUG DIARY (CHOP REGIMEN) 
AMC-068 CHOP Regimen Study Drug Administration Instruction Sheet 
 
Site Staff: Please complete the study drug instruction worksheet below. Circle the picture of the 
agent the participant should take. 
 
Please take your study drugs as follows: 
 
Drug Name: _____________________________ 
Please take __________ pills for __________ days. 
You should take this medication on (day and date): 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 
_____________________________ 
 


 
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AMC-068 CHOP Regimen Drug Diary 
 
The following fields are to be completed by the site staff before the diary is given to the study participant  
Participant Number: _________________________________ 
Treatment Cycle: _________________________________ 
Date Agent Dispensed: ____________________________ 
Number of Prednisone pills/day: ___________________ 
Participants: The study investigator or nurse will tell you have many pills to take. Please write the date you took each drug and how 
many pills you took. 
 
 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Date 
 
 
 
 
 
 
Medication (name) 
Medication 
(photo) 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
Number of 
Tablets Taken 
 
Prednisone 
 
 
 
 
 
 
 
 

ICF_001.pdf: 
AMC-068 Model Informed Consent (Version 8.0) 03DEC2019 
i 
NCI Version Date 03DEC2019 
SUMMARY OF CHANGES 
 
Randomized, Phase II Trial of CHOP vs. Oral Chemotherapy with Concomitant Antiretroviral 
Therapy in Patients with HIV-associated Lymphoma in Sub-Saharan Africa 
Version 8.0 
 
NCI Protocol #: AMC-068 
Local Protocol #: AMC-068 
 
NCI Version Date: 03DEC2019 
Protocol Date: 03DEC2019 
 
Due to the study closure and participants having completed study therapy, no changes were made 
in response to the disapproval letters for protocol versions 6 and 7. 
 
I. 
Scientific and Substantive Changes: 
 
# 
Section 
Description of Changes 
1. 
Follow-up 
after  
chemotherapy 
is completed 
 
How long will 
I be in the 
study? 
The follow-up period was changed from 5 years to 2 years as the protocol team believes 
sufficient data will be collected during the first 2 years of follow-up to complete study 
analysis.The follow-up period was modified in that participants who have completed 
study drug therapy and have not progressed will return for office visits to complete 
required follow-up procedures for to 2 years or until disease progression, whichever 
comes first. Participants who progress during treatment or follow up will not have to 
come back for office visits, but may be contacted for health updates for the duration or 
remainder of the 2 year follow-up.  
 
II. 
Administrative and Editorial Changes: 
 
# 
Section 
Description of Changes 
2. 
Global 
Version number and version date were updated to version 8.0 dated 03DEC2019. 
 


 
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MODEL INFORMED CONSENT 
 
AMC-068: Randomized, Phase II Trial of CHOP vs. Oral Chemotherapy with Concomitant 
Antiretroviral Therapy in Patients with HIV-associated Lymphoma in Sub-Saharan Africa 
 
INTRODUCTION 
 
This is a clinical trial (a type of research study). Clinical trials include only subjects who choose to 
take part. Before you decide to be a part of this research study, the risks and benefits should be fully 
explained so that you can make an informed decision. This process is known as informed consent.  This 
consent form provides information about the study and the required tests. Your doctor has also 
explained this study to you. You will be asked to sign this form if you want to take part. Your decision 
to take part in the study is voluntary. This means that you are free to choose if you will take part in the 
study or not.  Please take your time to ask questions and make your decision. Discuss it with your 
friends and family. 
 
You are being asked to take part in this research study because you are infected with human 
immunodeficiency virus (HIV), the virus that causes AIDS, and have non-Hodgkin’s Lymphoma 
(NHL), a type of cancer associated with AIDS.   
 
This study will take place at 4 hospitals in Africa that are part of the AIDS Malignancy Clinical Trials 
Consortium (AMC).  The AMC is a group of researchers who study cancer treatments for people with 
HIV infection.  The AMC is sponsored by the National Institutes of Health, a part of the U.S. 
government. 
 
WHY IS THIS STUDY BEING DONE? 
 
The purpose of this study is to see if a mixture of anti-cancer medicines given by mouth is as good as 
a mixture of anti-cancer medicines given by vein for treating Africans with AIDS and NHL. This study 
will help develop better treatments for people with AIDS and cancer in Africa.  
 
If you take part in this study, you will be given one of two mixtures of anti-cancer medicines.  The first 
mixture contains 4 anti-cancer medicines: cyclophosphamide, doxorubicin, vincristine, and 
prednisone. This mixture is sometimes called “CHOP”, and is a standard treatment for NHL in many 
parts of the world. However, many African centers have trouble giving this treatment  The second 
mixture also contains 4 anti-cancer medicines: lomustine, etoposide, cyclophosphamide and 
procarbazine. These medicines have been approved by the United States Food and Drug 
Administration (FDA) for treating cancer, but they are non-standard (experimental) for treating your 
type of NHL. They have been given to people with HIV and NHL in several countries, including a 
small number of Africans with HIV and NHL in Uganda and Kenya.  We do not know if taking 
treatment by mouth or by vein is better.  This study will try to find out more about using these two 
different drug mixtures  in people with NHL who are also being treated for HIV. 
 
HOW MANY PEOPLE WILL TAKE PART IN THE STUDY? 
 
About 90 people will take part in this study. 
 


 
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WHAT DO I HAVE TO DO IF I AM IN THIS STUDY? 
 
Before you begin the study 
 
To be able to join this research study, you need to be at least 18 years old and have a positive blood 
test for HIV. You must also have had a biopsy (cutting out of a piece of your tissue) that shows you 
have NHL.  Samples of your biopsy must be available for review to be sure that you have NHL.  The 
biopsy will be reviewed by a doctor at the study site and will also be sent to an outside laboratory in 
the United States for a review of the diagnosis.  You must not have received treatment for NHL in the 
past. You must be willing and able to sign this informed consent. 
 
If you agree to join this study and sign this informed consent, you will need to have some or all of the 
following exams, tests, or procedures to find out if you can be in the study. These exams, tests or 
procedures are part of regular cancer care.  They may be done even if you do not join the study. If you 
have had some of the tests recently, they may not need to be done again.  
• 
A medical history and review of any medications you are taking, including HIV medications 
• 
Physical exam (including neurological exam) 
• 
Vital signs (height, weight, blood pressure, pulse, temperature) 
• 
Blood tests to check your blood cell numbers and how well your liver and kidneys are working. 
Approximately 10 milliliters (2 small spoonfuls) of blood will be taken from your arm. If there is 
no copy of a previous positive HIV test available, some of this blood will be used to test for HIV. 
• 
Blood tests to check the effect of HIV on your immune system (the part of the body that fights 
infections and diseases) and the amount of HIV virus in your blood (viral load) 
• 
Pregnancy test (if you are a woman who could have children). The test results must be negative to 
take part in this study. 
• 
A test of the fluid that surrounds the brain and spinal cord. A sample of this fluid will be tested to 
check if you have cancer in your brain or spinal cord or in the fluid around your spinal cord.  This 
test is obtained by lumbar puncture (description of procedure under “Lumbar Puncture: Definition 
and Risks” below).  It is also called a spinal tap. 
During the study 
 
If the exams, tests, and procedures show that you can be in the study, and you choose to take part, the 
following will happen: Patients will be asked to maintain a medication diary and to bring their 
medication bottles during all future visits.  
 
Tests before you begin treatment 
 
Besides the tests done to find out if you can be in the study, you will be given the following tests and 
procedures before you begin treatment in the study. 
• 
A chest X-ray, an ultrasound of the abdomen, and CT scans (tests that take pictures) of your chest, 
abdomen, and pelvis so that your doctor can measure your cancer. 
• 
Bone marrow biopsies to see if you have cancer in the tissue of your bones (description of 
procedure under “Bone Marrow Examination: Definition and Risks” below). 
• 
If samples of your NHL biopsy are not available for review, you may need to have another biopsy 
before starting treatment.  The biopsy will be reviewed by a doctor at the study site.  The tissue 
sample will also be sent to a laboratory in the United States for more tests to find out more about 
your NHL. 


 
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• 
Blood tests to check your blood cell numbers and how well your liver and kidneys are working. 
Approximately 10 milliliters (2 small spoonfuls) of blood will be taken from your arm.  
• 
Pregnancy test (if you are a woman who could have children). The test results must be negative to 
take part in this study. 
 
If you are not taking medicines to treat your HIV infection, your doctor will prescribe them for you.  
If you are already taking anti-HIV medications, continue taking them unless your study doctor tells 
you to change them.  You should take all your anti-HIV medications during and after the study, unless 
your doctor tells you to stop or change them. 
 
Treatment description 
 
A computer program will randomly assign you to one of two treatment arms – this is called 
randomization.  Each participant will be assigned the CHOP treatment group or the lomustine, 
etoposide, cyclophosphamide and procarbazine treatment group. Your study doctor will tell you which 
treatment you will receive.   
 
Depending on which anti-cancer medications you are assigned you will be given the medications in 
one of two ways: roughly half of the patients will be given six (6) cycles of a mixture of medications 
called CHOP given by vein and prednisone by mouth, with each cycle lasting 21 days.  The other half 
of patients will be given three (3) cycles of a mixture of chemotherapy medicines by mouth, with each 
cycle lasting 42 days. The total treatment time will be the same in both groups: 126 days or 18 weeks. 
 
Below is an outline of the two combinations of drugs and dosing of the drugs you may receive. Drugs 
in Table 1 are all given through a vein (by an intravenous catheter) except prednisone which is given 
by mouth.  Your study doctor or nurse will tell you how many prednisone pills to take and when to 
take them.  You will come to the study center to receive these medications on the following days of 
each cycle: 
 
Table 1: CHOP Given Through Arm Vein 
DRUG YOU WILL 
RECEIVE 
DAYS YOU WILL 
RECEIVE DRUG 
CYCLE WHEN  
DRUG IS TAKEN 
Cyclophosphamide 
Day 1 
Cycles 1 to 6 
Doxorubicin 
Days 1 
Cycles 1 to 6 
Vincristine 
Day 1 
Cycles 1 to 6 
Prednisone (by mouth)* 
Days 1, 2, 3, 4, 5 
Cycles 1 to 6 
*Prednisone will be given at the study center on Day 1. Doses on Days 2-5 will be taken at home. 
 
Drugs in Table 2 are given by mouth as pills or capsules.  The number of pills or capsules you need to 
take will depend on your height and weight, and may be changed during your treatment if you have 
changes in your blood counts. Your study doctor or nurse will tell you how many pills or capsules to 
take and when to take them.  The medications will be taken on the following days of each cycle: 
 


 
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Table 2: Study Medication Taken by Mouth 
DRUG YOU WILL 
RECEIVE 
DAYS YOU WILL 
RECEIVE DRUG 
CYCLE WHEN  
DRUG IS TAKEN 
Lomustine 
Day 1 
Cycle 1 and cycle 3 only 
Etoposide 
Days 1, 2 and 3 
Cycles 1, 2, and 3 
Cyclophosphamide 
Days 22, 23, 24, 25 and 26 
Cycles 1, 2, and 3 
Procarbazine 
Days 22, 23, 24, 25 and 26 
Cycles 1, 2, and 3 
 
Tests and procedures 
 
During study drug therapy 
 
During the study, you will also have the following tests or procedures performed while you are 
receiving study medication therapy: 
• 
Physical exam (on Day 1 of each cycle if receiving IV medications and Day 1 and Day 22 of each 
cycle if receiving oral medications) 
• 
Vital signs (blood pressure, pulse, temperature, weight) 
• 
Blood tests (on Day 1 of each cycle if receiving IV medications and Day 1 and Day 22 of each 
cycle if receiving oral medications). 
• 
Blood tests to check your blood cell numbers and how well your liver and kidneys are working. 
Approximately 10 milliliters (2 small spoonfuls) of blood will be taken from your arm.  
• 
Blood tests to check the effect of HIV on your immune system (the part of the body that fights 
infections and diseases) and the amount of HIV virus in your blood (viral load) 
• 
If you are a woman who could have children, a pregnancy test (on Day 1 of each cycle if receiving 
IV medications and Day 1 and Day 22 of each cycle if receiving oral medications). The test results 
must be negative to continue receiving study drug therapy. 
• 
Review of the medicines you are taking, including your HIV medications 
 
At the end of study drug therapy 
 
After you have finished therapy, you will have the following tests or procedures performed: 
• 
Blood tests to check your blood cell numbers and how well your liver and kidneys are working. 
Approximately 10 milliliters (2 small spoonfuls) of blood will be taken from your arm.  
• 
Blood tests to check the effect of HIV on your immune system (the part of the body that fights 
infections and diseases) and the amount of HIV virus in your blood (viral load) 
• 
Chest X-ray, sonogram or ultrasound of the abdomen, and CT scan (tests that take pictures) so that 
your doctor can measure your cancer. 
• 
Bone marrow biopsy, if it is known that you have cancer in the tissue of your bones. 
 
 
 


 
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Follow-up after study chemotherapy is completed 
 
• 
After you finish taking study chemotherapy, you will need to return for office visits 3 months, 6 
months, 12 months, 18 months and 24 months later. At these visits, the doctor will do tests to see 
if your cancer is getting better or worse. At these visits, you may need to have blood collected to 
check your general health (approximately 10 milliliters or 2 small spoonfuls), chest X-rays, scans, 
sonograms or ultrasounds done.  
 
HOW LONG WILL I BE IN THE STUDY? 
 
If you join this study, you will be in the study for a total of 2.5 years. For the first 18 weeks, you will 
be getting treatment for your NHL. After that, you may need to come back for check-ups and tests, or 
we will follow your health for up to 2 years. 
 
You can stop participating at any time. However, if you decide to stop participating in the study, we 
encourage you to talk to the study staff and your regular doctor first. 
 
The study doctor may need to take you off the study early without your permission if: 
• 
The study is stopped or canceled. 
• 
You are not able to attend the study visits as required by the study. 
 
The study doctor may also need to take you off the study drugs without your permission if: 
• 
Your condition worsens or your doctor believes that further treatment would be of no benefit to 
you or would be dangerous;  
• 
continuing one or more of these drugs may be harmful to you; 
• 
you need a treatment that you may not take while taking these drugs; or 
• 
you are not able to take these drugs as required. 
• 
you become pregnant and/or insist upon breastfeeding 
 
WHAT ARE THE RISKS OF THE STUDY? 
 
You may have side effects from the study medications while on the study. Your doctor and the study 
team will watch you carefully for any side effects. However, doctors don’t know all the side effects 
that may happen. Side effects may be mild or very serious. Your health care team may give you 
medicines to help lessen side effects. Many side effects go away soon after you stop taking the drugs 
in this study. In some cases, side effects can be serious, long lasting, or may never go away. There also 
is a risk of death. 
 
You should talk to your doctor about any side effects that you have while taking part in the study. It is 
also possible one of the treatments is better than the other treatment.  
 
Risks of Chemotherapy Drugs used in this study 
 
Chemotherapy drugs often have side effects. Your doctor and the study team will watch you carefully 
for any side effects.  However, doctors don’t know all the side effects that may happen. The drugs used 
in this program may cause all, some or none of the side effects listed.  In addition, there is always the 
risk of very uncommon or previously unknown side effects occurring which may be life-threatening 


 
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or severe enough to cause death.  Your health care team may give you medicines to help lessen side 
effects.  You should talk to your doctor about any side effects that you have while taking part in the 
study. 
 
Doxorubicin 
 
Common side effects: 
• 
Nausea and vomiting 
• 
Temporary hair loss 
• 
Low white blood cell count, which can lead to infection 
• 
Low platelet count, which can lead to bruising or bleeding 
• 
Fatigue (tiredness) and loss of appetite 
 
Rare side effects: 
• 
Heart damage may occur at high doses 
 
Very rare, but serious side effects:  
• 
Liver damage may occur at high doses 
• 
Other cancers, like leukemia (cancer of the blood) 
 
Vincristine 
 
Common side effects: 
• 
Nausea and vomiting 
• 
Temporary hair loss 
• 
Constipation 
• 
Tingling or numbness of the arms or legs 
• 
Fatigue (tiredness) and loss of appetite 
 
Rare side effects: 
• 
Low white blood cell count, which can lead to infection 
• 
Low platelet count, which can lead to bruising or bleeding 
 
Prednisone 
 
Common side effects: 
• 
High blood pressure 
• 
Skin changes (thinning of skin, delayed healing) 
• 
Swelling 
• 
Increased risk of infection 
• 
Thinned bones 
• 
Difficulty sleeping 
 
Rare side effects: 


 
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• 
High blood sugars 
 
Very rare, but serious side effects:  
• 
Worsening of tuberculosis 
• 
Vision changes 
 
Lomustine 
 
Common side effects: 
• 
Low white blood count, which can lead to infection 
• 
Low platelet count, which can lead to bleeding or bruising 
• 
Nausea and vomiting 
 
Rare side effects: 
• 
Mouth sores 
• 
Hair loss 
• 
Confusion 
• 
Drowsiness (feeling sleepy) 
• 
Loss of muscle coordination 
• 
Mild liver damage 
 
Very rare, but very serious side effects:  
• 
Other cancers, like leukemia (cancer of the blood) 
 
Cyclophosphamide (given by mouth and given by arm vein) 
 
Common side effects: 
• 
Nausea and vomiting 
• 
Temporary hair loss 
• 
Low white blood cell count, which can lead to infection 
• 
Low platelet count, which can lead to bruising or bleeding 
• 
Fatigue (tiredness) and loss of appetite 
• 
Nasal congestion, watery eyes and headache 
• 
Skin rash; darkening of skin 
• 
Metallic taste in the mouth 
• 
Light-headedness and a hot feeling for a few minutes after taking the drug 
 
Rare side effects: 
• 
Bladder irritation with burning during urination – this may be prevented by drinking 8 to 10 glasses 
of water a day while on the drug. 
• 
Both men and women may be unable to have children after receiving this chemotherapy.  This may 
be a permanent side effect. 
• 
Women may stop having menstrual periods 
 


 
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Very rare, but serious side effects:  
• 
Scarring of the lungs, cough and shortness of breath 
• 
Liver and heart damage may occur at high doses 
• 
Other cancers, like leukemia (cancer of the blood) 
 
Etoposide 
 
Common side effects: 
• 
Low white blood cell count, which can lead to infection 
• 
Low platelet count, which can lead to bruising or bleeding 
• 
Nausea and Vomiting 
• 
Hair loss 
• 
Fatigue 
• 
Mouth sores 
 
Rare side effects: 
• 
Chest discomfort 
• 
Low blood pressure 
• 
Liver damage 
• 
Allergic reactions 
 
Very rare, but serious side effects: 
• 
Other cancers, especially leukemia (cancer of the blood) 
 
Procarbazine 
 
Common side effects: 
• 
Nausea and Vomiting 
• 
Hair loss 
• 
Diarrhea 
• 
Muscle aches and joint pains 
• 
Rash on the hands and feet  
• 
Fatigue 
• 
Irregular menstrual cycles in women 
• 
Loss of ability to have children 
• 
Severe reactions, including very high blood pressure, chest pain, and heart problems if you also eat 
cheeses or drink wine, beer, or other alcoholic beverages 
• 
Drowsiness (sleepiness); avoid using sleeping pills, pain medicines or tranquilizers at the same 
time 
• 
Low white blood cell count, which can lead to infection 
• 
Low platelet counts, which can lead to bruising or bleeding 
 


 
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Rare side effects: 
• 
Loss of muscle coordination 
• 
Depression, confusion, nightmares, hallucinations 
• 
Trouble sleeping 
 
Risk to the Unborn Child and Fertility (Men and Women) 
 
Both men and women will be included in this study. A pregnancy test will be performed at the time of 
enrollment and if you are pregnant you will not be able to participate in this study. The study therapy 
may decrease your ability to have children.  Because the drugs in this study can affect an unborn baby, 
you should not become pregnant or father a baby while on this study.  You must also not be nursing a 
baby during this study.  When you are taking the study drugs, you must use two methods of birth 
control that you discuss with the study staff. One method must be a barrier method. You must continue 
to use both methods of birth control until 6 weeks after stopping the study drugs. If you are a woman 
and are unable to use two methods, your doctor will talk with you about your options. You may choose 
from any of the following birth control methods: 
 
• 
Birth control drugs that prevent pregnancy given by pills, shots or placed on or under the skin  
• 
Male or female condoms with or without a cream or gel that kills sperm 
• 
Diaphragm or cervical cap with a cream or gel that kills sperm 
• 
Intrauterine device (IUD) 
• 
Not having sex 
 
If you or your partner becomes pregnant while in this study you must tell the study doctor immediately. 
The doctor will advise you of the possible risks to your unborn baby and discuss your choices for how 
to proceed. Women who become pregnant or who will not stop  breastfeeding during drug treatment 
will stop receiving treatment for her cancer, but will be asked to continue study visits.  
 
Bone Marrow Biopsy: Definition and Risks 
 
A bone marrow biopsy is the removal of a sample of bone marrow and a small amount of bone (usually 
from the hip) through a large needle. The doctor will first give an injection of numbing medicine to 
lessen pain from the test, but you may still have some pain.  The pain normally lessens within minutes 
to hours and may remain as soreness for several days.  The doctor will then take two samples of bone 
marrow, one from each hip bone, using a needle. The doctors at the study center will then look for 
cancer cells in the bone marrow under a microscope.  You must keep the area clean and dry for 24 
hours to prevent a small risk of infection or bleeding.  This test will be done in the outpatient 
department.  
 
Lumbar Puncture: Definition and Risks  
 
A lumbar puncture (also called a spinal tap) is a procedure in which a very thin needle is put into the 
sac of liquid around the lower part of the spine.  A small amount of this liquid, which is called 
cerebrospinal fluid, is collected to look for cancer cells.  A lumbar puncture has a small risk of 
infection, bleeding, nerve damage, or headache.  Rarely, leakage of spinal fluid into the tissue can 
cause a severe headache that lasts for days to weeks.  Headache can be treated with paracetamol.  You 
will be given medications to numb the area before the test to prevent pain. The pain usually lasts for a 


 
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short time (a minute or two) but sometimes lasts longer.  This test will be done in the outpatient 
department. 
 
Risk of Non-Study Medications 
 
There is a risk of serious and/or life-threatening side effects when certain medications are taken 
together. For your safety, you must tell the study doctor or nurse about all medications you are taking 
before you start the study and also before you take any medications. You must also tell the study doctor 
or nurse before taking any non-study medications, vitamins, herbs or other remedies while you are on 
the study. Deaths have occurred when HIV-infected people have taken therapies such as herbs with 
anti-HIV drugs. In addition, you must tell the study doctor or nurse before enrolling in any other clinical 
trials while on this study. 
 
For more information about risks and side effects, ask your study doctor. 
 
ARE THERE BENEFITS TO TAKING PART IN THE STUDY? 
 
If you take part in this study, there may be a direct benefit to you, but no guarantee can be made.  A 
possible benefit is that your NHL may shrink or go away. It is also possible that you may receive no 
direct benefit from being in this study. Information learned from this study may help others who have 
HIV and NHL. 
 
WHAT OTHER OPTIONS ARE THERE? 
 
Your other choices may include: 
• 
Getting treatment or care for your cancer without being in a study 
• 
Taking part in another study 
• 
No therapy for your NHL at this time, with care to help you feel more comfortable.  
 
[Insert general information about NHL treatment availability in your country or locale] 
 
Talk to your doctor or clinic staff about other treatment choices in your area and the risks and the 
benefits of all the choices before you decide if you will take part in this study. 
 
WHAT ABOUT CONFIDENTIALITY? 
 
Efforts will be made to keep your personal information confidential. We cannot guarantee absolute 
confidentiality. Your personal information may be disclosed if required by law. Any publication of this 
study will not use your name or identify you personally.  
 
Organizations that may inspect and/or copy your research records for quality assurance and data 
analysis include groups such as trained staff at [Your Institution’s Name], your country’s national 
health agency, the Office for Human Research Protections (OHRP), and trained staff from the AIDS 
Malignancy Clinical Trials Consortium (AMC), the National Cancer Institute (NCI), and the AMC 
Operations and Data Management Center (Data Coordinators and Study Monitors), the pharmaceutical 
collaborator(s) (Sigma Tau and Mylan). 
 


 
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The NIH has given the AMC a Certificate of Confidentiality. The Certificate does not mean that the 
NIH or the U.S. Government recommend that you take part in this study. This Certificate helps us keep 
your health information private.  
 
Your records for this study will have information that may identify you. This Certificate lets us turn 
down legal demands for your study records. We can use the Certificate to turn down demands for 
records from a U.S. court. The Certificate can be used in any federal, state, or local legal matters. We 
will use the Certificate to turn down any demands for your study records. The cases where we cannot 
use the Certificate are explained below. 
 
We cannot use the Certificate to say no a demand from the U.S. Government for study records. This 
applies to audits or reviews of the AMC.  This also applies to study records that we have to report to 
the FDA. 
 
The Certificate does not stop you or your family members from sharing your health information. It 
does not stop you from talking about taking part in this study. You may give written permission for an 
insurer, employer, or other person to get copies of your study records. If you give permission, we 
cannot use the Certificate to say no to a request for your study records. 
 
The Certificate cannot be used to turn down legal demands outside of the U.S.  
 
WHAT ARE THE COSTS? 
 
There will be no cost to you for study-related visits, physical examinations, laboratory tests or other 
procedures. (Modify the prior statement to local requirements if subjects will be expected to cover the 
cost of any research-related care, tests, or supplies.) You, your insurance company, or your health 
care system will need to assume the cost of anti-HIV drugs, which are not provided by the study. (delete 
references to insurance company or health care system if not applicable at site). In some cases, it is 
possible that your insurance company or health care system will not pay for these costs because you 
are participating in a research study. (Insert site/country policy.) 
 
The study therapy you will receive if you take part in this study is being supplied by the AIDS 
Malignancy Consortium at no cost to you.  
 
You will receive no payment for taking part in this study. (insert information about help with 
transportation to and from study visits, if any). 
 
WHAT HAPPENS IF I AM INJURED OR, IF I BECOME PREGNANT, MY BABY IS 
INJURED? 
 
If you or your baby is injured as a result of your being in this study, you or your baby will be given 
immediate treatment for injuries, and be referred for further treatment, if necessary. However, you 
may/may not (per site/country policy) have to pay for this care. No funds have been set aside for any 
treatment for injuries, either through [this institution] or the NIH.  You will not be giving up any of 
your legal rights by signing this consent form. 
  
 
 


 
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WHAT ARE MY RIGHTS AS A PARTICIPANT? 
 
Taking part in this study is voluntary. You may choose not to take part in this study or may leave the 
study at any time. Leaving the study will not result in any penalty or loss of benefits to which you are 
entitled. 
 
We will tell you about new information that may affect your health, welfare, or willingness to stay in 
this study. 
 
WHAT IF I HAVE QUESTIONS OR PROBLEMS? 
 
For questions about this study or a research-related injury, contact: 
• 
(name & telephone number for the investigator or other study staff) 
 
For questions about your rights as a volunteer in a research study contact: 
• 
(name or title of person on the Institutional Review Board (IRB) or other organization appropriate 
for the site 
• 
(telephone number of above) 
 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required by 
U.S. Law. This website will not include information that can identify you. At most, the website will 
include a summary of the results. You can search this website at any time.  
 
SIGNATURE 
 
I have been given a copy of this form. I have read it or it has been read to me. All of my questions have 
been answered to my satisfaction.  I agree to participate in the clinical trial. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Participant’s Name (print) 
 
 
 
Participant’s Signature and Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Witness’s Name (print) 
 
 
 
Witness’s Signature and Date  
(As appropriate) 
 
 
I have fully explained this research study to the subject or guardian. In my judgment, there was 
sufficient access to information, including risks and benefits, to make an informed decision. 
 
_________________________________________________________________ 
Investigator Obtaining Consent Name (print) 
 
 
_________________________________________________________________ 
Investigator Obtaining Consent Signature and Date