Conditions: Anal Intraepithelial Neoplasia High-grade Squamous Intraepithelial Lesion HIV Infection
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 91
Healthy volunteers: no

Brief summary:
This randomized phase III trial studies imiquimod or fluorouracil to see how well they work compared to observation in treating patients with high-grade anal squamous skin lesions who are human immunodeficiency virus (HIV)-positive. Biological therapies, such as imiquimod, may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as fluorouracil, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. It is not yet known whether imiquimod or fluorouracil is more effective than observation in treating high-grade anal squamous skin lesions.

Detailed description:
PRIMARY OBJECTIVES:

I. To assess the efficacy of intra-anal imiquimod 2.5% for treatment of anal high-grade squamous intraepithelial lesions (HSIL) compared to observation only.

II. To assess the efficacy of intra-anal topical 5-fluorouracil (fluorouracil) 5% for treatment of anal HSIL compared to observation only.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5%.

II. To compare the efficacy of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5%.

III. To assess for partial response of intra-anal imiquimod 2.5% or topical 5-fluorouracil 5% as compared to observation only.

IV. To evaluate the effect of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5% on human papilloma virus (HPV) persistence.

V. To evaluate anal HSIL outcomes at week 44. VI. To evaluate the effect of behavioral patterns including tobacco smoking and sexual activity on treatment efficacy, tolerability and HPV.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Patients apply imiquimod intra-anally once daily (QD) for 16 weeks. (closed as of protocol version 5.0)

ARM B: Patients apply fluorouracil intra-anally twice daily (BID) on days 1-5. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity.

ARM C: Patients receive no treatment. Patients who still have HSIL at week 20 and who agree to randomization may cross-over to Arm A or B.

After completion of study treatment, patients are followed up at weeks 20, 24, 26, 32, 40, and 44.

Arms:
arm 1: Patients apply imiquimod intra-anally QD for 16 weeks. arm 2: Patients apply fluorouracil intra-anally BID on days 1-5. Treatment repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable toxicity. arm 3: Patients receive no treatment. Patients who still have HSIL at week 20 and who agree to randomization may cross-over to Arm A or B.

Interventions: intervention 1: imiquimod intervention 2: fluorouracil intervention 3: questionnaire administration intervention 4: laboratory biomarker analysis
Intervention descriptions: intervention 1: Given intra-anally intervention 2: Given intra-anally intervention 3: Ancillary studies intervention 4: Correlative studies

Protocol document:
Prot_SAP_000.pdf: 
AMC-088 Protocol (Version 8.0) 02AUG2023 
i 
NCI Version 02AUG2023 
SUMMARY OF CHANGES 
A Randomized, Phase III Study of Intra-anal Imiquimod 2.5% vs. Topical 5-fluorouracil 
5% vs. Observation for the Treatment of High-grade Anal Squamous Intraepithelial 
Lesions in HIV-positive Men and Women 
Version 8.0 
 
NCI Protocol #: AMC-088 
Local Protocol #: AMC-088 
 
NCI Version Date: 02AUG2023 
Protocol Date: 02AUG2023 
 
I. 
Scientific and Substantive Changes: 
# 
Section 
Comments 
1.  Synopsis 
1.2  
10.1 
10.3 
10.6.2 
The target accrual was updated from 118 participants to 88 participants due to 
feasibility concerns with the rate of accrual. 
 
Sample size estimation was updated to include the following information: 
• Due to the slow accrual rate, the sample size was reduced, and the 
revised sample size was decided by the expected accrual close date 
(01 July 2023). Thirty-five participants per arm (or 70 in total for 
observation and 5FU arms) would be the revised sample size. 
 
Table 10-A was updated to reflect the updated sample size, H0 (Futility) Bound 
Z (P-value), H1 (Efficacy) Bound Z (P-value) and Overall β (1-power) Spent 
 
II. 
Administrative and Editorial Changes: 
# 
Section 
Comments 
2.  
Global 
The protocol was updated from version 7.0 to version 8.0 and the date 
was updated from 28JAN2022 to 02AUG2023. 
3.  
Global 
The AMC Operations & Data Management Center email address was 
updated to amc-088@emmes.com in roster and throughout the document. 
4.  
Global 
Minor grammatical corrections were applied throughout the document. 
5.  
Global 
Hyperlinks were updated throughout the document. 
6.  
Protocol Title 
page 
Protocol 
The Protocol Co-chair was updated to replace Naomi Jay with Cristina 
Brickman. 


AMC-088 Protocol (Version 8.0)02AUG2023 
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# 
Section 
Comments 
Roster 
10.6 
7.  
Protocol 
Roster 
Second protocol statistician, Mayuri Jain, added to roster.   
8.  
Protocol 
Roster 
 
APPENDIX 
VI 
 
APPENDIX 
VII 
The positions of AMC Biorepository Director and AMC Laboratory 
Resources Committee Chair were combined and updated to AMC 
Laboratory Director. Sylvia Silver (AMC Biorepository Director) was 
replaced with Jeff Bethony (AMC Laboratory Director). 
 
9.  
List of 
Abbreviations 
The List of Abbreviations table was updated. 
10.  
10.6 
The AMC statistician was updated to replace Lee with Kwon. 
11.  
References 
The reference list was updated to match the references in the protocol. 


AMC-088 Protocol (Version 8.0) 02AUG2023 
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AIDS MALIGNANCY CONSORTIUM 
 
 
AMC PROTOCOL #088 
A Randomized, Phase III Study of Intra-anal Imiquimod 2.5% vs. 
Topical 5-fluorouracil 5% vs. Observation for the Treatment of 
High-grade Anal Squamous Intraepithelial Lesions in HIV-
positive Men and Women 
 
A Multi-Center Trial of the 
AIDS Malignancy Consortium (AMC)  
 Sponsored by: 
National Cancer Institute 
Office of HIV and AIDS Malignancies 
 NCT Registration Number: 
NCT02059499 
 IND Status 
Exempt 
 Commercially Available 
Agents: 
5-fluorouracil 5% (NSC #19893) 
Imiquimod 2.5% (NSC #741062) 
 Protocol Chair: 
Timothy Wilkin, MD MPH 
 Protocol Co-Chair: 
Cristina Brickman, MD MSCE 
 
 
Version 8.0, 02AUG2023 
NCI Version Date: 02AUG2023 
 
 
 


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AMC PROTOCOL SIGNATURE PAGE 
 
I,              , Principal Investigator at site       , agree to conduct and follow this protocol: AMC 
Protocol #088: A Randomized, Phase III Study of Intra-anal imiquimod 2.5% vs. Topical 5-
fluorouracil 5% vs. Observation for the Treatment of High-grade Anal Squamous 
Intraepithelial Lesions in HIV-positive Men and Women, (Version 8.0, 02AUG2023), as 
written according to AMC, NCI, and FDA guidelines. I understand that no deviations from the 
protocol eligibility criteria or waivers for protocol deviations will be permitted. 
 
 
_________________________________ 
_____________________ 
 
Signature 
Date (DDMMMYYYY) 


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TABLE OF CONTENTS 
 
SUMMARY OF CHANGES ......................................................................................................... I 
I. 
Scientific and Substantive Changes: ........................................................................ i 
II. 
Administrative and Editorial Changes: .................................................................... i 
AMC PROTOCOL SIGNATURE PAGE .................................................................................. 2 
TABLE OF CONTENTS ............................................................................................................. 3 
LIST OF TABLES ........................................................................................................................ 6 
SITES PARTICIPATING IN THE STUDY .............................................................................. 7 
PROTOCOL ROSTER ................................................................................................................ 8 
PROTOCOL SYNOPSIS ........................................................................................................... 10 
LIST OF ABBREVIATIONS .................................................................................................... 12 
STUDY SCHEMA ...................................................................................................................... 15 
1.0 
INTRODUCTION........................................................................................................... 16 
1.1 
Rationale ............................................................................................................... 16 
1.2 
Study Rationale ..................................................................................................... 20 
2.0 
OBJECTIVES ................................................................................................................. 22 
2.1 
Primary Objective ................................................................................................. 22 
2.2 
Secondary Objectives............................................................................................ 22 
3.0 
PARTICIPANT SELECTION ...................................................................................... 23 
3.1 
Inclusion Criteria .................................................................................................. 23 
3.2 
Exclusion Criteria ................................................................................................. 24 
3.3 
Recruitment Procedures ........................................................................................ 26 
3.4 
Enrollment Procedures .......................................................................................... 26 
4.0 
DATA COLLECTION AND MONITORING ............................................................. 28 
4.1 
Records to Be Kept ............................................................................................... 28 
4.2 
Role of Data Management .................................................................................... 28 
4.3 
Clinical Site Monitoring and Record Availability ................................................ 28 
5.0 
TREATMENT PLAN ..................................................................................................... 29 
5.1 
Summary of Treatment Plan ................................................................................. 29 
5.2 
Concurrent Medications ........................................................................................ 30 
5.3 
Criteria for Dose Modification .............................................................................. 30 
5.4 
Criteria for Discontinuing Study Treatment ......................................................... 31 


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5.5 
Criteria for Study Discontinuation ........................................................................ 32 
6.0 
STUDY EVALUATIONS ............................................................................................... 33 
6.1 
Screening (Visit -1) ............................................................................................... 33 
6.2 
Randomization Visit/HRA Evaluation (Visit 1) ................................................... 34 
6.3 
Visits 2 (Week 2) 14 days after initiating treatment +/- 3 days ............................ 35 
6.4 
Visit 3 (Week 8) +/- 14 days ................................................................................. 36 
6.5 
Visit 4 (Week 16) +/- 14 days ............................................................................... 37 
6.6 
Visit 5 (Week 20) +/- 21 days ............................................................................... 37 
6.7 
Visit 6 (Week 24) +/- 14 days ............................................................................... 38 
6.8 
Visit 7 (Weeks 26): 14 days after initiating treatment +/- 3 days ......................... 39 
6.9 
Visit 8 (Week 32) +/- 14 days ............................................................................... 39 
6.10 
Visit 9 (Week 40) +/- 14 days ............................................................................... 40 
6.11 
Visit 10 (Week 44) / Study Discontinuation +/- 21 days ...................................... 41 
6.12 
Early Treatment Discontinuation Visit ................................................................. 42 
7.0 
ADVERSE EVENT REPORTING ............................................................................... 43 
7.1 
Adverse Events and Potential Risks ..................................................................... 43 
7.2 
Classification of AEs by Severity and Relationship to Study Drug Administration
............................................................................................................................... 44 
7.3 
Expedited Adverse Event Reporting ..................................................................... 44 
7.4 
Routine AE Reporting........................................................................................... 47 
7.5 
Secondary Malignancy.......................................................................................... 48 
7.6 
Second Malignancy ............................................................................................... 48 
8.0 
PHARMACEUTICAL INFORMATION ..................................................................... 49 
8.1 
Efudex (5-fluorouracil 5%) ................................................................................... 49 
8.2 
Zyclara (imiquimod 2.5%) .................................................................................... 49 
8.3 
Study Agent Supply, Distribution and Accountability ......................................... 50 
9.0 
RESPONSE CRITERIA ................................................................................................ 51 
9.1 
Definition of Clinical Response (by Subject) ....................................................... 51 
10.0 
STATISTICAL CONSIDERATIONS .......................................................................... 52 
10.1 
Rate of Accrual ..................................................................................................... 52 
10.2 
Randomization ...................................................................................................... 52 
10.3 
Sample Size Estimation ........................................................................................ 52 
10.4 
Analysis Population .............................................................................................. 52 


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10.5 
Safety Analysis ..................................................................................................... 52 
10.6 
Monitoring ............................................................................................................ 52 
10.7 
Primary Analyses .................................................................................................. 53 
10.8 
Secondary Analyses .............................................................................................. 54 
10.9 
AMC Policy for Monitoring of Phase III Trials ................................................... 55 
10.10 Publication of Research Findings ......................................................................... 55 
11.0 
ETHICAL AND REGULATORY CONSIDERATIONS ........................................... 56 
11.1 
IRB Approval and Informed Consent ................................................................... 56 
11.2 
Changes to the Protocol ........................................................................................ 56 
11.3 
Subject Confidentiality ......................................................................................... 56 
11.4 
Women and Minorities ......................................................................................... 57 
12.0 
 REFERENCES ............................................................................................................... 58 
APPENDIX I: PERFORMANCE STATUS SCALES ............................................................ 61 
APPENDIX II: SCHEDULE OF EVALUATIONS................................................................. 62 
APPENDIX III: ANAL CYTOLOGY AND HPV SAMPLING............................................. 64 
APPENDIX IV: HIGH RESOLUTION ANOSCOPY (HRA) AND ANAL BIOPSIES ...... 65 
APPENDIX V: BIOPSY PLAN FOR AMC-088...................................................................... 66 
APPENDIX VI: ACSR SPECIMEN PREPARATION & SHIPPING INSTRUCTIONS ... 67 
APPENDIX VII: PATHOLOGY SPECIMENS ...................................................................... 70 
APPENDIX VIII: AMC DATA SAFETY MONITORING PLAN ........................................ 72 
APPENDIX IX: PARTICIPANTAPPLICATION INSTRUCTIONS AND DIARY FOR 
IMIQUIMOD (ZYCLARA) ........................................................................................... 77 
APPENDIX X: PARTICIPANT APPLICATION INSTRUCTIONS AND DIARY FOR 
EFUDEX (5-FLUOROURACIL 5%) ........................................................................... 85 
APPENDIX XI: PROTOCOL AMC-088 SMOKING STATUS/ RECENT SEXUAL 
HISTORY QUESTIONNAIRE ..................................................................................... 95 
 
 
 


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LIST OF TABLES 
 
TABLE 5-A: DOSE MODIFICATIONS .................................................................................. 31 
TABLE 7-A: ROUTINE AE REPORTING REQUIREMENTS BY GRADE AND 
RELATIONSHIP TO STUDY AGENTS ..................................................................... 47 
TABLE 10-A: STATISTICAL TEST BOUNDARIES AND ASSOCIATED OPERATING 
CHARACTERISTICS FOR TESTING EFFICACY OF 5-FLUOROURACIL 5% 
VS. OBSERVATION ...................................................................................................... 53 
TABLE 11-A: ACCRUAL TARGETS ..................................................................................... 57 
 


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SITES PARTICIPATING IN THE STUDY 
This protocol will be open to all interested AMC sites approved by the HPV Working Group. The 
approval will be based on the certification to perform high resolution anoscopy (HRA). 


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PROTOCOL ROSTER 
AMC Protocol #088 
A Randomized, Phase III Study of Intra-anal Imiquimod 2.5% vs. Topical 5-fluorouracil 
5% vs. Observation for the Treatment of High-grade Anal Squamous Intraepithelial 
Lesions in HIV-positive Men and Women 
 
 
Protocol Co-Chairs: 
Cristina Brickman, MD MSCE 
University of California, San Francisco 
UCSF at Mount Zion 
1600 Divisadero Street 
H Bldg, 3rd Floor 
San Francisco, CA 94115 
Tel: (415) 885-7817 
Email: cristina.brickman@ucsf.edu 
 
Timothy J. Wilkin, MD, MPH 
Associate Professor of Medicine 
Weill Medical College of Cornell University 
Cornell Clinical Trials Unit 
53 W. 23rd St. 6th Floor 
New York, NY 10010 
Tel: (212) 746-7202 
Fax: (212) 746-7203 
Email: tiw2001@med.cornell.edu 
 
AMC HPV Working Group Chair: 
Elizabeth Stier, MD  
Boston Medical Center 
Department of Obstetrics and Gynecology  
85 E. Concord Street 6th Floor 
Boston, MA 02118 
Tel: (617) 414-5175 
Fax: (617) 414-7300 
Email: elstier@bu.edu 
Statistician: 
Himanshu Joshi, MBBS, MPH, MSc, PhD 
Assistant Professor 
Institute for Healthcare Delivery Science, Mount 
Sinai Health System 
Dept of Population Health Science and Policy 
Icahn School of Medicine at Mount Sinai 
1425 Madison Ave, Suite 2-70 
New York, NY 10029 
Tel: (212) 659-9635 
Email: Himanshu.Joshi@mountsinai.org 
 
Mayuri Jain, MPH 
Icahn School of Medicine at Mount Sinai 
1425 Madison Avenue, NYC, NY  10029 
Tel: (857) 269-5623 
Email: mayuri.jain@mountsinai.org 
 
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: amc-088@emmes.com 
 
AMC Laboratory Director: 
Jeff Bethony, PhD 
George Washington University Medical Center 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2663 
Fax: (202) 994-5056 
Email: jbethony@gwu.edu 


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PROTOCOL SYNOPSIS 
 
Title: 
A Randomized, Phase III Study of Intra-anal Imiquimod 2.5% 
vs. Topical 5-fluorouracil 5% vs. Observation for the Treatment 
of High-grade Anal Squamous Intraepithelial Lesions (HSIL) in 
HIV-positive Men and Women 
Phase of Study: 
Phase III 
Study Design: 
Prospective, randomized, three-arm, open-label study to evaluate 
the complete response rate of intra-anal high-grade squamous 
intraepithelial lesions (HSIL) treated with imiquimod 2.5% or 
topical 5-fluorouracil 5% (5FU) as compared to spontaneous 
regression in human immunodeficiency virus (HIV)-infected 
participants. 
As of protocol version 5.0, the imiquimod 2.5% arm was dropped 
because of product unavailability. 
At randomization, participants will be randomized to intra-anal 
topical 5FU or observation. Participants will be followed with 
anal cytology and anoscopy without biopsy through 16 weeks of 
treatment or observation. At Week 20 (four weeks after 
completing randomized treatment), high-resolution anoscopy 
(HRA) with biopsies and cytology will be performed for the 
primary endpoint. Participants originally assigned to the 
observation arm having anal HSIL at Week 20 will be offered 
5FU for 16 weeks (Weeks 24-40). Participants originally 
assigned 5FU with anal HSIL at Week 20 will be referred for 
treatment off study according to the local standard of care. All 
participants will be seen at Week 44 for HRA with biopsies of 
visible lesions. 
Accrual Target: 
88 participants 
Population: 
HIV-infected participants with biopsy-proven high-grade anal 
intraepithelial lesions (AIN; AIN2 with positive p16 stain, AIN2-
3, or AIN3). 
Regimen: 
• Arm A: Imiquimod 2.5% cream applied to the intra-anus daily 
for 16 weeks. Perianal disease will also be treated if present. 
Closed as of protocol version 5.0. 
• Arm B: Topical 5FU cream to the intra-anus twice daily for 
five days followed by nine days off. This cycle is repeated 
eight times over 16 weeks. Perianal disease will also be treated 
if present. 
• Arm C: No treatment is given for 16 weeks. 
Duration of Participation: 
44 weeks 


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Primary Objective: 
Complete response is defined as no anal biopsies with HSIL and 
cytology without HSIL at Week 20. 
 
• To assess the efficacy of intra-anal topical 5FU for treatment 
of anal HSIL compared to observation only. 
Secondary Objectives: 
 
• To describe the efficacy of intra-anal imiquimod 2.5% for 
treatment of anal HSIL compared to observation only. 
• To assess the safety and tolerability of intra-anal imiquimod 
2.5% and topical 5FU. 
• To compare the efficacy of intra-anal imiquimod 2.5% and 
topical 5FU. 
• To assess for partial response of intra-anal imiquimod 2.5% or 
topical 5FU as compared to observation only. 
• To evaluate the effect of intra-anal imiquimod 2.5% and 
topical 5FU on human papillomavirus (HPV) persistence. 
• To evaluate anal HSIL outcomes at Week 44. 
• To evaluate the effect of behavioral patterns including tobacco 
smoking and sexual activity on treatment efficacy, tolerability 
and HPV. 
 
 


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LIST OF ABBREVIATIONS 
5FU 
5-fluorouracil 5% 
ACD 
Acid citrate dextrose 
ACSR 
AIDS and Cancer Specimen Resource 
AE 
Adverse event 
AIDS 
Acquired immunodeficiency syndrome 
AIN 
Anal intraepithelial neoplasia 
AMC 
AIDS Malignancy Consortium 
AML 
Acute myelocytic leukemia 
ANC 
Absolute neutrophil count 
ANCHOR 
Anal Cancer HSIL Outcomes Research 
ART 
Antiretroviral therapy 
ASCCP 
American Society for Colposcopy and Cervical Pathology 
Beta-HCG 
Beta-human chorionic gonadotropin 
BID 
Twice daily (bis in die) 
CBC 
Complete blood count 
CDC 
Centers for Disease Control and Prevention 
CDUS 
Clinical Data Update System 
CIN 
Cervical intraepithelial neoplasia 
CIP 
Cancer Imaging Program 
CR 
Complete response 
CRF 
Case report form 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTEP 
Cancer Therapy Evaluation Program 
CTEP-AERS 
Cancer Therapy Evaluation Program Adverse Event Reporting System 
DARF 
Drug accountability record form 
DHHS 
Department of Health and Human Services 
DMU 
Data mapping utility 
DNA 
Deoxyribonucleic acid 
DSMB 
Data and Safety Monitoring Board 
ECOG 
Eastern Cooperative Oncology Group 


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EGW 
External genital warts 
FDA 
Food and Drug Administration 
FTP 
File transfer protocol 
GEE 
Generalized estimating equations 
H&E 
Hematoxylin and eosin 
HIV 
Human immunodeficiency virus 
HPV 
Human papillomavirus 
HRA 
High resolution anoscopy 
HSIL 
High-grade squamous intraepithelial lesions 
IDB 
Investigational Drug Branch 
IEC 
Institutional ethics committee 
IL 
Interleukin 
IME 
Important medical event 
IRB 
Institutional review board 
IRC 
Infrared coagulation 
IND 
Investigational new drug 
ITT 
Intent-to-treat 
LEEP 
Loop electroexcision procedure 
LSIL 
Low grade squamous intraepithelial lesions 
KPS 
Karnofsky Performance Score 
LTFU 
Lost to follow-up 
MDS 
Myelodysplastic syndrome 
MOP 
Manual of Procedures 
MSM 
Men who have sex with men 
NCI 
National Cancer Institute 
NSAID 
Non-steroidal anti-inflammatory drug 
ODMC 
Operations and data management center 
OHAM 
Office of HIV and AIDS Malignancy 
PBMC 
Peripheral blood mononuclear cell 
PCR 
Polymerase chain reaction 
PET 
Position emission tomography 


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PHI 
Protected health information 
PIN 
Penile intraepithelial lesions 
PR 
Partial response 
PrEP 
Pre-exposure prophylaxis 
REB 
Research ethics board 
RNA 
Ribonucleic acid 
SAE 
Serious adverse event 
SCC 
Squamous cell carcinoma 
SIL 
Squamous intraepithelial lesion 
SOP 
Standard Operating Procedure 
SPECT 
Single-photon emission computerized tomography 
SWG 
Scientific Working Group 
TNF 
Tumor necrosis factor 
TORO 
Transfer of Regulatory Obligations 
UCSF 
University of California San Francisco 
VIN 
Vulvar intraepithelial lesions 
5FU 
5% 5-fluorouracil cream 
 
 


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STUDY SCHEMA 
 
Visit -1 
 
 
 
 
Visit 1 
(Week 0) 
 
 
 
 
Visit 2 to 4     
(Week 2, 8, 16) 
 
 
 
 
 
 
Visit 5 
(Week 20) 
 
 
 
 
Visit 6 
(Week 24) 
 
 
Visit 7 
(Week 26) 
 
 
Visit 8 
(Week 32) 
 
 
Visit 9 
(Week 40) 
 
 
Visit 10 
(Week 44) 
Screening 
Arm A 
Imiquimod 
for 16 weeks 
(closed with v5) 
Arm C 
Observation 
only 
(No Visit 2) 
Randomization 
HRA Evaluation 
Anal Biopsies and Cytology 
Anal Biopsies and Cytology 
Arm B 
5FU 
for 16 weeks 
Arm A 
Local Standard 
of Care 
(No Visit 6-9) 
 
 
Arm B 
Local Standard 
of Care 
(No Visit 6-9) 
 
Arm C 
Assign to 5FU 
Arm C 
Imiquimod 
for 16 weeks 
(closed with 
v5) 
Arm C 
5FU 
for 16 weeks 


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1.0 
INTRODUCTION 
There are limited therapeutic options for treatment of anal high-grade squamous 
intraepithelial lesions (HSIL), particularly intra-anal HSIL. Topical therapies including 5-
fluorouracil 5% (5FU; Efudex) and imiquimod 5% (Aldara) are frequently reported as case 
studies but there are few controlled studies and these have widely varying results. Results 
vary in part due to: 1) differences in treatment regimens; 2) differences in treatment site, 
e.g., perianal versus intra-anal, or both; 3) differences in inclusion criteria with some 
studies reporting on treatment for both low-grade squamous intraepithelial lesions (LSIL) 
and HSIL as a single group and others reporting results for HSIL separately; and, 4) 
differences in treatment populations, e.g., immunocompetent vs. immunocompromised, or 
both. Study methods also differ with regards to the amount of disease treated, use of high 
resolution anoscopy (HRA) and histology for determination of efficacy. There are no data 
available on daily application of imiquimod 2.5% (Zyclara) for treatment of anal HSIL. 
This multisite, randomized study seeks to determine the efficacy of treatment using 5-
fluorouracil 5% compared to observation in human immunodeficiency virus (HIV)-
infected individuals with HRA-guided biopsy-proven intra-anal HSIL. Given the lack of 
drug availability and resulting arm closure, the assessment of the efficacy of treatment 
using imiquimod 2.5% compared to observation will be exploratory. 
1.1 
Rationale 
Human papilloma virus (HPV)-associated cancers of the anus in HIV-infected individuals 
are increased at rates that are estimated to be up to 128 times greater than the general 
population, particularly in men who have sex with men (MSM) (1). The anal cancer 
precursor lesion, anal HSIL, also disproportionately affects HIV-infected individuals and 
is found in up to 50% of HIV-infected men and 25% of HIV-infected women (2-4). Anal 
HSIL can be difficult to treat particularly in HIV-infected individuals who frequently 
present with multifocal and extensive disease. Recurrences are common post-treatment and 
vary widely, depending on treatment and length of follow-up, from 22%-79% in HIV-
infected individuals (5-8). 
There are limited therapeutic options for the treatment of anal HSIL. Infrared coagulation 
(IRC), an in-office ablative therapy, is an effective treatment but often requires multiple 
treatments for multifocal lesions and has potential post-procedure complications including 
pain, bleeding, or abscess formation. While IRC can eliminate a given lesion 64-81% of 
the time, up to 70% of patients may develop anal HSIL at other untreated sites (7, 9-11). 
Ablation may be inappropriate for extensive circumferential disease, which is a common 
presentation, and is contra-indicated in patients on anticoagulant therapies or with 
thrombocytopenia. New non-invasive treatment options for anal HSIL are needed. 
A self-applied topical compound may be better tolerated for treating large areas of disease 
compared with ablative therapies; a partial response where the disease burden is reduced 
by a topical treatment may then allow for a less involved ablative therapy. There are no 
approved topical therapies for anal HSIL. Based on similarities between the 
pathophysiology of other genital squamous cell intraepithelial lesions to anal HSIL, both 
imiquimod 2.5% and 5FU have been used for treatment of perianal and intra-anal HSIL, 
but their usage is considered off-label and they have only been studied sporadically in 
clinical trials. Imiquimod 5% cream was first approved by the U.S. Food and Drug 


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Administration in 1997 for topical treatment of external genital and perianal warts. In 2004 
it received approval for treatment of clinically superficial basal cell carcinoma and actinic 
keratosis. Imiquimod 2.5% was approved in 2009. Topical 5-fluorouracil in concentrations 
of 2% to 5% has been used for more than 50 years in the treatment of vulvar and vaginal 
high-grade intraepithelial neoplasia and skin pre-cancers. Studies are needed to evaluate 
any systemic toxicity arising from intra-anal use. 
The Anal Cancer HSIL Outcomes Research (ANCHOR) trial is a large, randomized 
clinical trial that enrolled adults living with HIV with anal HSIL detected on histology. 
Participants were randomized to treatment of anal HSIL or active monitoring without 
treatment. The trial followed participants at least every six months. 4,459 adults were 
randomized. Results indicated that treatment of anal HSIL reduced the risk of anal cancer 
by 57% (95% CI 6% - 80%). The rate of cancer in the active monitoring group was about 
402/100,000 person years (about two people out of 1000 were predicted to develop cancer 
over the 6-month observation period). The rate of cancer in the treatment group was about 
173/100,000 person-years (about one person out of 1000 was predicted to develop cancer 
over the 6-month period of randomized therapy). 
1.1.1 Background: topical 5-fluorouracil 5% 
Topical treatment with 5-fluorouracil was first reported in 1962 for treatment of 
skin cancers following a report that systemic 5-fluorouracil induced regression of 
keratosis (12). It is a pyrimidine analog made by fluorination of uracil on position 
5 of the pyrimidine ring. Its principal mechanism of action is to inhibit 
deoxyribonucleic acid (DNA) synthesis by blocking the conversion of uracil 
deoxyribonucleotide to thymine deoxyribonucleotide. It creates a thymine 
deficiency resulting in a DNA deficiency, thus leading to disordered function 
resulting in the inability of cells to replicate. A secondary effect of 5-fluorouracil is 
direct interference with ribonucleic acid (RNA) synthesis and function, inhibiting 
the incorporation of uracil into RNA by competing with uracil-active enzymes. Its 
most marked effect is on rapidly proliferating tissues. It is commercially available 
as 1, 2, and 5 percent fluorouracil topical cream or gel. The most commonly used 
concentration is 5%. It causes erythema and edema followed by erosion, ulceration, 
and necrosis when applied topically to a neoplasm. It has been shown to 
preferentially treat neoplasms with only an inflammatory response on adjacent 
healthy skin. 
Topical 5-fluorouracil has been used since the 1970s to treat female lower genital 
track disease associated with HPV-related infections and has been well documented 
(13-15). There are limited data and very few randomized placebo-controlled trials 
evaluating 5-fluorouracil for genital warts; however, a Cochrane review suggests 
that in spite of the paucity and heterogeneity of the literature there is evidence for 
a therapeutic effect against genital warts (16) Topical 5FU has been used for 
treatment of vulvar intraepithelial neoplasia (41% improvement), vaginal 
intraepithelial neoplasia (85% improvement), and cervical intraepithelial neoplasia 
(66% improvement). A randomized study evaluated 5-fluorouracil 5% as 
prophylactic therapy to prevent recurrence of high-grade cervical intraepithelial 
neoplasia (CIN) following loop electroexcision procedure (LEEP) in HIV-infected 
women (14). Recurrence of CIN in the 5FU group was 28% compared to 47% in 


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the observation group. 
There are limited reports of 5FU specifically for treatment of anal lesions. In one 
study evaluating treatment of patients with perianal HSIL, 7 of 8 patients treated 
with topical 5FU cream applied twice weekly for 16 weeks had no evidence of 
Bowen’s disease on follow-up biopsies at 12 months post-treatment (17). An open-
label study has been reported in 46 patients; multifocal lesions were seen in 76% 
and 74% had anal HSIL. All were HIV-positive. In this study, 1 g of 5-fluorouracil 
5% was inserted using an applicator twice weekly at night for 16 weeks. Complete 
responses were seen in 12 of 34 patients with anal HSIL and partial responses with 
a decrease in HSIL to LSIL were seen in an additional eight subjects. Moderate to 
severe side effects were reported in 48% (18). Results were recently reported in a 
study of 11 patients using a slightly different schedule in which approximately 
0.25 g of 5FU was placed intra-anally at bedtime for a median treatment time of 20 
weeks. One patient discontinued therapy due to side effects and 73% of patients 
experienced some amount of irritation. Six patients had improvement in their 
disease including one with extensive condyloma who had no lesions on follow-up 
HRA (19). Jay et al. (20) described the results of a trial from the University of 
California San Francisco (UCSF) Anal Neoplasia Clinic using intra-anal 5FU twice 
daily for five days, followed by a nine-day rest period. The cycle was repeated four 
times and patients re-evaluated. Twenty patients with extensive anal HSIL 
involving more than 75% of the circumference were evaluable. Complete histologic 
regression was seen in three, no response in one, and 16 had a significant decrease 
in volume of disease to 25-50% that allowed in-office ablation using infrared 
coagulation. Subjects experienced pain, ulceration, bleeding, and exacerbation of 
herpes simplex. However, only two of the entire group of 27 discontinued treatment 
because of side effects, and four were considered non-compliant and not evaluable 
because they completed less than two cycles (20). 
While these results are difficult to compare due to differences in treatment 
protocols, all the studies suggest that anal HSIL may resolve or improve with 
topical 5FU therapy. 
1.1.2 Background: imiquimod 2.5% 
Imiquimod has been used for treatment of external genital warts since 1997. It is an 
imidazoquinoline amine, which is a topical synthetic compound that exhibits 
antiviral activity by up-regulating the immune response. The compound initially 
binds to cell surface receptors resulting in secretion of a variety of inflammatory 
mediators including interferon alpha, tumor necrosis factor (TNF)-alpha, 
interleukin (IL)-12, IL-1, 6, 8, and 10. These cytokines then activate the cell-
mediated immune response and in turn the release of interferon-gamma, 
responsible for activating virus-infected cell killing cytotoxic T-cells. Imiquimod 
has no direct antiviral activity or direct effect on T-cells but is a strong inducer of 
Th-1 type cytokines resulting in recruitment of dense CD4+ infiltrates, which is an 
important mechanism for HPV clearance and one that is reduced in HIV-infected 
populations. 
Off-label use of imiquimod is common in both skin and mucosal disease (21, 22) 


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with extensive case reports noted in the medical literature. Treatment with 
imiquimod has been reported for treatment of infectious diseases including 
molluscum contagiosum, genital herpes, and leishmaniasis (23-25) Finally, 
imiquimod has been used for treatment of anogenital intraepithelial neoplasias 
including vulvar intraepithelial neoplasias (VIN) (26, 27), penile intraepithelial 
neoplasia (PIN) (28, 29), and anal intraepithelial neoplasia (AIN) (30). 
There are relatively few randomized studies of imiquimod for perianal or anal 
disease. A randomized, controlled trial of 100 patients assigned to imiquimod 5% 
cream or placebo for 16 weeks showed minimal total clearance of warts in the 
intent-to-treat analysis (11% drug vs. 6% placebo.) However, 47% of patients in 
the imiquimod group reported greater than 50% reduction in total wart area vs. 20% 
in the placebo arm (p=.026). Response rates to imiquimod for genital warts are 
better in HIV-seronegative patients compared to HIV-infected patients, with 
response rates of 62% and 31%, respectively (31). 
The role of imiquimod in clearing anal HPV infection in patients with anogenital 
condyloma was investigated in a single-arm study involving 239 HIV-infected and 
-uninfected men and women. At baseline, 95% had low risk HPV, 60% had high 
risk HPV, and 56% had both. Condylomata were treated with imiquimod 5% cream 
for external warts and suppositories for intra-anal disease, three times a week for 
26 weeks. At 12 weeks, 30% of subjects with high-risk HPV had cleared their 
infection as did 66% of subjects with low-risk HPV (32). 
There are limited reports using imiquimod for treatment of anal HSIL in cohort 
studies and case reports that demonstrate efficacy (33). In one study, 14 of 19 (74%) 
HIV-positive MSM had complete regression of SIL after treatment with imiquimod 
5%, and five developed recurrent HSIL. A decrease in HPV types and HPV viral 
load was also seen following treatment (32). The results from a randomized, 
double-blind, placebo-controlled study of imiquimod 5% for anal HSIL were 
reported in 53 patients. In the treatment arm, four resolved and eight downgraded 
to LSIL versus only one of 25 in the placebo arm that had a spontaneous regression. 
Patients were treated with open-label imiquimod 5% after completing the study and 
when grouped together 29 of 47 (61%) had sustained regression of HSIL after 
treatment with imiquimod 5%. Interestingly, patients were instructed to use only 
half a packet applied no more than 2 cm into the canal, they were treated for four 
months and the dosage reduced if significant symptoms developed (34). 
Zyclara is 2.5% (or 3.75%) imiquimod cream. It has a Food and Drug 
Administration (FDA) indication for treatment of actinic keratosis in adults and for 
treatment of external genital warts (EGW) (Zyclara package insert; 
http://pi.medicis.us/zyclara.pdf). In two double-blind, randomized, placebo-
controlled clinical studies, 601 subjects with EGW were treated with 2.5% 
imiquimod cream or a matching placebo cream. The baseline wart count ranged 
from two to 48 warts. Most subjects had two or more treated anatomic areas at 
baseline. Up to one packet of study cream was applied once daily. Subjects 
continued applying the study cream for up to eight weeks, stopping if they achieved 
complete clearance of all (baseline and new) warts in all anatomic areas. The 
complete clearance rates in the two studies were 27% and 29% compared to 10% 


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and 9% for placebo creams. Local site reactions to Zyclara were common in these 
studies: 32% (126/400) of subjects who used Zyclara cream and 2% (4/202) of 
subjects who used vehicle cream discontinued treatment temporarily (required rest 
periods) due to adverse local skin reactions, and 1% (3/400) of subjects who used 
Zyclara cream discontinued treatment permanently due to local skin/application 
site reactions. These studies did not evaluate intra-anal use. 
In summary, few of these studies were randomized and/or placebo-controlled and 
they are difficult to compare due to different treatment regimens, and differences 
in whether treatment targeted intra-anal or perianal disease, or whether efficacy was 
reported for LSIL, HSIL, or a combination. Similar to topical 5FU the studies 
suggest that anal HSIL may regress or improve with imiquimod 2.5% treatment. 
1.2 
Study Rationale 
Richel et al. (35) reported on 148 HIV-infected MSM with squamous intraepithelial lesions 
(SIL; 57% with HSIL) randomized to 4-month treatments with 2% 5-fluorouracil, 5% 
imiquimod, or monthly electrocautery. The response rate was 17%, 24%, and 39%, 
respectively in the intention to treat group with severe side effects reported as 27%, 43%, 
and 18%, respectively. Recurrence rates were 58%, 71%, and 68% at 72 weeks post-
treatment. In the per protocol group with HSIL, the complete response rate was 21%, 21%, 
and 50% respectively. This is the first report comparing fluorouracil to imiquimod in a 
randomized study. While these data indicate that monthly ablation may be superior to either 
topical cream in the population studied, it may not be appropriate or be the best treatment 
for those with extensive anal HSIL. In addition, the treatment regimens are differently than 
what is commonly used for treatment in North America. Richel et al. studied one dose of 
2% 5-fluorouracil applied twice weekly, which is lower than what we are proposing in this 
trial. Further, inserting either agent with suppositories may inadvertently bypass the anal 
mucosa thereby reducing efficacy. Richel et al. may have confirmed this in that they 
reported better efficacy of treatment to perianal lesions compared to intra-anal lesions. Our 
study proposes application of the agents directly to the anal mucosa. 
We are proposing an arm with no treatment for up to 20 weeks. This group is necessary to 
clearly show the activity of these compounds. There are few data on the regression of anal 
HSIL in the absence of treatment. Fox et al. observed regression in one out of 25 
participants randomized to placebo. The risk of progression for this duration of observation 
is very low, especially with interim anoscopy during the treatment period. 
The imiquimod arm was closed as of protocol version 5.0 due to product unavailability.  
Rationale in the context of ANCHOR results: The absolute risk of cancer over the course 
of randomized therapy (24 weeks) was very low in both arms. There are ongoing 
randomized controlled trials of HPV therapeutic vaccines that randomize women with 
cervical HSIL to no treatment for a similar short period. We believe the risk is small and 
is lessened by interim anoscopic monitoring of participants with the option to remove the 
participant from the study for fear of imminent progression. Participants who appear at risk 
for progression to cancer are not enrolled into AMC-088. As of 19NOV2021, no cases of 
invasive cancer have developed in AMC-088.   
Version 8.0 reduces the sample size from 118 to 88. The primary analysis is not changing. 


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The effect of this sample size change on statistical power is discussed in Section 10.0. The 
motivation for the change is because of the slow accrual despite multiple strategies to 
increase enrollment. Enrollment closed as of 01JUL2023. 
1.2.1 HPV genotyping 
Anal swabs will be collected for polymerase chain reaction (PCR) and reverse line 
blot analysis to determine the HPV genotype at the AMC HPV Genotype Core 
Laboratory per AMC Standard Operating Procedure (SOP). 


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2.0 
OBJECTIVES 
2.1 
Primary Objective 
Complete response is defined as no anal biopsies with HSIL and cytology without HSIL at 
Week 20. 
• To assess the efficacy of intra-anal topical 5FU for treatment of anal HSIL compared 
to observation only. 
2.2 
Secondary Objectives 
• To describe the efficacy of intra-anal imiquimod 2.5% for treatment of anal HSIL 
compared to observation only. Note: this objective is no longer powered to establish 
efficacy. 
• To assess the safety and tolerability of intra-anal imiquimod 2.5% and topical 5FU. 
• To compare the efficacy of intra-anal imiquimod 2.5% and topical 5FU. 
• To assess for partial response of intra-anal imiquimod 2.5% or topical 5FU as compared 
to observation only. 
• To evaluate the effect of intra-anal imiquimod 2.5% and topical 5-FU on HPV 
persistence. 
• To evaluate anal HSIL outcomes at Week 44. 
• To evaluate the effect of behavioral patterns including tobacco smoking and sexual 
activity on treatment efficacy, tolerability, and HPV. 


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3.0 
PARTICIPANT SELECTION 
A rostered AMC investigator (CTEP-registered physician investigator) or a CTEP-
registered associate advanced practice clinician (i.e., nurse practitioner or physician 
assistant) who is certified in HRA by the AMC must document that each protocol 
participant meets all stated eligibility criteria. Participating sites must have documentation 
that each eligibility requirement is satisfied prior to subject enrollment. If delegating 
eligibility review to an HRA-certified, CTEP-registered advanced practice clinician, the 
site Principal Investigator must document this assigned responsibility in the institution’s 
delegation log. In compliance with CTEP policy, no exceptions to eligibility criteria will 
be granted in any circumstance. 
NOTE: Institutions may use this section of the protocol as an eligibility checklist for source 
documentation if it has been reviewed, signed, and dated before registration/randomization 
by the study investigator. If used as source documentation, this checklist must be printed, 
the investigator must check each item to document their assessment that the participant 
meets each eligibility criterion, and the completed checklist must be maintained in the 
participant’s chart. 
Participant ID Number: 088 - ___ ___ ___ - ___ ___ ___ 
Patient’s Initials (F M (optional) L): ___ ___ ___ 
NOTE: All questions regarding eligibility should be directed to the study chair. 
3.1 
Inclusion Criteria 
Each participant must comply with the following criteria: 
____ 3.1.1 HIV-positive, male or female, ≥ 21 years of age. Documentation of HIV-1 infection 
by means of any one of the following: 
• Documentation of HIV diagnosis in the medical record by a licensed health care 
provider; 
• Documentation of receipt of antiretroviral therapy (ART) (at least two different 
medications, except pre-exposure prophylaxis [PrEP] regimens [e.g., Truvada]) 
by a licensed health care provider (documentation may be a record of an ART 
prescription in the participant’s medical record, a written prescription in the 
name of the participant for ART, or pill bottles for ART with a label showing 
the participant’s name); 
• HIV-1 RNA detection by a licensed HIV-1 RNA assay demonstrating >1000 
RNA copies/mL; 
• Any licensed HIV screening antibody and/or HIV antibody/antigen 
combination assay confirmed by a second licensed HIV assay such as a HIV-1 
Western blot confirmation or HIV rapid multispot antibody differentiation 
assay. 
NOTE: A “licensed” assay refers to a U.S. FDA-approved assay, which is required 
for all investigational new drug (IND) studies. 


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____ 3.1.2 Biopsy-proven HSIL (AIN2 with a positive p16 stain, AIN2-3, or AIN3) of the anal 
canal at either the squamocolumnar junction or distal anus, documented within 60 
days prior to enrollment, but not less than seven days prior to randomization. 
____ 3.1.3 HSIL comprising two or more lesions, or anal HSIL in at least two octants, or anal 
HSIL that has recurred or is persistent after prior ablative treatment. 
Note: HSIL should be in the anal canal at either the squamocolumnar junction or 
distal anus on HRA at screening or randomization. The extent of HSIL should be 
based on available biopsy results and visual appearance. 
____ 3.1.4 Anal HSIL lesions are visible at randomization and no lesions are suspicious for 
invasive cancer. 
____ 3.1.5 Ability to understand and willing to provide informed consent. 
____ 3.1.6 Participants must, in the opinion of the investigator, be capable of complying with 
the requirements of this protocol including self-administration of study treatment. 
____ 3.1.7 Karnofsky performance status (KPS) of > 70% or ECOG performance status ≤ 1 
(Appendix I). 
____ 3.1.8 CD4 count ≥ 200 within 120 days prior to enrollment or plasma HIV-1 RNA <200 
copies/mL within 120 days prior to randomization. 
____ 3.1.9 For females, documentation that the participant is being followed with cervical 
cytology and/or HPV testing per current “Guidelines for the Prevention and 
Treatment of Opportunistic Infections in HIV-Infected Adults and Adolescents” 
and American Society for Colposcopy and Cervical Pathology (ASCCP) 
guidelines.1,2 Cervical cytology must be performed prior to randomization for 
women who are overdue for screening per the guidelines. Women should also have 
confirmation of absence of cancer or suspected cancer upon visual examination of 
the vulva, vagina, and cervix within 12 months prior to randomization. 
____ 3.1.10 Absolute neutrophil count (ANC) >750 cells/mm3; hemoglobin ≥ 9.0 g/dL; platelet 
count ≥75,000/mm3 within 90 days prior to randomization. 
3.2 
Exclusion Criteria 
Participants meeting the following criteria will be excluded from the study: 
____ 3.2.1 History of anal cancer 
 
 
1 
Panel on Opportunistic Infections in HIV-Infected Adults and Adolescents. Guidelines for the prevention and 
treatment of opportunistic infections in HIV-infected adults and adolescents: recommendations from the Centers 
for Disease Control and Prevention, the National Institutes of Health, and the HIV Medicine Association of the 
Infectious 
Diseases 
Society 
of 
America. 
Available 
at 
http://aidsinfo.nih.gov/contentfiles/lvguidelines/adult_oi.pdf. Accessed March 2, 2016. 
2 
Massad LS, Einstein MH, Huh WK, Katki HA, Kinney WK, Schiffman M, Solomon D, Wentzensen N, Lawson 
HW; 2012 ASCCP Consensus Guidelines Conference. 2012 updated consensus guidelines for the management 
of abnormal cervical cancer screening tests and cancer precursors. Obstet Gynecol. 2013 Apr;121(4):829-46. 


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____ 3.2.2 Prior intra-anal use of topical 5FU or imiquimod 2.5%, 3.75% or 5% for treatment 
of HSIL at any point, use of intra-anal or topical 5FU or imiquimod 2.5%, 3.75% 
or 5% for treatment of condyloma within 6 months prior to randomization or 
perianal imiquimod 2.5%, 3.75% or 5% or topical 5FU within six months prior to 
randomization. 
____ 3.2.3 Extensive concurrent perianal or lower vulvar HSIL or condyloma requiring a 
different treatment modality than the study treatment, or treatment that cannot be 
deferred in observation arm, per examining provider. 
____ 3.2.4 Condyloma occupying more than 50% of the circumference of the anal canal or 
that obscures a satisfactory exam. 
____ 3.2.5 Ongoing use of anticoagulant therapy other than aspirin or non-steroidal anti-
inflammatory drugs (NSAIDs) that places the participant at increased bleeding risk 
in the opinion of the site investigator. 
____ 3.2.6 Acute treatment for an infection (excluding fungal infection of the skin and sexually 
transmitted infections) or other serious medical illness within 14 days prior to 
randomization. 
____ 3.2.7 Malignancy requiring systemic therapy. Note: Kaposi sarcoma limited to the skin 
is not exclusionary unless requiring systemic chemotherapy. 
____ 3.2.8 Concurrent systemic corticosteroids, cytokines, and immunomodulatory therapy 
(e.g., interferons). 
____ 3.2.9 Participants who received investigational agents, other than investigational 
antiretroviral agents for HIV, within the four weeks before randomization, unless 
approved by the study chair. 
____ 3.2.10 Treatment for anal or perianal HSIL, LSIL, or condyloma within four months of 
randomization. Please note that IRC or electrocautery of a biopsy site to stop 
bleeding does not constitute treatment. 
____ 3.2.11 Female participants who are pregnant or breastfeeding: Women of childbearing 
potential must have a negative urine or serum pregnancy test within 72 hours prior 
to randomization. All women of childbearing potential must be willing to comply 
with an acceptable birth control regimen to prevent pregnancy while receiving 
treatment and for three months after treatment is discontinued as determined by the 
investigator. Post-menopausal women must be amenorrheic for at least 12 months 
to be considered of non-childbearing potential. (Note: A woman of childbearing 
potential is one who is biologically capable of becoming pregnant. This includes 
women who are using contraceptives or whose sexual partners are either sterile or 
using contraceptives.) 
 
Physician Signature: ______________________________ Date: ___________________ 
(Optional unless this section is used as an eligibility checklist) 
 
 


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3.3 
Recruitment Procedures 
This study will be open to all AMC sites certified by the HPV Working Group in HRA. 
This includes appropriate staff trained and certified by the HPV Working Group in HRA, 
and the availability of supplies and equipment, including colposcope, biopsy instruments, 
and the capability for acquiring and maintaining photo documentation of HRA images of 
dysplasia. 
Participants will be selected from established HSIL-positive clinic patients or referrals 
from physicians, such as primary care physicians, HIV specialists, dermatologists, or 
colorectal surgeons. Participants may originate from different health care settings. The 
Investigator or designated individual will review the potential participants’ laboratory 
results, and if the criteria are met, they will be scheduled for the screening visit. Participants 
who sign the informed consent form and meet all eligibility and screening criteria will be 
invited to participate in this protocol. If participants do not meet eligibility criteria, they 
will be informed and offered appropriate alternative treatment and/or follow-up screening. 
Note: Participants who were or are in the ANCHOR trial are allowed to enroll into AMC-
088. 
3.4 
Enrollment Procedures 
This study will be available for enrollment at all AMC sites that have HRA-certified 
providers. Sites must have this protocol approved by their Institutional Review Boards 
(IRB) and be registered with the AMC Operations and Data Management Center (AMC 
ODMC) before they may enroll participants. 
3.4.1 Screening registration 
After it is determined that the participant is potentially eligible for the study and the 
participant has signed the informed consent form, the participant must be enrolled 
in Segment A (screening segment) of the protocol on-line via the AMC 
AdvantageEDCSM Internet Data Entry System. After successful registration, the 
participant will receive a nine-digit participant ID and will then enter the screening 
process. Participants can immediately proceed to Segment B (randomization) if all 
necessary data are available. 
3.4.2 Randomization 
If the participant meets all of the eligibility criteria for the study during the 
screening evaluation, the participating site will complete the protocol-specific 
eligibility checklist and will enroll the participant into Segment B of the protocol 
(online via the AMC Internet Data Entry System, AdvantageEDC). Enrollment 
should occur no more than one week prior to the initiation of treatment. (Enrollment 
one day prior to or on the day of treatment is strongly encouraged). Once the 
eligibility checklist is submitted, a system generated confirmation email with 
randomization to treatment or observation will be sent to the site staff, AMC 
ODMC, and Protocol Chair upon successful registration on Segment B. If the 
online system is inaccessible, the site should notify the AMC ODMC via email at 
amc-088@emmes.com or via phone at 301-251-1161 for further instructions. 


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3.4.3 Cross-over  
For participants who were assigned to the observation arm upon enrollment into 
Segment B of the protocol, who have biopsy-proven HSIL present at Week 20, and 
who agree to receive 5FU at Week 24, the participating site will enroll the 
participant into Segment C of the protocol (online via AdvantageEDC). Enrollment 
should occur no more than one week prior to the initiation of treatment. (Enrollment 
one day prior to or on the day of treatment is strongly encouraged). Once the 
eligibility checklist is submitted, a system generated confirmation email with the 
randomization assignment will be sent to the site staff, AMC ODMC, and Protocol 
Chair upon successful registration on Segment C. If the online system is 
inaccessible, the site should notify the AMC ODMC via email at amc-
088@emmes.com or via phone at 301-251-1161 for further instructions. 


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4.0 
DATA COLLECTION AND MONITORING 
4.1 
Records to Be Kept 
Case report forms (CRFs) will be provided for each participant via AdvantageEDC upon 
enrollment. Participants must not be identified by name on any study documents. Data will 
be recorded on the CRFs using the unique participant identification number assigned at 
registration. Sample CRFs will be available on the AMC ODMC web site 
(www.AIDSCancer.org). 
4.2 
Role of Data Management 
Instructions concerning the recording of study data on CRFs will be provided by the AMC 
ODMC. The AMC AdvantageEDC User’s Guide can be found on the AMC ODMC web 
site (www.AIDSCancer.org). Each site is responsible for entering data and submitting 
forms according to the target submission dates set forth by AdvantageEDC. 
It is the responsibility of the AMC ODMC to assure the quality of electronic data reported 
for each AMC study. This role extends from protocol development to generation of the 
final study databases. 
4.3 
Clinical Site Monitoring and Record Availability 
This study will be monitored by the AMC Data and Safety Monitoring Board, an 
independent body to the AMC, as outlined in its Charter and as required by the National 
Cancer Institute (NCI) Data and Safety and Monitoring Guidelines for randomized phase 
III investigations. The study will adhere to the AMC Data Safety Monitoring Plan 
(Appendix VIII). 
This study will be monitored in compliance with AMC policies and by the Clinical Data 
Update System (CDUS) Version 3.0. Cumulative protocol- and participant-specific CDUS 
data will be submitted via FTP burst to CTEP on a quarterly basis. Reports are due January 
31, April 30, July 31, and October 31. Instructions for submitting data using the CDUS can 
be found on the CTEP Web site (http://ctep.cancer.gov/reporting/cdus.html). 
The AMC ODMC is responsible for compiling and submitting CDUS data to CTEP for all 
participants and for providing the data to the Principal Investigator for review. 


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5.0 
TREATMENT PLAN 
5.1 
Summary of Treatment Plan 
Entry to Week 16 
Arm A (closed as of protocol version 5.0): 
Participants randomized to Arm A will begin applying imiquimod 2.5%. The participant 
will apply one pump actuation of cream intra-anally using a syringe or gloved finger inside 
the anus as described in  Appendix IX. If the participant is tolerating after two weeks 
(adverse event [AE] of Grade 1 or less), the dose should be increased to one pump actuation 
to the right side of the anus and one pump actuation to the left side of the anus. An 
additional pump actuation can be used to cover any areas of perianal or lower vulvar HSIL 
as needed if instructed by the investigator. The cream should be applied at night before bed 
or longest period of rest once a day. This should be continued for 16 weeks. Study treatment 
should be stopped after 16 weeks even if continuous treatment was not completed in the 
case of treatment interruptions due to lapses in participant adherence or adverse events. 
Imiquimod 2.5% (enough for at least 112 pump actuations; approximately 28 actuations 
per 7.5 gm bottle) should be dispensed at entry and Week 8. Additional containers can be 
dispensed if needed to treat perianal or lower vulvar SIL. When continuing treatment at 
Week 8, new containers should be dispensed. 
Containers should be weighed before dispensing drug to the participant. Empty or partially 
used containers should be brought back at each visit to be weighed as a measurement of 
adherence. Approximately 3.3 gm of cream should be used by Week 2 and 23.1 gm of 
cream should be used by Week 8. If using additional cream for perianal or lower vulvar 
HSIL then 6.6 gm should be used by Week 2, and 36.3 gm of cream should be used by 
Week 8. 
Arm B: 
Participants randomized to Arm B will begin applying 1 mL of topical 5FU cream. One 
gram of topical 5FU is the equivalent of 1 mL. The total daily dose will be 1 gram of cream, 
and the weekly dose is 5 grams of cream. 5FU contains 5 grams of 5-fluororacil per 100 
grams. The daily dose is therefore 50 mg of 5-fluorouracil delivered in divided doses of 
25 mg twice daily (BID), and the total weekly dose is 250 mg delivered in 5 grams of 
cream. 
Participants can apply the cream with a syringe or finger. If using a syringe, the participant 
will apply 0.5 mL (equivalent to 0.5 gm) of cream using a syringe inserted into the anal 
opening. If applying with a finger, the participant will apply 0.25 mL (equivalent to 0.25 
gm) of cream using a finger to the right side of the anus and a second 0.25 mL (equivalent 
to 0.25 gm) to the left side of the anus as described in Appendix X. The cream should be 
applied in a thin film twice daily for 5 days followed by 9 days of no treatment. Any areas 
of perianal or lower vulvar HSIL should be covered with an additional 0.25 mL as needed 
if instructed by the investigator. This cycle should be repeated to complete eight cycles or 
16 weeks. Study treatment should be stopped after 16 weeks even if eight cycles were not 
completed (in the case of treatment interruptions due to lapses in participant adherence or 
adverse events). 


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40 grams of 5FU should be dispensed at Week 0 and Week 8. The partially used 5FU tube 
should be replaced with a new 40 gm tube at Week 8. 
Tubes should be weighed before dispensing drug to the participant. Empty or partially used 
tubes should be brought back at each visit to be weighed as a measurement of the total 
amount of cream used during treatment. Approximately 5 gm of cream should be used by 
Week 2 and 20 gm of cream should be used by Week 8. If using additional cream for 
perianal or lower vulvar HSIL then 7.5 gm should be used by Week 2, and 30 gm of cream 
should be used by Week 8. 
Arm C: 
No treatment. 
If receiving topical treatment after Week 20, participants should follow the instructions for 
Arm A or B as appropriate. 
5.2 
Concurrent Medications 
All pain medications, anticoagulants, HPV vaccines (if ever received), and ART should be 
recorded in the appropriate electronic case report forms at the time of study entry, and any 
changes to the participant’s medications should be updated as those changes occur. Any 
additional therapies prescribed for treatment of study product related adverse events should 
be recorded as well. 
5.3 
Criteria for Dose Modification 
Participants experiencing Grade 3 AEs that are at least possibly related to the study product 
should have the product held until the AE resolves or reduces in severity to Grade 1. The 
study product should be restarted at the discretion of the site investigator using a reduced 
dose (described in Table 5-A below). If the AE continues to be resolved or is Grade 1 at 
the reduced dose, then the dose can be escalated again at the discretion of the site 
investigator. 
Participants experiencing Grade 2 AEs that are at least possibly related to study product 
can either continue the product at the standard dose (preferred) or dose reduce one level. If 
the participant tolerates the reduced dose after two weeks, then the dose can be escalated 
again at the discretion of the site investigator. 
Participants experiencing Grade 1 AEs that are at least possibly related to study product 
can continue the product at the standard dose. A dose reduction should only be done if 
necessary for continued adherence to study follow-up. 


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Table 5-A: Dose modifications 
 
Topical 5-fluorouracil 5% 
Imiquimod 2.5% 
(closed as of version 5.0) 
Standard dose 
Twice daily for 5 days followed by 9 days off 
(5 gm of cream per 2 week cycle) 
2 pump actuations once a day 
at night 
Reduced dose 
Twice daily for 3 days followed by 11 days 
off 
(3 gm of cream per 2 week cycle) 
1 pump actuation once a day 
at night 
Minimal dose 
Once daily for 3 days followed by 11 days off 
(1.5 gm of cream per 2 week cycle) 
1 pump actuation three times 
a week at night 
 
5.3.1 Dose delays 
Participants may experience dose delays for several reasons including adverse and 
logistical issues. Sites should strive to complete 16 weeks of study treatment. The 
end of dosing and the Week 16 visit may be delayed up to three weeks to allow 
participants to complete 16 weeks of study treatment. The last dose of study 
treatment should be no later than 19 weeks after randomization. For participants 
whose last dose is delayed, the Week 20 visit should be delayed to ensure at least 
two weeks after the last dose of study treatment. For participants who are 
randomized to topical treatment at Visit 6/Week 24, the visit schedule should be 
based on the date of cross-over randomization (e.g., Visit 7 should occur two weeks 
following the Visit 6 date, Visit 8 should occur eight weeks following the Visit 6 
date, etc.). Please contact the protocol chairs for advice on specific participants as 
needed. 
5.4 
Criteria for Discontinuing Study Treatment 
The investigator should discontinue the study treatment if there is evidence of Grade 4 AEs 
at least possibly due to study treatment. 
The investigator may discontinue study treatment, at his or her discretion, if the participant 
experiences Grade 3 AEs at least possibly due to study treatment. Alternatively, study 
treatment may be held and dose reduced as described in Section 5.3. 
Participants who prematurely discontinue treatment should remain in study follow-up 
according to the schedule of events. If treatment is discontinued prior to Week 16, then the 
participant should undergo HRA with biopsies for the primary endpoint at Week 20. Off-
study treatment for anal HSIL prior to Week 20, other than randomized treatment, should 
be avoided. 
Similarly, participants who prematurely discontinue study treatment administered 
beginning at Week 24 should undergo HRA with biopsies at Week 44. 
Participants should discontinue assigned study treatment (or observation without 
treatment) if progression of disease is suspected. For example, the pathologist suspects 
possible superficial invasion or there is worsening of histology, as evidenced by an 


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endophytic growth pattern and pushing borders, or if the clinician notes suspicious 
friability, ulceration, mass effect, heaped-up borders, and/or markedly abnormal vascular 
pattern on HRA. These participants should remain in study follow-up and receive treatment 
as determined by the site investigator. 
5.5 
Criteria for Study Discontinuation 
Participants may withdraw from the study at any time, for any reason. Removal of the 
participant from the study by the physician should occur for any of the following reasons: 
• Evidence of invasive carcinoma in any anal cytology or biopsy specimens. 
• Worsening of Karnofsky performance status to ≤ 60 (ECOG ≥ 2) 
If a participant is terminated because of progression to squamous cell carcinoma (SCC), 
the adverse finding will be reported to the protocol chair and the NCI as a serious AE (see 
Section 7.0 for further instructions). Such participants should receive appropriate treatment 
outside the study. The results of any anal biopsies obtained to evaluate disease progression 
should be recorded in the CRF. 
If a participant fails to attend three study visits in a row, the participant may be withdrawn 
for failure to attend study appointments. 


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6.0 
STUDY EVALUATIONS 
Schedule of Evaluations is provided in Appendix II. 
6.1 
Screening (Visit -1) 
The screening HRA may occur prior to obtaining informed consent provided that the HRA 
was performed as part of routine clinical care and according to the AMC guidelines for 
HRA. 
All screening procedures must occur prior to randomization in AdvantageEDC. 
6.1.1 Complete medical history 
To include 
• Duration of HIV and AIDS diagnoses, history of opportunistic illnesses, and 
date of initial diagnosis of anal HSIL. If at all possible, the investigator should 
obtain a copy of the pathology report from the first diagnosis of anal HSIL. 
• CDC HIV risk categories and history of AIDS defining conditions. 
• Current medications (as required by Section 5.2) and history of drug allergies. 
• All antiretroviral medications taken within the past 30 days will be documented. 
Current pain medication usage will be quantified. 
• Concurrent anal problems including condyloma, hemorrhoids, fissure, skin tag, 
fistula, sexually transmitted infections, bleeding, pruritus, and pain or irritation. 
• Prior treatments of anal HSIL and condyloma. 
• T-cell nadir: The participant’s prior nadir CD4+ cell count (absolute value and 
date) must be documented, when possible, with a copy of the nadir CD4+ cell 
count report and entered on the CRF. If this documentation is not available, then 
participant recollection of nadir CD4 will suffice. For participants who do not 
know the exact nadir value and for whom there is no source documentation, 
then recall of the categorical nadir (e.g., <50, <100, <200 cells/mm3) and year 
will suffice. 
6.1.2 Clinical assessment 
Complete physical examination to include: 
• Performance status (Appendix I), blood pressure, temperature, pulse, weight, 
and height. 
• A complete genital examination in men that includes evaluation of penis and 
scrotum for lesions, discharge, tenderness, testicular asymmetry, and masses. 
• Female participants must have received a routine gynecologic examination 
including a cervical pap test (if having a cervix) as required in Section 3.1.9. 
• A complete external genital examination in women that includes gross 
evaluation of the vulva for lesions. 


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• HRA exam of the anal canal will be performed within 60 days but not less than 
seven days prior to randomization (Appendix IV). 
• HRA guided biopsies will be obtained to assure eligibility for the study and to 
be enrolled and randomized. If the participant has had biopsies within 60 days 
but not less than seven days of enrollment, new biopsies are not necessary 
unless there is concern for progression towards invasive cancer. See Appendix 
V for biopsy protocol. 
• The number of involved octants, location, and percent circumference of HSIL 
will be documented. If this is not available at the screening HRA, then this can 
be documented at entry prior to randomization. 
6.1.3 Laboratory tests must be obtained within 90 days prior to enrollment (unless 
otherwise noted) and will include the following: 
• Anal biopsy: Results of biopsy diagnostic of HSIL (within 60 days to one week 
prior to enrollment). 
• Anal cytology (within 60 days prior to enrollment). If anal cytology is not 
available prior to entry, then this may be obtained at entry prior to HRA. 
• Anal swab for HPV testing. If not obtained at the time of screening HRA, then 
may be obtained at entry prior to HRA. 
• Safety laboratory testing: Baseline laboratory testing will include complete 
blood count (CBC) with differential and platelet count. 
• HIV viral load (within 120 days): Viral load studies will be performed using an 
assay with a limit of detection of 75 copies/mL or less. 
• T cells (within 120 days): CD4/CD8 counts and percentages will be quantified. 
• Pregnancy test: Urine or serum beta-human chorionic gonadotropin (beta-
HCG) will be performed (and results obtained) within 72 hours prior to 
enrollment when indicated (women of childbearing potential). 
• AIDS and Cancer Specimen Resource (ACSR) donation: If the participant has 
consented, a whole blood specimen shall be collected for donation to the ACSR. 
Specimen handling instructions and informed consent are in Appendices VI and 
VII. 
6.2 
Randomization Visit/HRA Evaluation (Visit 1) 
The baseline visit for study entry and randomization must occur within 60 days after the 
screening visit and seven to 60 days after the HRA with biopsies used for eligibility 
(Visit 1). 
6.2.1 History and targeted physical exam 
• Clinical assessment: The participant’s medical history will be updated for any 
changes. A review of systems for any new or changed local symptoms, such as 
hematochezia, dyschezia, erythema, swelling, or pruritus. A targeted physical 
exam should be performed as indicated.  


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• A targeted physical examination is to include pulse, blood pressure, and any 
previously identified or new signs or symptoms, including diagnoses that the 
participant has experienced since the last visit. Staff should inquire about 
symptoms and examine the treatment areas for any AEs. 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results 
obtained) when indicated (women of childbearing potential). 
• HRA exam of the anal canal will be performed. The number of involved octants, 
location, and percent circumference of HSIL will be documented per Section 
9.1. If there are any lesions suspicious for invasive anal cancer, then the 
participant should not be randomized. Entry criteria in Section 3.1.4 should be 
confirmed prior to randomization (e.g., anal HSIL is visible at study entry and 
no lesions are suspicious for invasive cancer). 
• If during an HRA exam, the clinician notes suspicious friability, ulceration, 
mass effect, heaped-up borders, and/or markedly abnormal vascular pattern, 
these could be indicative of invasive disease. This participant should not be 
randomized, and additional biopsies should be obtained. 
• All lesions, all aspects of the anal transformation zone, distal canal and perianus 
will be photographically documented prior to treatment. 
• The study clinician should explain how the study treatment is applied and observe 
the participant apply the first dose of medication or a proxy white cream to assess 
for adequate application technique. Sites should use an anesthetic cream (e.g., 4% 
lidocaine cream) that is used during HRA for the proxy cream. The treatment diary 
will be distributed to the participant. Topical treatment must be initiated within 
two weeks after randomization. 
• AMC-088 Smoking Status and Recent Sexual History Questionnaire: A review of 
smoking and recent sexual behavior. 
• Study agent must be weighed prior to distribution to the participant to allow for 
accurate measurement of adherence. 
6.2.2 Eligibility review and randomization 
Pursuant to NCI policy, no exceptions from the eligibility criteria shall be made. If 
all criteria are met, eligible participants will enrolled for randomization to treatment 
or observation (Segment B) through AdvantageEDC and commence the study as 
specified in the protocol according to the arm of the study indicated on the 
participant registration screen from randomization. Participants who do not meet 
all of the eligibility criteria will be considered screen failures and the Screen Failure 
Form must be completed in AdvantageEDC. 
6.3 
Visits 2 (Week 2) 14 days after initiating treatment +/- 3 days 
6.3.1 For study participants randomized to imiquimod 2.5% or 5-fluorouracil 5% arm 
only: 
• Clinical assessment: The participant’s medical history will be updated for any 
changes. A review of systems for any new or changed local symptoms, such as 


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hematochezia, dyschezia, erythema, swelling, or pruritus. A targeted physical 
exam should be performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results 
obtained) when indicated (women of childbearing potential). 
• Anoscopy or HRA may be performed at the discretion of the treating provider 
to investigate symptoms that the participant may be experiencing or to evaluate 
for inflammation and ulceration in the anal canal to assure that the positioning 
of the study treatment is correct. 
• Collect the treatment diary and evaluate treatment adherence. Partially used 
containers should be weighed to measure the amount of cream used, then 
returned to participant. Additional instruction on proper administration of study 
treatment should be given as needed. 
6.4 
Visit 3 (Week 8) +/- 14 days 
6.4.1 The following evaluations will be performed, and laboratory samples will be 
collected for all participants: 
• Clinical assessment: The participant’s medical history will be updated for any 
changes. A review of systems for any new or changed local symptoms, such as 
hematochezia, dyschezia, erythema, swelling, or pruritus. A targeted physical 
exam should be performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results 
obtained) when indicated (women of childbearing potential). 
• Anal swab for HPV testing. 
• For study participants randomized to the 5-fluorouracil 5% arm only: HRA will 
be performed provided that the participant is not experiencing significant anal 
discomfort from the study treatment. In such a case, anoscopy should be 
performed without soaking the anal canal with acetic acid. Acetic acid and/or 
Lugol’s solution should only be used sparingly to avoid further participant 
discomfort. The number of involved octants, location, and percent 
circumference of HSIL will be documented. Anal biopsies should be performed 
only if the clinician notes suspicious friability, ulceration, mass effect, heaped-
up borders, and/or markedly abnormal vascular pattern. This could be indicative 
of progression of the lesion toward invasive disease. 
• HRA may be performed in the observation arm if disease progression is 
suspected. 
• If performing HRA, all lesions, all aspects of the anal transformation zone, distal 
canal and perianus will be photographically documented. 
• Collect study diary and evaluate treatment adherence. Additional instruction on 
proper administration of study treatment should be given as needed. Partially 
used containers should be weighed to measure the amount of cream used. 
Participants will receive new replacement containers as needed for their 


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appropriate study arm. Study agent must be weighed prior to distribution to the 
participant to allow for accurate measurement of adherence. 
6.5 
Visit 4 (Week 16) +/- 14 days 
• Clinical assessment: The participant’s medical history will be updated for any changes. 
A review of systems for any new or changed local symptoms, such as hematochezia, 
dyschezia, erythema, swelling, or pruritus. A targeted physical exam should be 
performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results obtained) 
when indicated (women of childbearing potential). 
• Anal swab for HPV testing. 
• Anoscopy or HRA may be performed at the discretion of the treating provider to 
investigate symptoms that the participant may be experiencing, to evaluate for 
inflammation and ulceration in the anal canal to assure that the positioning of the study 
treatment is correct, or if disease progression is suspected. If performing HRA or 
anoscopy and the participant is experiencing significant anal discomfort from the study 
treatment, HRA or anoscopy should be performed without soaking the anal canal with 
acetic acid. Acetic acid and/or Lugol’s solution should only be used sparingly to avoid 
further participant discomfort. If performing anoscopy or HRA, the number of involved 
octants, location, and percent circumference of HSIL will be documented. Anal 
biopsies should be performed only if the clinician notes suspicious friability, ulceration, 
mass effect, heaped-up borders, and/or markedly abnormal vascular pattern. This could 
be indicative of progression of the lesion toward invasive disease. 
• If HRA is performed, then all lesions, all aspects of the anal transformation zone, distal 
canal and perianus will be photographically documented. 
• Collect the treatment diary and evaluate adherence. All containers of study treatment 
should be collected. Partially used containers should be weighed to measure the amount 
of cream used.  
6.6 
Visit 5 (Week 20) +/- 21 days 
Note this visit must occur at least two weeks after the last dose of study drug. 
6.6.1 The following evaluations will be performed, and laboratory samples will be 
collected for all participants. 
• Clinical assessment: The participant’s medical history will be updated for any 
changes. A review of systems for any new or changed local symptoms, such as 
hematochezia, dyschezia, erythema, swelling, or pruritus. A targeted physical 
exam should be performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results 
obtained) when indicated (women of childbearing potential). 
• Anal cytology (standard of care). If the result is not evaluable, then the site 
should repeat the cytology to obtain an interpretable result. 
• Anal swab for HPV testing. 


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• HRA exam of the anal canal will be performed per Section 9.1. The number of 
involved octants, location, and percent circumference of HSIL will be 
documented. 
• All participants should have biopsies obtained as per Appendix V. Please note 
that pathologists should remain blinded to the treatment assignment. 
• If anal HSIL is present, then participants originally randomized to observation 
have the option of receiving 5-fluorouracil 5%. Cross-over should occur as 
outlined in Section 3.4.3. If these participants decline cross-over, then they 
should be referred off study to be treated according to the local standard of care 
as described below. 
• Participants originally randomized to 5-fluorouracil 5% arms, with HSIL at 
Week 20 should be referred off study to be treated according to the local 
standard of care. Participants can be treated with ablative methods such as 
office-based infrared coagulation, hyfrecation, electrocautery, laser, or 80-85% 
trichloroacetic acid if preferred. Topical treatments such as 5-fluorouracil 5%, 
imiquimod, Veregen 15%, or cidofovir should not be used. 
• Condyloma can be treated at the discretion of the local provider with ablative 
methods such as office-based infrared coagulation, hyfrecation, electrocautery, 
laser, or 80-85% trichloroacetic acid if preferred. Topical treatments such as 5-
fluorouracil 5%, imiquimod, Veregen 15%, or cidofovir should not be used. 
• All lesions, all aspects of the anal transformation zone, distal canal and perianus 
will be photographically documented. 
• AMC-088 Smoking Status and Recent Sexual History Questionnaire: A review 
of smoking and recent sexual behavior. 
6.7 
Visit 6 (Week 24) +/- 14 days 
This visit is only necessary for participants who started on the observation arm, still have 
HSIL at Week 20, and agree to be randomized to treatment in the crossover portion of the 
study. They will be randomized to a study-provided topical therapy (intra-anal topical 5-
fluorouracil 5%) for 16 weeks of treatment. Participants who started on the observation 
arm and do not have HSIL at Week 20 will be treated with local standard of care and only 
return for Visit 10 (same as Arm A and B). Participants who started on the observation arm 
who do not agree to the second randomization will be treated with local standard of care 
and only return for Visit 10 (same as Arm A and B). 
6.7.1 History and physical exam 
• Clinical Assessment: The participant’s medical history will be updated for any 
changes. A review of systems for any new or changed local symptoms, such as 
hematochezia, dyschezia, erythema, swelling, or pruritus. A targeted physical 
exam should be performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results 
obtained) when indicated (women of childbearing potential). 
• Participants will be assigned to 5-fluorouracil 5%. 


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• The study clinician should explain how the study treatment is applied and 
observe the participant apply the first dose of medication or a proxy white cream 
to assess for adequate application technique. Sites should use an anesthetic 
cream (e.g., 4% lidocaine cream) that is used during HRA for the proxy cream. 
The treatment diary will be distributed to the participant. 
• All lesions, all aspects of the anal transformation zone, distal canal and perianus 
will be photographically documented prior to treatment. 
• AIDS and Cancer Specimen Resource (ACSR) donation: If the participant has 
consented, a whole blood specimen shall be collected for donation to the ACSR. 
Specimen handling instructions and informed consent are in Appendices VI and 
VII. 
• Study agent must be weighed prior to distribution to the participant to allow for 
accurate measurement of adherence. 
• Treatment diary distributed to participant. 
6.8 
Visit 7 (Weeks 26): 14 days after initiating treatment +/- 3 days 
This visit is only required for those participants starting a topical treatment at 
Week 24. 
• Clinical assessment: The participant’s medical history will be updated for any changes. 
A review of systems for any new or changed local symptoms, such as hematochezia, 
dyschezia, erythema, swelling, or pruritus. A targeted physical exam should be 
performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results obtained) 
when indicated (women of childbearing potential). 
• Anoscopy or HRA may be performed at the discretion of the treating provider to 
investigate symptoms that the participant may be experiencing or to evaluate for 
inflammation and ulceration in the anal canal to assure that the positioning of the study 
treatment is correct. 
• Collect the treatment diary and evaluate treatment adherence. Partially used containers 
should be weighed to measure the amount of cream used, then returned to participant. 
Additional instruction on proper administration of study treatment should be given as 
needed. 
6.9 
Visit 8 (Week 32) +/- 14 days 
This visit is only required for those participants starting a topical treatment at 
Week 24. 
The following evaluations will be performed, and laboratory samples will be collected for 
all participants: 
• Clinical assessment: The participant’s medical history will be updated for any changes. 
A review of systems for any new or changed local symptoms, such as hematochezia, 
dyschezia, erythema, swelling, or pruritus. A targeted physical exam should be 
performed as indicated (see Section 6.2.1). 


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• Pregnancy test: Urine or serum beta-HCG will be performed (and results obtained) 
when indicated (women of childbearing potential). 
• Anal swab for HPV testing. 
• HRA will be performed provided that the participant is not experiencing significant 
anal discomfort from the study treatment. In such a case, anoscopy should be performed 
without soaking the anal canal with acetic acid. Acetic acid and/or Lugol’s solution 
should only be used sparingly to avoid further participant discomfort. The number of 
involved octants, location, and percent circumference of HSIL will be documented. 
Anal biopsies should be performed only if the clinician notes suspicious friability, 
ulceration, mass effect, heaped-up borders, and/or markedly abnormal vascular pattern. 
This could be indicative of progression of the lesion toward invasive disease. 
• If performing HRA, all lesions, all aspects of the anal transformation zone, distal canal 
and perianus will be photographically documented. 
• Participants receiving imiquimod 2.5% or 5-fluorouracil 5% should bring back empty 
or partially used study drug containers, which are to be weighed by staff. 
• Collect study diary and evaluate treatment adherence. Additional instruction on proper 
administration of study treatment should be given as needed. Partially used containers 
should be weighed to measure the amount of cream used. New containers will be 
dispensed according to treatment arm. Study agent must be weighed prior to distribution 
to the participant to allow for accurate measurement of adherence. 
6.10 
Visit 9 (Week 40) +/- 14 days 
This visit is only required for those participants starting a topical treatment at 
Week 24. 
• Clinical assessment: The participant’s medical history will be updated for any changes. 
A review of systems for any new or changed local symptoms, such as hematochezia, 
dyschezia, erythema, swelling, or pruritus. A targeted physical exam should be 
performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results obtained) 
when indicated (women of childbearing potential). 
• Anal swab for HPV testing. 
• Anoscopy or HRA may be performed at the discretion of the treating provider to 
investigate symptoms that the participant may be experiencing, to evaluate for 
inflammation and ulceration in the anal canal to assure that the positioning of the study 
treatment is correct, or if disease progression is suspected. If performing HRA or 
anoscopy and the participant is experiencing significant anal discomfort from the study 
treatment, HRA or anoscopy should be performed without soaking the anal canal with 
acetic acid. Acetic acid and/or Lugol’s solution should only be used sparingly to avoid 
further participant discomfort. If performing anoscopy or HRA, the number of involved 
octants, location, and percent circumference of HSIL will be documented. Anal 
biopsies should be performed only if the clinician notes suspicious friability, ulceration, 


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mass effect, heaped-up borders, and/or markedly abnormal vascular pattern. This could 
be indicative of progression of the lesion toward invasive disease. 
• If performing HRA, all lesions, all aspects of the anal transformation zone, distal canal 
and perianus will be photographically documented. 
• Participants receiving 5-fluorouracil 5% must bring back all study drug containers, 
which are to be weighed by staff. 
• Collect the treatment diary and evaluate treatment adherence. All containers of study 
treatment should be collected. Partially used containers should be weighed to measure 
the amount of cream used. 
6.11 
Visit 10 (Week 44) / Study Discontinuation +/- 21 days 
This visit is required for all participants. Please note that this visit must occur at least two 
weeks after the last dose of study drug. 
6.11.1 The following evaluations will be performed, and laboratory samples will be 
collected for all participants. 
• Clinical assessment: The participant’s medical history will be updated for any 
changes. A review of systems for any new or changed local symptoms, such as 
hematochezia, dyschezia, erythema, swelling, or pruritus. A targeted physical 
exam should be performed as indicated (see Section 6.2.1). 
• Pregnancy test: Urine or serum beta-HCG will be performed (and results 
obtained) when indicated (women of childbearing potential). 
• Anal swab for HPV testing. 
• Anal cytology (standard of care). 
• HRA exam of the anal canal. The number of involved octants, location, and 
percent circumference of HSIL will be documented per Section 9.1. This only 
applies to participants who began on Arm C (observation) and were randomized 
at Visit 6 (Week 24). 
• All participants should have biopsies obtained as per Appendix V. Please note 
that pathologists should remain blinded to the treatment assignment. 
• Any HSIL diagnosed at this visit should be treated off study at the discretion of 
the treating provider. 
• Ablative treatments should not be performed within two weeks of the Week 44 
visit if at all possible. 
• All lesions, all aspects of the anal transformation zone, distal canal and perianus 
will be photographically documented. 
• AMC-088 Smoking Status and Recent Sexual History Questionnaire: A review 
of smoking and recent sexual behavior. 


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6.12 
Early Treatment Discontinuation Visit 
• Clinical assessment: The participant’s medical history will be updated for any changes. 
A review of systems for any new or changed local symptoms, such as hematochezia, 
dyschezia, erythema, swelling, or pruritus. A targeted physical exam should be 
performed as indicated (see Section 6.2.1). 
• Anal swab for HPV testing. 
• Anal cytology (standard of care) and anal swab for HPV testing. 
• HRA exam of the anal canal. The number of involved octants, location, and percent 
circumference of HSIL will be documented per Section 9.1. 
• All participants should have biopsies obtained as per Appendix V. Please note that 
pathologists should remain blinded to the treatment assignment. 
• Any HSIL diagnosed at this visit should be treated off study at the discretion of the 
treating provider. 
• All lesions, all aspects of the anal transformation zone, distal canal and perianus will be 
photographically documented. 
• Collect the treatment diary and evaluate adherence. All containers of study treatment 
should be collected. Partially used containers should be weighed to measure the amount 
of cream used. 
• AMC-088 Smoking Status and Recent Sexual History Questionnaire: A review of 
smoking and recent sexual behavior. 


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7.0 
ADVERSE EVENT REPORTING 
CTEP Version 5.0 of the NCI Common Terminology Criteria for Adverse Events 
(CTCAE) will be utilized for AE reporting. CTCAE Version 5.0 is identified and located 
on the CTEP website at:  
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
All appropriate treatment areas should have access to a copy of the CTCAE Version 5.0. 
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. 
7.1 
Adverse Events and Potential Risks 
7.1.1 Expected adverse events related to the procedure 
Pap smear collection, High Resolution Anoscopy (HRA) and anal biopsy. 
Participants will likely experience pressure and urgency to defecate during the Pap 
smear collection and HRA. Anal bleeding may occur up to one week after the 
biopsy is taken. 
The risk of infection is less than 1%. 
7.1.2 Expected adverse events related to imiquimod 
Most expected adverse events are local effects where the cream is applied. These 
include pain, burning, irritation, pruritus, erythema, edema, ulceration, bleeding, 
flaking and crusting of the skin, allergic reactions. Participants receiving 
imiquimod have also experienced headache, rash at other sites, back pain, 
pain/erythema/ulceration at adjacent sites (e.g. scrotum). Sinus infection, nausea, 
fever, and flu-like illness have also been reported. 
7.1.3 Expected adverse events related to topical 5-fluorouracil 5% 
Most expected adverse events are local effects where the cream is applied. These 
include pain, burning, irritation, pruritus, erythema, edema, ulceration, bleeding, 
flaking and crusting of the skin, allergic reactions. Scarring of treated areas has also 
been reported. Participants receiving 5-fluorouracil 5% have also experienced 
emotional upset, medicinal taste, thrombocytopenia, leukocytosis, hair loss, rash at 
other sites, pain/erythema/ulceration at sites adjacent to treated sites (e.g. scrotum), 
eye and nasal irritation, and herpes simplex reactivation. Women received 5-
fluorouracil 5% have reported miscarriages, and one birth defect (ventriculoseptal 
defect) occurred in an infant born to a woman who was exposed to 5-fluorouracil 
5% during pregnancy. 
7.1.4 Expected adverse events related to the study disease 
Anal HSIL may progress to anal carcinoma, whether observed or treated with study 
provided treatments. If suspected progression to SCC occurs, as outlined in Section 
5.5 of the protocol, the investigator may withdraw the participant from the 
randomized strategy and pursue treatment of anal HSIL or invasive cancer outside 
of the study as clinically indicated. If progression to SCC occurs, then the 


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participant must be withdrawn from the protocol and appropriate therapy instituted. 
Such participants should remain in study follow-up. 
7.2 
Classification of AEs by Severity and Relationship to Study Drug Administration 
7.2.1 Adverse Event: Any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom or disease temporally associated with the use of a 
medical treatment or procedure regardless of whether it is considered related to the 
medical treatment or procedure (attribution of unrelated, unlikely, possible, 
probable, or definite). 
7.2.2 Life-threatening Adverse Event: Any AE that places the subject or subject, in view 
of the Investigator, at immediate risk of death from the reaction. 
7.2.3 Serious Adverse Event (SAE): Any AE occurring at any dose that results in any of 
the following outcomes: Death, a life-threatening AE, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/ 
incapacity, or a congenital anomaly/birth defect. 
7.2.4 Please note for hospitalization – All hospitalizations (or prolongation of existing 
hospitalization) for medical events equivalent to CTCAE Grade 3, 4, 5 must be 
reported regardless of the requirements for Phase of study, expected or unexpected, 
and attribution. For example, do not report an admission for pharmacokinetic 
sampling, but do report an admission for a myocardial infarction. 
7.2.5 Toxicity: Toxicity is a term NOT clearly defined by regulatory organizations. 
Toxicity has been described as an AE that has an attribution of possibly, probably 
or definitely related to investigational treatment. To minimize confusion the NCI 
would recommend that the term toxicity NOT be utilized for AE reporting 
purposes. The CTCAE continues to use the term ‘toxicity’ because of familiarity. 
7.2.6 Unexpected Adverse Event: Any AE that is not listed in available sources including 
the package insert, the Investigator’s Brochure, or the protocol. 
7.2.7 Cancer Therapy Evaluation Program Adverse Event Reporting System (CTEP-
AERS): An electronic system for expedited submission of AE reports. 
7.2.8 Attribution: The determination of whether an AE is related to a medical treatment 
or procedure. Attribution categories: 
Definite – The AE is clearly related to the investigational agent. 
Probable – The AE is likely related to the investigational agent. 
Possible – The AE may be related to the investigational agent. 
Unlikely – The AE is doubtfully related to the investigational agent. 
Unrelated – The AE is clearly NOT related to the investigational agent. 
7.3 
Expedited Adverse Event Reporting 
7.3.1 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 


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(http://ctep.cancer.gov). These requirements are briefly outlined in the table below 
(Section 7.3.3). 
A 24-hour notification is to be made to the AMC by telephone at 301-251-1161, 
only when Internet connectivity is disrupted. Once Internet connectivity is restored, 
a 24-hour notification phoned in must be entered electronically into CTEP-AERS 
by the original submitter at the site. 
7.3.2 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 email recipients. 
7.3.3 Expedited reporting guidelines 
Use the NCI protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
Note: A death on study requires both routine and expedited reporting regardless of 
causality, unless as noted below. Attribution to treatment or other cause must be 
provided. 
Death due to progressive disease should be reported as Grade 5 “General 
disorders and administration site conditions – Disease Progression”. Evidence 
that the death was a manifestation of underlying disease (e.g., radiological changes 
suggesting tumor growth or progression: clinical deterioration associated with a 
disease process) should be submitted. 
 
 


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FOR USE IN CIP STUDIES INVOLVING COMMERCIAL (NON-IND/IDE) AGENTS 
ONLY 
CIP Commercial Agent Studies: Expedited Reporting Requirements for Adverse Events that 
Occur in a CIP Non-IND/IDE trial within 30 Days of the Last Administration of a 
Commercial Imaging Agent 1, 2 
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:  
• 
Death 
• 
A life-threatening adverse event  
• 
An adverse event that results in 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 serious when, based upon medical judgment, they may jeopardize the 
patient or subject and may require medical or surgical intervention to prevent one of the outcomes listed 
in this definition. (FDA, 21 CFR 312.32; ICH E2A and ICH E6). 
ALL SERIOUS adverse events that meet the above criteria MUST be immediately reported to the NCI 
via CTEP-AERS within the timeframes detailed in the table below. 
Hospitalization 
Grade 1 
Timeframes 
Grade 2 
Timeframes 
Grade 3 
Timeframes 
Grade 4 & 5 
Timeframes 
Resulting 
in 
Hospitalization ≥ 24 hrs 
10 Calendar Days 
24-Hour 5 
Calendar 
Days 
Not resulting in 
Hospitalization ≥ 24 hrs 
Not required 
10 Calendar 
Days 
NOTE: Protocol specific exceptions to expedited reporting of serious adverse events are found in the 
Specific Protocol Exceptions to Expedited Reporting (SPEER) portion of the CAEPR 
Expedited AE reporting timelines are defined as: 
• 
“24-Hour; 5 Calendar Days” - The AE must initially be reported via CTEP-AERS within 24 hours 
of learning of the AE, followed by a complete expedited report within 5 calendar days of the initial 
24-hour report. 
• 
“10 Calendar Days” - A complete expedited report on the AE must be submitted within 10 calendar 
days of learning of the AE. 
1Serious adverse events that occur more than 30 days after the last administration of investigational 
agent/intervention and have an attribution of possible, probable, or definite require reporting as follows:  
Expedited 24-hour notification followed by complete report within 5 calendar days for: 
• 
All Grade 4, and Grade 5 AEs 


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Expedited 10 calendar day reports for: 
• 
Grade 2 adverse events resulting in hospitalization or prolongation of hospitalization 
• 
Grade 3 adverse events 
2 For studies using PET or SPECT agents, the AE reporting period is limited to 10 radioactive half-lives, rounded 
UP to the nearest whole day, after the agent/intervention was last administered. Footnote “1” above applies after 
this reporting period. 
Effective Date: May 5, 2011 
7.4 
Routine AE Reporting 
All Grade 3 or greater AEs, whether or not ascribed to the study drug administration, will 
be recorded on the Adverse Event Form. Unexpected Grade 1 and 2 AEs that are considered 
to be related to study drug administration will be captured on the AMC Adverse Event 
Form. Expected Grade 1 and 2 AEs that are related to study drug administration will be 
captured on the Expected Toxicity form, and do not require reporting in the Adverse Event 
form. Grade 1 and 2 adverse events that are not considered related to study drug 
administration will not require reporting for this protocol. These requirements are 
summarized in the chart below. 
Table 7-A: Routine AE reporting requirements by grade and relationship to study 
agents 
Relationship to Study Agents 
Grade 1 or 2 
Grades 3, 4, or 5 
Unrelated 
(attribution of unrelated or 
unlikely) 
Not Required 
Adverse Event 
Form 
Related 
(attribution of possible, 
probable, or definite) 
Expected: Expected Toxicity 
Form 
Unexpected: Adverse Event 
Form 
Adverse Event 
Form 
Participants withdrawn from the study due to AEs will be followed by the Investigator until 
the outcome is determined and, when appropriate, additional written reports and 
documentation will be provided. 
7.4.1 Clinical laboratory abnormalities 
Clinical laboratory results that are outside of the normal ranges will be considered 
AEs if deemed clinically significant by the Investigator. 
An abnormal lab value should be deemed clinically significant if either of the 
following conditions is met: 
• 
The abnormality suggests a disease and/or organ toxicity that is new or has 
worsened from baseline. 
• 
The abnormality is of a degree that requires additional active management, e.g., 
change of dose, discontinuation of the drug, close observation, more frequent 
follow-up assessments, or further diagnostic investigation. 


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7.5 
Secondary Malignancy 
A secondary malignancy is a cancer caused by treatment for a previous malignancy (e.g., 
treatment with investigational agent/intervention, radiation, or chemotherapy). A 
secondary malignancy is not considered a metastasis of the initial neoplasm. 
All secondary malignancies that occur following treatment with an agent under this 
protocol will 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 mechanisms outlined in each protocol. 
7.6 
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. 
 
 


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8.0 
PHARMACEUTICAL INFORMATION 
8.1 
Efudex (5-fluorouracil 5%) 
8.1.1 Product description 
Efudex cream is a topical preparation, available in a 40 gm tube, containing the 
fluorinated pyrimidine 5-fluorouracil, an antineoplastic antimetabolite. 5% 5-
fluororacil contains 5 grams of 5-fluororacil per 100 grams. Efudex Cream contains 
5% fluorouracil in a vanishing cream base consisting of white petrolatum, stearyl 
alcohol, propylene glycol, polysorbate 60 and parabens (methyl and propyl). 
Chemically, fluorouracil is 5-fluoro-2,4(1H,3H)-pyrimidinedione. It is a white to 
practically white, crystalline powder which is sparingly soluble in water and 
slightly soluble in alcohol. One gram of fluorouracil is soluble in 100 mL of 
propylene glycol. The molecular weight of fluorouracil is 130.08 and the molecular 
formula is C4H3FN2O2. 
8.1.2 Storage 
Store at 25°C (77°F); excursions permitted to 15°C-30°C (59°F-86°F). 
8.1.3 Route of administration 
The agent will be administered per rectum. Participants will self-apply the 
medications with a syringe or their gloved fingers as described in Section 5.1. 
Refer to the approved package insert for complete prescribing and toxicity 
information. 
8.2 
Zyclara (imiquimod 2.5%) 
Zyclara was discontinued on this protocol as of version 5.0 due to product unavailability. 
8.2.1 Product description 
Imiquimod belongs to the chemical class of substances known as imidazoquinoline 
amines. Chemically, imiquimod is 1-(2-methylpropyl)-1H-imidazo[4,5-c]quinolin-
4-amine. Imiquimod has a molecular formula of C14H16N4 and a molecular 
weight of 240.3. Imiquimod is available as a white to faintly yellow oil-in-water 
cream base consisting of isostearic acid, cetyl alcohol, stearyl alcohol, white 
petrolatum, polysorbate 60, sorbitan monostearate, glycerin, xanthan gum, purified 
water, benzyl alcohol, methylparaben, and propylparaben. 
Imiquimod cream (Zyclara), 2.5% is available in 7.5 and 15 gm pump bottles, each 
gram of cream contains 25 mg of imiquimod. Pump bottles dispense 5.9 mg of 
imiquimod in 0.235 gm of cream per full actuation of the pump after priming. The 
7.5 gm pump delivers no fewer than 28 full actuations and the 15 gm pump delivers 
no fewer than 56 full actuations. 
8.2.2 Storage 
Store at 25ºC (77ºF); excursions permitted to 15º to 30ºC (59º to 86ºF). Avoid 
freezing. Store ZYCLARA Cream pumps upright. 


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8.2.3 Route of administration 
The agent will be administered per rectum. Participants will self-apply the 
medications with a syringe or their gloved-fingers as described in Section 5.1. 
Refer to the approved package insert for complete prescribing and toxicity 
information. 
8.3 
Study Agent Supply, Distribution and Accountability 
Study agents will be supplied by the manufacturers. 
8.3.1 Study agent acquisition 
Participating sites are to refer to the study drug request form located on the AMC 
Operations Center web site (www.AIDSCancer.org). 
8.3.2 Study agent accountability 
For all study-supplied topical agents, 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 Investigational Agent 
Accountability Record Form (DARF), available on the CTEP home page 
(http://ctep.cancer.gov) or by calling the Pharmaceutical Management Branch at 
240-276-6575. The DARF documents 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 DARF and if the paper printout is 
identical to the DARF. 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. 
8.3.3 Study agent transfers 
Agent may not be transferred from one subject to another subject, from one center 
to another center, or from one protocol to another protocol. 
8.3.4 Study agent destruction 
Agent returned by participants must be weighed prior to destruction and return must 
be documented in source documents. 
Expired agent may be destroyed according to local policies. At the end of the study, 
unused agent may be destroyed according to local policy with written authorization 
from the AMC ODMC.  
 
 


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9.0 
RESPONSE CRITERIA 
CTEP-registered advanced practice clinicians who are non-physician investigators (i.e., NP 
or PA) may perform toxicity and response assessment as allowed per local licensure.  
9.1 
Definition of Clinical Response (by Subject) 
9.1.1 Complete Response (CR): The absence of HSIL histology for all biopsies and the 
absence of HSIL cytology. 
9.1.2 Partial Response (PR): 1) The regression of HSIL histology but HSIL cytology is 
present, or 2) Reduction in number of octants with HSIL.  
9.1.3 No Response: The presence of HSIL histology with no change in the number of 
octants with HSIL with or without HSIL cytology. 
9.1.4 Spontaneous Regression: The absence of HSIL histology and HSIL cytology 
following no treatment. 
Please note that LSIL is treated the same as no SILs for the purpose of these definitions. 
For example, a participant with all biopsies showing LSIL and cytology showing LSIL 
would be considered a CR. 
 
 


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10.0 
STATISTICAL CONSIDERATIONS 
10.1 
Rate of Accrual 
This study is expected to accrue eight participants per month for a total of 118 participants 
(50 per arm for observation and 5FU arms and 18 to the imiquimod arm, which closed 
because of lack of drug availability). However, the rate of accrual has been approximately 
one participant per month from 2021-2023. With Version 8.0, the sample size has been 
reduced to 88 participants (35 per arm for observation and 5FU arms and 18 to the 
imiquimod arm). 
10.2 
Randomization 
The study will use a stratified, random permuted block randomization scheme with strata 
being sites. This approach ensures that arms are balanced within sites. 
10.3 
Sample Size Estimation 
The original sample size was based on the assumption that treatment of anal HSIL lesion 
with topical therapy (topical 5-fluorouracil 5%) will have a minimum CR rate of 40% as 
compared to a maximum regression rate of 10% in the observation arm. Due to the slow 
accrual rate, the sample size was reduced, and the revised sample size was decided by the 
expected accrual close date (01 July 2023). Thirty five participants per arm (or 70 in total 
for observation and 5FU arms) would be the revised sample size. Eighteen participants 
were accrued to the imiquimod arm prior to this arm being closed because of lack of drug 
availability. The comparison of imiquimod to observation is no longer sufficiently powered 
to test efficacy; comparisons to imiquimod will be considered exploratory.  
10.4 
Analysis Population 
The primary analysis population for efficacy and safety is intent-to-treat (ITT) population, 
which consists of all participants who were randomized. 
10.5 
Safety Analysis 
AEs will be summarized at the event level and participant level according to severity. 
Proportions and their exact 95% confidence intervals will be calculated. 
10.6 
Monitoring 
10.6.1 Safety monitoring. 
The occurrence of at least two Grade 3 SAEs that are at least possibly related to 
study conduct or study treatment (including progression to SCC), or a single Grade 
4 or 5 AE that is at least possibly related to study conduct will cause the study to 
halt enrollment. The study will restart only after a review of available safety data 
and SAE reports by the safety review team: The AMC Medical Monitor (located at 
the AMC ODMC), the study chairs (Wilkin and Brickman), HPV Working Group 
chairs (Palefsky and Stier) and the AMC statistician (Kwon). If consensus about 
restarting the study is not reached among these members, then the decision will be 
made by the AMC Executive Committee. This process will be repeated after every 
two serious and related Grade 3 AEs or after each Grade 4 or 5 AE that is at least 
possibly related to study conduct or treatment. For unanticipated adverse effects 
that present an unreasonable risk to participants, the study must be terminated 


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within 5 days of the determination and not later than 15 days after notification of 
the event. The study may not be resumed without approval from the FDA and 
reviewing IRBs. 
10.6.2  Futility and efficacy halting rules 
An interim analysis is planned after 50% of the ITT population has completed 
assessment for the primary endpoint to assess the futility of achieving a significant 
result if the study continues and to potentially demonstrate efficacy before all 
participants are enrolled. For the comparing topical 5-fluorouracil 5% vs 
observation, group sequential methods will be used to compare efficacy endpoints 
preserving the overall one-sided significance level of 0.025 for each comparison. 
To assess superiority of a treatment arm in comparison to observation the Lan-
DeMets stopping boundaries will be used. To assess futility, the O’Brien-Fleming 
futility boundaries will be used. The interim analyses will be reviewed by the AMC 
Data and Safety Monitoring Board (DSMB) by the 50% point.  
Table 
10-A: 
Statistical 
test 
boundaries 
and 
associated 
operating 
characteristics for testing efficacy of 5-fluorouracil 5% vs. observation 
Analysis 
Total 
Number 
(%) of 
Subjects* 
H0 (Futility) 
Bound 
Z (P-value) 
H1 (Efficacy) 
Bound 
Z (P-value) 
Overall α 
Spent 
Overall β 
(1-power) 
Spent 
1 
(Interim) 
35 (50%) 
0.258 (0.398) 
2.963 (0.002) 
0.002 
0.020 
2 (Final) 
70 (100%) 
1.955 (0.025) 
1.955 (0.025) 
0.025 
0.100 
*Total number of subjects equals the number in 5FU arm plus observation arm.  
10.6.3 Lost to follow-up (LTFU) rate 
Since the LTFU rate in potential complete responders would affect the primary 
endpoint (see Section 10.7), the LTFU rate for each arm will be closely monitored 
by the study team. After 50% of the ITT population has completed assessment for 
the primary endpoint, a report will be sent to the DSMB documenting the LTFU 
rate by arm, as well as the response at any visit(s). When assessing this rate, all 
participants not providing evaluable endpoint data will be included. Consideration 
will be given to halting the study if the absolute LTFU rates differ by at least 15%, 
since a significant arm difference in the CR rate could be an artifact of differential 
LTFU rates. 
10.7 
Primary Analyses 
The primary analysis population for efficacy and safety is an intent-to-treat (ITT) 
population, which consists of all participants who are randomized to 5-fluorouracil 5% or 
observation. The proportion of participants achieving complete response in the 5-
fluorouracil 5%, and the proportion of participants with spontaneous regression in the 
observation arm will be calculated as the number achieving complete response or 
experiencing spontaneous regression through the primary endpoint visit (Week 20) divided 
by the number in the intent-to-treat population. For the treatment comparison (topical 5-


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fluorouracil 5% vs. observation) the proportions will be compared across sites using 
stratified Mantel-Haenszel-Cochran tests at the one-sided 0.05 alpha level. This means that 
participants who drop out or do not provide evaluable data contribute to the analysis since 
they are included in the denominator, i.e., they are essentially treated as failures.  
Since the imiquimod arm was stopped early, we will describe comparisons between 
imiquimod and observation using only the participants randomized to imiquimod and 
observation prior to closure of the imiquimod arm. As a secondary objective, imiquimod 
2.5% and topical 5-fluorouracil 5% will be compared using a stratified Mantel-Haenszel-
Cochran test at the two-sided 0.05 alpha level using participants randomized prior to the 
closure of the imiquimod arm. 
The primary endpoint will include intra-anal HSIL present on cytology or histology. 
Perianal HSIL will be descriptively reported separately, as well as combined with the 
primary endpoint. In addition to the primary intent-to-treat analysis (which includes all 
randomized participants), we will perform a sensitivity analysis that treats participants who 
receive HSIL treatment other than randomized treatment (or observation participants that 
receive any treatment) prior to Week 20 as failures; participants who are lost to follow-up 
or inevaluable are also still treated as failures. We will also perform a per-protocol analysis 
using the subset of participants who were adherent to the protocol. 
10.8 
Secondary Analyses 
To examine the tolerability and safety of the three arms, descriptive statistics for AEs will 
be computed. AEs will be summarized at the event level and subject level according to 
severity. AEs will be stratified according to those reported at or before Week 20 and after 
Week 20 since those in the observation arm have to option of being randomized to 
imiquimod or 5FU at Week 20. Proportions and their exact binomial 95% confidence 
intervals will be calculated. We will compute summary statistics for the amount of study 
drug taken by measuring the mass of study drug dispensed (weight of study drug container 
at baseline – weight of study drug at the end of treatment). 
Similarly, we will assess for PR in two ways. We will compare between arms the number 
of quadrants with HSIL found on biopsies treating the response as an ordinal variable. The 
biopsy plan for Week 20 and 48 (see Appendix V) specifies that at least one biopsy be 
obtained from each quadrant. Biopsies used for eligibility will generally be obtained 
through routine care and will not necessarily have four quadrant biopsies, so we are not 
able to look at the within participant change in the number of quadrants with HSIL on 
biopsy. Therefore, this comparison between arms assumes that the extent of disease at 
enrollment is balanced between arms, which is reasonable given randomization. We will 
also compare the proportion of participants achieving CR or PR (as per Section 9) with 
imiquimod or 5FU as compared to observation only using similar approaches as the 
primary objective. 
We will evaluate the effect of imiquimod and 5FU on persistence of HPV type specific 
infections. We will report the frequency and proportion of HPV types present at baseline 
that are no longer detected at Week 20. We will also report the frequency and proportion 
of new HPV infections detected at Week 20 that were not present at baseline. Proportions 
and their exact binomial 95% confidence intervals will be calculated. 


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HSIL outcomes at Week 44 will be analyzed similarly to those at Week 20. Results for the 
observation arm will be stratified into cross-over treatment groups. 
To evaluate the relationship between smoking and sexual behaviors on treatment efficacy, 
tolerability, and HPV, regression models will be fit for each treatment arm. For treatment 
efficacy, a logistic regression model will be fit; for endpoints that are available over time, 
a generalized estimating equations (GEE) model may be fit. A model that incorporates 
treatment arm will be developed to assess the role of treatment on these endpoints in the 
presence of behavioral covariates. 
10.9 
AMC Policy for Monitoring of Phase III Trials 
10.9.1  This study will be monitored by the AMC DSMB, as outlined in its Charter and as 
required by the NCI Data and Safety Monitoring Policy for Phase III investigations. 
The study will adhere to the AMC Data Safety Monitoring Plan (Appendix VIII). 
10.9.2 Central Pathology Review 
Slides from all biopsies used for eligibility and slides from all biopsies obtained 
post-randomization will be submitted for central review by a single pathologist. 
Any discrepancies of interpretation (normal, low-grade AIN, or high-grade AIN) 
will be referred for adjudication. 
10.10 Publication of Research Findings 
Publication of the results of this trial will be governed by AMC policies. 


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11.0 
ETHICAL AND REGULATORY CONSIDERATIONS 
11.1 
IRB Approval and Informed Consent 
The principles of Institutional Review Board (IRB) approval and informed consent 
described in the Food and Drug Administration (FDA) regulations (21 CFR Part 50 and 
56) and Department of Health and Human Services (DHHS) regulations for the Protection 
of Human Subjects regulations (45 CFR Part 46) must be followed. IRB approval of the 
protocol and the informed consent form must be given in writing. 
The sponsor’s designee (AMC ODMC) must receive a copy of the letter of approval from 
the IRB, which specifically approves the protocol and informed consent, before subject 
enrollment. The IRB must also approve any significant changes to the protocol and 
documentation of this approval must be sent to the AMC ODMC. The IRB must review 
the research project at least once every 365 days during the duration of the project. 
Continuing approval of the project must also be given in writing and provided to the AMC 
ODMC. 
Records of all study review and approval documents must be kept on file by the 
Investigator and are subject to inspection during or after completion of the study. AEs must 
be reported to the IRB according to local procedures. The IRB should receive notification 
of completion of the study and final report within 3 months of study completion and 
termination. The Investigator will maintain an accurate and complete record of all 
submissions made to the IRB, including a list of all reports and documents submitted. 
Written informed consent will be obtained from the subject. The nature, significance, and 
risks associated with the study must be explained to the subject. The informed consent will 
describe the purpose of the study, the procedures to be followed, the risks and benefits of 
participation, all risks of the investigational agent(s) and/or study participation as listed in 
the model informed consent form, and all other elements of informed consent as required 
by regulation. A copy of the consent form will be given to the subject to keep. 
In addition, any institution(s) conducting research according to the guidelines of this 
protocol is required to adhere to local and national laws and regulations governing the 
confidentiality and disclosure of health information. 
11.2 
Changes to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must 
be approved by CTEP and the Investigator before implementation. All amendments require 
approval by the IRB/IEC/REB of the treating institution. A copy of the written approval of 
the IRB/IEC/REB must be sent to the ODMC. 
11.3 
Subject Confidentiality 
In order to maintain subject privacy, all data capture records, drug accountability records, 
subject number. The Investigator will grant monitor(s) and auditor(s) from the AMC or the 
NCI and regulatory authorities (FDA) access to the subject’s original medical records for 
verification of data gathered on the data capture records and to audit the data collection 
process. The subject’s confidentiality will be maintained and will not be made publicly 
available to the extent permitted by the applicable laws and regulations. 
 
 


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11.4 
Women and Minorities 
This study is being conducted by the NCI-sponsored AIDS Malignancy Consortium 
(AMC). As part of their contractual obligations, each participating site within the AMC 
and the AMC as a whole is required to assure that the participation of women and minority 
subjects reflects the percentage representation of these populations in their geographic 
region and, for the AMC, the United States as a whole. As such, it is expected that the 
representation of subjects on this trial will reflect the constitution of the respective 
populations. 
Table 11-A: Accrual targets 
Racial Categories 
Ethnic Categories 
Total 
Not Hispanic or 
Latino 
Hispanic or 
Latino 
 
Female 
Male 
Female 
Male 
 
American Indian/ Alaska Native 
0 
1 
0 
0 
1 
Asian 
0 
1 
0 
0 
1 
Native Hawaiian or Other Pacific 
Islander 
0 
1 
0 
0 
1 
Black or African American 
3 
17 
1 
4 
25 
White 
5 
57 
3 
17 
82 
More Than One Race 
0 
5 
0 
3 
8 
Total 
8 
82 
4 
24 
118 
 
 


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12.0 REFERENCES 
1. Crum-Cianflone N, Hullsiek KH, Marconi V, et al. Trends in the incidence of cancers among 
HIV-infected persons and the impact of antiretroviral therapy: a 20-year cohort study. 
AIDS. 2009 Jan 2;23(1):41-50. PMID: 19050385. 
2. Palefsky JM, Holly EA, Efird JT, et al. Anal intraepithelial neoplasia in the highly active 
antiretroviral therapy era among HIV-positive men who have sex with men. AIDS. 2005 
Sep 2;19(13):1407-14. PMID: 16103772. 
3. Chin-Hong PV, Vittinghoff E, Cranston RD, et al. Age-related prevalence of anal cancer 
precursors in homosexual men: the EXPLORE study. J Natl Cancer Inst. 2005 Jun 
15;97(12):896-905. PMID: 15956651. 
4. Hessol NA, Holly EA, Efird JT, et al. Anal intraepithelial neoplasia in a multisite study of 
HIV-infected and high-risk HIV-uninfected women. AIDS. 2009 Jan 2;23(1):59-70. 
PMID: 19050387. 
5. Chang G, Berry J, Jay N, et al. Surgical Treatment of High-grade Squamous Intraepithelial 
Lesions - a prospective study. Dis Colon Rectum. 2002 Apr;45(4):453-8. PMID: 
12006924. 
6. Pineda CE, Berry JM, Jay N, Palefsky JM, Welton ML. High-resolution anoscopy targeted 
surgical destruction of anal high-grade squamous intraepithelial lesions: a ten-year 
experience. Dis Colon Rectum. 2008 Jun;51(6):829-35; discussion 35-7. PMID: 18363070. 
7. Stier EA, Goldstone SE, Berry JM, et al. Infrared coagulator treatment of high-grade anal 
dysplasia in HIV-infected individuals: an AIDS malignancy consortium pilot study. J 
Acquir Immune Defic Syndr. 2008 Jan 1;47(1):56-61. PMID: 18156992. 
8. Nathan M, Sheaff M, Fox P, Goon P, Gilson R, Lacey C. Early treatment of anal intraepithelial 
neoplasia. BMJ.343:d7717. PMID: 22127454. 
9. Cranston RD, Hirschowitz SL, Cortina G, Moe AA. A retrospective clinical study of the 
treatment of high-grade anal dysplasia by infrared coagulation in a population of HIV-
positive men who have sex with men. Int J STD AIDS. 2008 Feb;19(2):118-20. PMID: 
18334066. 
10. Goldstone SE, Hundert JS, Huyett JW. Infrared Coagulator Ablation of High-Grade Anal 
Squamous Intraepithelial Lesions in HIV-Negative Males Who Have Sex with Males. Dis 
Colon Rectum. 2007 May;50(5):565-75. PMID: 17380365. 
11. Goldstone SE, Kawalek AZ, Huyett JW. Infrared coagulator: a useful tool for treating anal 
squamous intraepithelial lesions. Dis Colon Rectum. 2005 May;48(5):1042-54. PMID: 
15868241. 
12. Falkson G, Schulz EJ. Skin changes in patients treated with 5-fu. Br J Dermatol. 1962 
Jun;74:229-36. PMID: 13891467. 
13. Brodman M, Dottino P, Friedman F, Jr., Heller D, Bleiweiss I, Sperling R. Human 
papillomavirus-associated lesions of the vagina and cervix. Treatment with a laser and 
topical 5-FU. J Reprod Med. 1992 May;37(5):453-6. PMID: 1324311. 


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14. Maiman M, Watts DH, Andersen J, Clax P, Merino M, Kendall MA. Vaginal 5-ful for high-
grade cervical dysplasia in human immunodeficiency virus infection: a randomized trial. 
Obstet Gynecol. 1999 Dec;94(6):954-61. PMID: 10576182. 
15. Krebs HB. Treatment of vaginal condylomata acuminata by weekly topical application of 5-
FU. Obstet Gynecol. 1987 Jul;70(1):68-71. PMID: 3601270. 
16. Batista CS, Atallah AN, Saconato H, da Silva EM. 5-FU for genital warts in non-
immunocompromised 
individuals. 
Cochrane 
Database 
Syst 
Rev. 
2010 
Apr 
14;(4):CD006562. PMID: 20393949. 
17. Graham BD, Jetmore AB, Foote JE, Arnold LK. Topical 5-fluorouracil 5% in the management 
of extensive anal Bowen's disease: a preferred approach. Dis Colon Rectum. 2005 
Mar;48(3):444-50. PMID: 15747068. 
18. Richel O, Wieland U, De Vries HJ, et al. Topical 5-FU treatment of anal intraepithelial 
neoplasia in human immunodeficiency virus-positive men. Br J Dermatol. 2010 
Dec;163(6):1301-7. PMID: 20716208. 
19. Snyder SM, Siekas L, Aboulafia DM. Initial Experience With Topical Fluorouracil for 
Treatment of HIV- Associated Anal Intraepithelial Neoplasia. J Int Assoc Physicians AIDS 
Care (Chic). 2011 Mar-Apr;10(2):83-8. PMID: 21266323. 
20. Jay N, Berry MJ, Darragh T, Palefsky J. Treatment of diffuse high-grade anal intraepithelial 
neoplasia with 5% fluorouracil cream. Proceedings of the 25TH INTERNATIONAL 
PAPILLOMAVIRUS CONFERENCE CLINICAL & EDUCATIONAL WORKSHOP 
May 
8 
- 
14 
2009 
Malmö, 
Sweden. 
2009. 
P.19-16. 
http://www.hpv2009.org/Abstractbok_hela%20webb%20low%5B1%5D.pdf. 
21. David CV, Nguyen H, Goldenberg G. Imiquimod: a review of off-label clinical applications. 
J Drugs Dermatol. 2011 Nov;10(11):1300-6. Review. PubMed PMID: 22052312. 
22. Grossberg AL, Gaspari AA. Topical antineoplastic agents in the treatment of mucocutaneous 
diseases. Curr Probl Dermatol. 2011;40:71-82. Epub 2011 Feb 10. Review. PubMed 
PMID: 21325841. 
23. Hengge UR, Cusini M. Topical immunomodulators for the treatment of external genital warts, 
cutaneous warts and molluscum contagiosum. Br J Dermatol. 2003 Nov;149 Suppl 66:15-
9. PMID: 14616340. 
24. Hengge UR, Esser S, Schultewolter T, et al. Self-administered topical 5% imiquimod for the 
treatment of common warts and molluscum contagiosum. Br J Dermatol. 2000 
Nov;143(5):1026-31. PMID: 11069514. 
25. Gill VL, Bergman PJ, Baer KE, Craft D, Leung C. Use of imiquimod 5% cream (Aldara) in 
cats with multicentric squamous cell carcinoma in situ: 12 cases (2002-2005). Vet Comp 
Oncol. 2008 Mar;6(1):55-64. PMID: 19178663. 
26. Mathiesen O, Buus SK, Cramers M. Topical imiquimod can reverse vulvar intraepithelial 
neoplasia: a randomised, double-blinded study. Gynecol Oncol. 2007 Nov;107(2):219-22. 
PMID: 17655918. 


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27. van Seters M, Fons G, van Beurden M. Imiquimod in the treatment of multifocal vulvar 
intraepithelial neoplasia 2/3. Results of a pilot study. J Reprod Med. 2002 Sep;47(9):701-
5. PMID: 12380448. 
28. Poluri RM, Higgins SP. Successful treatment of penile Bowen's disease with 5% imiquimod 
cream. Int J STD AIDS. 2005 Sep;16(9):649. PMID: 16176641. 
29. Ramoni S, Cusini M, Gaiani F, Arancio L, Alessi E. Penile intraepithelial carcinoma treated 
with imiquimod 1% in an HIV-positive patient. J Dermatolog Treat. 2009;20(3):177-8. 
PMID: 19016064. 
30. Kreuter A, Hochdorfer B, Stucker M, et al. Treatment of anal intraepithelial neoplasia in 
patients with acquired HIV with imiquimod 5% cream. J Am Acad Dermatol. 2004 
Jun;50(6):980-1. PMID: 15153912. 
31. Wagstaff AJ, Perry CM. Topical imiquimod: a review of its use in the management of 
anogenital warts, actinic keratoses, basal cell carcinoma and other skin lesions. Drugs. 
2007;67(15):2187-210. PMID: 17927284. 
32. Kreuter A, Potthoff A, Brockmeyer NH, et al. Imiquimod leads to a decrease of human 
papillomavirus DNA and to a sustained clearance of anal intraepithelial neoplasia in HIV-
infected men. J Invest Dermatol. 2008 Aug;128(8):2078-83. PMID: 18273049. 
33. Mahto M, Nathan M, O'Mahony C. More than a decade on: review of the use of imiquimod in 
lower anogenital intraepithelial neoplasia. Int J STD AIDS. 2010 Jan;21(1):8-16. PMID: 
20029061. 
34. Fox PA, Nathan M, Francis N, et al. A double-blind, randomized controlled trial of the use of 
imiquimod cream for the treatment of anal canal high-grade anal intraepithelial neoplasia 
in HIV-positive MSM on HAART, with long-term follow-up data including the use of 
open-label Imiquimod. AIDS. Sep 24;24(15):2331-5. PMID: 20729710. 
35. Richel O, De Vries H, Van Noesel C, Djikgraaf M, Prins J. Treatment of Anal Intraepithelial 
Neoplasia in HIV+ MSM: A Triple-arm randomized clinical trial of imiquimod, topical 5-
fluoruracil, and electrocautery. 19th Conference on retroviruses and opportunistic 
infections. 
Seattle; 
2012. 
Paper 
#135LB. 
http://www.retroconference.org/2012b/Abstracts/45356.htm. 
 
 


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


 
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APPENDIX II: SCHEDULE OF EVALUATIONS 
Shaded visits should only be performed for those receiving study-provided topical treatments. 
EVALUATIONS 
Screening 
Visit 
-1 
Visit 1 
Week 
0 
Visit 2 
Week 
2 
Visit 3 
Week 
8 
Visit 4 
Week 
16 
Visit 5 
Week 
20 
Visit 6 
Week 
24 
Visit 7 
Week 
26 
Visit 8 
Week 
32 
Visit 9 
Week 
40 
Visit 10 
Week 
44 
Premature 
d/c 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV Documentation 
X 
 
 
 
 
 
 
 
 
 
 
 
Complete Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
Clinical Assessment7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Dispense Drug and Treatment Diary  
 
X 
X 
X4 
 
 
X9 
X 
X4 
 
 
 
Collect Diary / Adherence Assessment 
 
 
X 
X 
X 
 
 
X 
X 
X 
 
X 
Safety Bloodwork (CBC w diff, platelets) 
X1 
 
 
 
 
 
 
 
 
 
 
 
CD4/CD8 (Counts + %) 
X 
 
 
 
 
 
 
 
 
 
 
 
HIV-1 Plasma RNA 
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy Test 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Anal Biopsies 
X 
 
 
X5 
X5 
X 
 
 
X5 
X5 
X 
X 
Anal Cytology 
X 
 
 
 
 
X 
 
 
 
 
X 
X 
Anal Swab for HPV testing 
X6 
 
 
X 
X 
X 
 
 
X 
X 
X 
X 
HRA 
X 
X 
 
X2 
 
X 
 
 
X2 
 
X 
X 
Optional anoscopy or HRA8 
 
 
X2 
 
X2 
 
 
X2 
 
X2 
 
 
Photo Documentation of Lesions 
 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
Smoking 
and 
Recent 
Sexual 
History 
Questionnaire 
 
X 
 
 
 
X 
 
 
 
 
X 
X 
ACSR Donation 
X3 
 
 
 
 
 
X3 
 
 
 
 
 
Randomization 
 
X 
 
 
 
 
X9 
 
 
 
 
 
 
 
1 At subsequent visits, routine laboratory testing and/or referral for testing for sexually transmitted infections should be conducted only if clinically indicated. 
2 See description in Appendix IV for modification to standard HRA procedure and criteria for biopsies at this visit with respect to the use of acetic acid. These HRA procedure 
modifications are for participants receiving study treatment only. 
3 Whole blood specimens to be collected at Visit -1 and Visit 6 (Week 24) for participants randomized at this visit, with participant consent for the ACSR donation. 


 
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4 Cream will be weighed for adherence assessment and returned to the participant at Visits 3 and 8. 
5 Anal biopsies should only be performed at visits 3, 4, 8, and 9 if clinician notes any markers indicative of progression as listed in Section 6.4.1. 
6 If the anal swab for HPV testing is not collected at the screening visit, it can be collected at entry (Visit 1) prior to HRA. 
7 As defined per Section 6 for each visit. 
8 If participant can tolerate. 
9 Participants originally randomized to observation with HSIL at Week 20 may receive 5FU beginning at Week 24. 


 
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APPENDIX III: ANAL CYTOLOGY AND HPV SAMPLING 
All anal cytology specimens will be examined at the local institution. 
The participant should undress so that buttocks are exposed, and either bend over the exam table 
or lay on their side in left lateral decubitus. The examiner should use one hand to spread the 
buttocks and expose the anal verge. 
Procedure for obtaining an anal swab specimen: 
A synthetic swab moistened in tap water will then be inserted as far as is comfortable into the anus, 
a minimum of 1-2 inches. If there is difficulty inserting the swab, the participant should also retract 
their buttocks and the swab reoriented in the canal. With pressure on the distal end of the swab 
rotate it firmly in a circular fashion for approximately 20 seconds and slowly remove from the 
canal. Do not retract the buttocks when the swab is close to the verge to ensure that it is sampled 
as well. Immediately immerse the swab in a liquid-cytology vial agitating vigorously over 20 to 
45 seconds to disperse the cells. 
For anal HPV testing: A second swab should be obtained and placed in Digene STM. 
Specimen packaging and shipment instructions are provided in the Manual of Procedures (MOP). 
Specimens will be sent to the AMC Biorepository for storage before batch shipment to the AMC 
HPV Genotyping Core Laboratory. 


 
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APPENDIX IV: HIGH RESOLUTION ANOSCOPY (HRA) AND ANAL BIOPSIES 
Procedure for performing HRA: 
High resolution anoscopy should only be done after the specimens for anal cytology and HPV 
testing are collected. The patient will already be positioned for anal evaluation. A mixture of an 
anesthetic cream (e.g. 4% lidocaine cream) and water-soluble lubricating jelly should be used as a 
lubricant. A digital anal rectal exam should then be performed palpating the entire anal canal, distal 
colon, and perianus, noting any masses or areas of induration. The procedure for HRA is as 
follows: 
1. Insert the anoscope, remove obturator, and place a cotton swab wrapped in gauze soaked in 
5% acetic acid into anus. 
2. Remove the anoscope over the swab and leave swab in place for 1 to 2 minutes. 
3. Remove the swab and re-insert the anoscope. Carefully examine the anal canal with a 
colposcope. 
4. Re-apply acetic acid frequently to ensure adequate detection of lesions and verify that all 
aspects of the Anal Transformation Zone (AnTZ) have been visualized. 
5. If acetowhitening is noted, note vascular characteristics, if present. 
6. Lugol’s solution (iodine) may be used as desired to aid in identifying areas of possible LSIL 
and HSIL near the squamocolumnar junction. 
7. Biopsy abnormal appearing areas (colposcope-directed biopsies) clinically suspicious for 
HSIL; areas suspicious for LSIL may also be biopsied if more severe lesions are not seen. 
Local anesthetic (e.g., 1% lidocaine with or without epinephrine or .5% bupivacaine) may be 
used at the provider’s discretion prior to biopsy. 
8. Attain hemostasis prior to removal of the anoscope at the discretion of the provider (with 
pressure, Monsel’s solution, or silver nitrate). 
9. An external genital exam should be performed to note the presence of condyloma and other 
abnormalities. 
10. Apply acetic acid for one minute to perianal area and examine carefully with colposcope. 
11. Biopsy any external (perianal) areas clinically suspicious for HSIL, using a local anesthetic 
(e.g., 1% lidocaine with or without epinephrine or 0.5% bupivacaine) prior to biopsy. Perianal 
condyloma or LSIL can be biopsied at the discretion of the provider. 
12. Participants with signs or symptoms consistent with proctitis or sexually transmitted infections 
other than HPV should be referred for appropriate diagnosis and treatment. 


 
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APPENDIX V: BIOPSY PLAN FOR AMC-088 
Biopsies used for eligibility may be obtained through routine care. If performing baseline HRA 
though AMC-088, then every quadrant must be sampled for eligibility purposes. HSIL lesions 
that were biopsied for clinical care prior to the visit may be used to document eligibility and 
will not require additional rebiopsy at screening if performed within 60 days but not less than 
1 week prior to enrollment. Subsequent study visits requiring biopsies will include 4-quadrant 
biopsies collected by a certified HRA-provider who is registered with CTEP as follows: 
• The anal mucosa should be divided into four quadrants: Anterior, Left, Posterior and Right 
• Lesions suspicious for HSIL should be identified and biopsied. 
• For quadrants without a lesion suspicious for HSIL, any areas suggestive of LSIL, condyloma, 
squamous metaplasia, or areas of prior HSIL lesions present at baseline should be biopsied. If 
no such areas are present, then a biopsy of normal appearing mucosa should be biopsied. 
• Please note that more than one biopsy can be obtained per quadrant if multiple HSIL lesions 
exist or if multiple biopsies of an extensive HSIL lesion are deemed necessary by the 
anoscopist. 
• Distal anal and perianal lesions concerning for HSIL should be biopsied. 
• For each anal biopsy obtained, the anoscopist should characterize the suspected result of the 
biopsy as invasive cancer, HSIL, LSIL or condyloma, squamous metaplasia or atypical 
squamous metaplasia, or normal mucosa. 
• Biopsies from different quadrants must go in separate formalin containers, and get separate 
pathologic interpretations. 


 
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APPENDIX VI: ACSR SPECIMEN PREPARATION & SHIPPING INSTRUCTIONS 
A. 
GENERAL 
To ship blood specimens, use a diagnostic shipper approved for a volume of at least 30 cc. 
The use of the SAF-T-PAK STP 210 diagnostic cardboard shipper is recommended. These 
shippers may be ordered at the SAF-T-PAK website: www.saftpak.com. The following 
instructions below are for use with the recommended STP-210 shipper. If using another 
federally approved diagnostic shipper, please follow instructions provided for that specific 
shipper. 
NOTE: Specimens MUST BE SHIPPED Mondays through Thursdays as an 
OVERNIGHT PRIORITY shipment. Specimens are NOT ACCEPTED ON 
SATURDAYS OR SUNDAYS in the ACSR. 
B. SPECIMEN PREPARATION, PACKAGING, AND SHIPMENT 
BLOOD SPECIMENS 
Draw two 10 cc (mL) yellow top [acid citrate dextrose (ACD)] tubes from study patient. 
With a black, water resistant, sharpie pen, label each specimen with the following 
information: 
• AMC Protocol #088 
• AMC Participant ID# 
• Date and time of collection 
• Specimen type, i.e., WB=Whole Blood, P=Plasma, S=Serum, or Tissue 
• Specimen purpose: Donation 
Specimen Shipment 
• Seal the tops of the two 10 cc yellow tops with parafilm. 
• Place the two sealed tubes into bubble wrap (provided in STP-210 kit). 
• Tape around the bubble wrap so that the roll stays together and the tubes cannot fall 
out or break. 
• Place absorbent material sheet around the bubble wrapped tubes and slip into a 
biohazard poly-bag and “self-seal.” 
• Place poly-bag containing tubes into the white TYVEK bag and seal. 
• Place the TYVEK bag into the STP-210 diagnostic cardboard shipper. Seal the 
cardboard shipper with clear packing/shipping tape. 
• Affix the FED-EX airbill on blank side of the shipper making sure that it is marked 
“FED-EX PRIORITY OVERNIGHT.” 
• Mark “OTHER” in the airbill under “Packaging.” Please use the FedEx #  available on 
the AMC member’s only website.  


 
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• Under airbill section “Special Handling” indicate “YES-SHIPPERS DECLARATION 
NOT REQUIRED.” 
• Place “From/To” information onto areas provided on the shipper. 
Blood specimens should be shipped by overnight express at room temperature to: 
Jeff Bethony, PhD 
George Washington University Medical Center 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2663 
Fax: (202) 994-5056 
Email: jbethony@gwu.edu 
• Make certain that shipper is already either pre-labeled with ‘UN#3373’ stamp, or make 
a paper label with ‘UN#3373” and affix it to the shipper. 
• Make certain that the net volume of the specimen being shipped is written in the space 
provided on the shipper or make a separate label with the volume in mL and affix to 
the shipper. 
• Affix airbill to shipper so that the ‘UN’ and ‘VOLUME’ labels are visible. 
• RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
• Place the box in the FedEx pickup area at your site or call to request a package pickup. 
Please Note: The shippers will be mailed back to each AMC site. 
INSTRUCTIONS FOR BLOOD SPECIMENS COLLECTED ON FRIDAY OR 
SATURDAY 
Preparation of Plasma and Mononuclear Cells 
Refer to the ACSR’s SOP on Separation of Plasma and Mononuclear Cells on the AMC 
Operations web site for instructions on preparing plasma and peripheral blood mononuclear 
cell (PBMC) aliquots. It is preferable that separation occurs as soon as possible. If 
necessary, whole blood in ACD (yellow top tubes) can be held at room temperature for no 
more than 24 hours. 
Freeze the cell suspension in 0.5 mL aliquots in sterile NUNC vials by placing the NUNC 
tubes in a room temperature, alcohol saturated, control rate freezer container and store in 
the -80°C freezer overnight. Transfer the cell suspension into the liquid nitrogen 
temperature freezer for long-term storage the next working day. 
***PLEASE DOUBLE CHECK PACKAGING OF SHIPPER AND DO NOT 
DEVIATE FROM REQUESTED LABELING. Shipping frozen aliquots requires 
the use of packaging acceptable for dry ice and Class 9 label with weight of dry 
ice written on package. 
 
 


 
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C. 
RECORD OF SPECIMENS 
This study will track specimens via GlobalTraceSM, a component of the AMC 
AdvantageEDC system. The GlobalTrace shipment manifest must accompany all specimen 
shipments. 


 
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APPENDIX VII: PATHOLOGY SPECIMENS 
All pathology specimens will be reviewed by the designated pathologist on site. The pathology 
slides will be reviewed later at UCSF. The central pathology review will not be done in real time. 
Slides at each site may be sent in two batch shipments each year (every 6 months). For central 
pathology review, one hematoxylin and eosin (H&E) stained slide from each biopsy and a copy of 
the pathology report (all protected health information [PHI] redacted) should be sent to the 
following address: 
Jeff Bethony, PhD 
George Washington University Medical Center 
2300 I Street, NW 
Washington, DC 20037 
Tel: (202) 994-2663 
Fax: (202) 994-5056 
Slide Labeling 
Refer to MOP for biopsy and slide labeling and preparation requirements. 
Shipping Instructions 
1. Place the labeled slides into a specimen container in bubble wrap or other adequate cushioning. 
Use sturdy outer packaging to prevent breakage. 
2. Affix the FedEx airbill on blank side of the shipper. 
3. Mark “OTHER” in the airbill under “Packaging.” 
4. Under airbill section “Special Handling” indicate “YES-SHIPPERS DECLARATION NOT 
REQUIRED.” 
5. Enter FedEx account (available on the AMC members only website).  
6. Place “From/To” information onto areas provided on the shipper. Specimens are accepted 
MONDAY through THURSDAY only. All specimens should be shipped by FedEx 2-day 
service to Dr. Darragh at the address listed above: 
7. Make certain that shipper is visibly labeled “Exempt human specimen.” 
8. RETAIN THE TOP COPY OF THE AIRWAY BILL FOR YOUR RECORDS. 
9. Place the box in the FedEx pickup area at your site or call to request a package pickup. 
Record of Specimens 
This study will track specimens via GlobalTraceSM, a component of the AMC AdvantageEDC 
system. The GlobalTraceSM shipment manifest must accompany all specimens. 
Distribution of Slides 
The AMC Biorepository will distribute slides received to Dr. Teresa Darragh for central pathology 
review upon receipt. 
Teresa M. Darragh, MD 
UCSF/Mt. Zion Medical Center 
Dept. of Pathology, Box 1785 


 
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1600 Divisadero Street, Room B621 
San Francisco, CA 94143 
Tel: (415) 353-7861 
Fax: (415) 353-7447 
All slides will be returned to the site by the AMC Biorepository following central pathology 
review. 
 
 


 
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APPENDIX VIII: AMC DATA SAFETY MONITORING PLAN 
(Version 9.0    October 6, 2020) 
 
Introduction 
The AIDS Malignancy Consortium (AMC) Data and Safety Monitoring Plan (DSMP) outlines the 
measures employed by the group to monitor the safety of participants and ensure the data validity 
and integrity for all clinical trials it conducts. This includes methods to: 1) monitor the progress of 
trials and the safety of participants; 2) comply with regulatory requirements for adverse event (AE) 
reporting; 3) processes for trial termination or temporary suspension and major modifications; and 
4) plans for ensuring data accuracy and protocol compliance. As the AMC conducts protocols of 
varying research phase, region of conduct (which may include trials conducted in the U.S., 
international sites, or both), IND sponsor (AMC investigator, CTEP, or industry-sponsored) and 
clinical data entry system use, this plan addresses broad processes applying to the range of trial 
designs and requirements. Refer to the individual AMC protocol to identify the applicable study 
characteristics for the relevant requirements described in this plan. 
Monitoring the Progress of Trials and the Safety of Participants 
Routine and expedited AE reporting 
All AMC protocols that collect safety data adhere to the National Cancer Institute (NCI), Cancer 
Therapy Evaluation Program (CTEP) Guidelines: Adverse Event Reporting Requirements 
(https://ctep.cancer.gov/protocolDevelopment/adverse_effects.htm), as applicable to the clinical 
protocol. AEs are to be recorded in the source documents, assessed by a clinical investigator for 
the AE reporting criteria, and promptly reported in the clinical data entry system as required by 
each protocol. For AMC trials conducted under a CTEP IND and AMC trials conducted within the 
U.S., all AEs that meet the NCI’s expedited reporting requirements are reported to the NCI via the 
CTEP Adverse Event Reporting System (CTEP-AERS) web application, either directly or through 
integration with Medidata Rave where this system is employed for AMC protocols. Use of this 
system ensures notification to the protocol chair and Investigational Drug Branch (IDB) at CTEP, 
as required for trials conducted under a CTEP IND, and a uniform expedited reporting and safety 
review process for AMC domestic trials. The system may also be programmed to include sponsor 
notification as required for trials with industry support. Alternate process for expedited AE 
reporting to the AMC protocol chairs and AMC Operations and Data Management Center 
(ODMC) within the clinical data entry system (AdvantageEDC or Advantage eClinical only) may 
be defined in the protocol for select trials (international studies and The ANCHOR Study). 
All serious adverse events (SAEs) received by the AMC ODMC will be reviewed by the AMC 
medical monitor at the AMC ODMC for consideration of individual participant safety, safe trial 
conduct, data reporting quality for AE term selection, and appropriate application of the regulatory 
criteria for seriousness, expectedness, and relatedness to the investigational therapy. If alternate 
procedures are followed for SAE review, the process for adequate medical monitoring will be 
defined in the AMC protocol and the Transfer of Regulatory Obligations (TORO) with the sponsor. 
AMC medical monitor review includes review of the CTEP-AERS report before CTEP submission 
for IDB review (if applicable), or review of the SAE report in the data entry system for trials not 
using CTEP-AERS for expedited reporting. The IND sponsor or its designee will issue the 
determination as to whether the AE requires IND safety reporting to FDA as a serious and 


 
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unexpected suspected adverse drug reaction (SUSAR). For protocols not conducted under an IND, 
in the event of disagreement between the reporting physician and the AMC medical monitor 
regarding the relationship of the AE to the investigational agent(s) (i.e., determination of whether 
the attribution is unrelated or unlikely, or possible, probable, or definite), the AMC medical 
monitor will provide the final determination of the relationship. IND safety reporting to FDA is 
performed by CTEP for trials conducted under a CTEP IND; IND safety reporting is performed 
by the sponsor or sponsor’s designee (AMC ODMC or other party defined in the study agreement 
or TORO) for IND studies sponsored by AMC investigators or industry sponsors. 
Expedited reporting to the Institutional Review Board (IRB) 
The requirements for IRB review will be identified in the protocol section on ethical and regulatory 
obligations. All AMC trials initiated before September 1, 2020 and all international sites for all 
AMC studies are subject to local IRB review; only U.S. sites are subject to the NCI requirement 
to use a single IRB for protocols initiated on or after September 1, 2020. For trials subject to local 
IRB review, the site principal investigator is responsible for ensuring that expedited AE reports 
for its trial participants and any unanticipated problems that affect the local institution only are 
submitted to the local IRB of the reporting institution, per the local IRB’s requirements for such 
reporting. For studies reviewed by the single IRB, the protocol chair will render a determination 
as to whether a SAE or other problem constitutes a trial-wide unanticipated problem that requires 
reporting to that RB, in accordance with its standards of procedure.  
To comply with investigator notification requirements for IND studies under 21 CFR 312.32 and 
312.55, IND safety reports from all trials the AMC conducts and reports from external sponsors 
investigating the same agents are made available to all investigators upon receipt from the sponsor 
or its designee, either via the password-protected section of the AMC Operations web site (AMC 
trials subject to local IRB review only) or the CTSU website (U.S. trials subject to single IRB 
review/CTEP IND agents). The site clinical investigator responsible for the applicable AMC 
protocol(s) is responsible for reviewing any IND safety reports received and documenting 
submission to the IRB of record (if required by local policy) within the timeline defined by the 
Clinical Trials Monitoring Branch (CTMB) audit guidelines. 
Procedures for monitoring trial progress and pharmacovigilance 
For trials using AdvantageEDC or Advantage eClinical for clinical data entry, the AMC ODMC 
provides on demand tabular listings of all reported AEs and SAEs on a participant level to the 
protocol chair and co-chair(s) for review via the password-protected section of the AMC 
Operations web site, www.AIDScancer.org. For trials using OPEN and Medidata Rave for clinical 
data collection, data listing will be made available using that system. Summary reports of AEs by 
frequency and relationship to the investigational agent(s) are provided to all AMC investigators 
and their staff It is the responsibility of each site to provide trial-specific AE listings to their 
respective IRB, if required by its policies. For blinded studies, the AE and SAE listings are 
reviewed and tabulated without treatment assignment. 
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 Scientific Working Group (SWG) during scheduled conference calls 
(monthly SWG calls and as required, protocol-specific monitoring conference calls). Summary 
accrual, summary AE, and individual SAE reports are provided to SWG leadership and protocol 
chairs to monitor participant safety during these monthly calls. 


 
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The AMC medical monitor reviews listings of all reported AEs on a quarterly basis for assuring 
compliance with the protocol requirements for AE reporting and the identification of any safety 
concerns (individual AE or increased frequency/severity of expected AEs) for the agents under 
investigation. Findings from these reviews are communicated to the protocol chairs and all AMC 
investigators, and posted to the AMC Operations web site. 
Data and Safety Monitoring Board Review (DSMB) review 
The AMC has formed an independent Data and Safety Monitoring Board (DSMB) for AMC trials 
and for the ANCHOR Study. As required by NCI policy, the AMC requires DSMB review for all 
phase III randomized trials. All other clinical trials that the AMC initiates will be reviewed by the 
AMC ODMC and AMC Statistical Center during protocol development to issue a recommendation 
as to whether the study requires DSMB oversight, which will require the approval of the AMC 
Executive Committee. This determination will be based on the phase of the study, experimental 
design, risk posed by the investigational approach, extent of data available on the safety of an 
investigational agent, risk posed by the natural course of the health condition under research, and 
the categories of vulnerable populations involved. The involvement of a DSMB in reviewing an 
AMC protocol will be identified in each clinical protocol as approved by CTEP and, as applicable, 
required by the IRB of record. 
Regarding the composition of the AMC DSMB, voting members usually include physicians, 
statisticians, an ethicist, and a patient advocate. All voting members have no other affiliation to 
the AMC and are appointed by the AMC Executive Committee with the approval of the OHAM 
Director. Nonvoting members are the AMC group statistician, the protocol statistician, an AMC 
ODMC staff member, two representatives (normally a clinician or statistician) from CTEP, and 
the grant program directors from the NCI Office of HIV and AIDS Malignancy (OHAM). 
The DSMB reviews all applicable AMC studies in accordance with the National Cancer Institute’s 
Policy for Data and Safety Monitoring. Confidential reports of all trials under review 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 issues and any other concerns about the conduct of 
the trial, as defined by the protocol plan for DSMB review. The report may contain information 
for the DSMB to render determinations for participant safety, early trial termination, results 
reporting, or continuing accrual or follow-up. 
The results of each DSMB meeting are summarized in a formal report sent by the DSMB chair to 
the AMC 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 or designee is then 
responsible for notifying the protocol chair and relevant SWG 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 OHAM program directors and the NCI division director or designee must be 
informed of the reason for the disagreement. The protocol chair, relevant SWG 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 protocol amendment will be required 
prior to any implementation of a change to the study. 


 
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Following a DSMB meeting, the DSMB’s recommendations are provided to all AMC investigators 
and staff. It is each site principal investigator’s responsibility for conveying this information to its 
local IRB as relevant for its protocol participation. For trials reviewed by a single IRB, the AMC 
ODMC will support notification to the IRB as required per its procedures. 
Cohort trial reviews not subject to DSMB review 
For phase I dose escalation trials, dose escalation (or dose de-escalation) is based on the rules in 
the protocol and the protocol chair, AMC medical monitor, and protocol statistician determine 
whether these criteria have been met based on a review of all safety data for the protocol-defined 
evaluation period. If applicable for phase II trials, stopping the trial for toxicity or efficacy, or 
suspending enrollment pending observation of responses in a multi-stage phase II trial, is based on 
meeting criteria stated in the protocol, and the protocol chair, AMC medical monitor, and protocol 
statistician determine whether these criteria have been met. 
Plans for Assuring Compliance with Requirements Regarding AE Reporting 
The protocol chair, AMC group chair, and the AMC ODMC share responsibility in assuring that 
participating investigators comply with applicable regulatory and protocol requirements for AE 
reporting. The AMC site principal investigator certifies compliance with NCI and FDA 
requirements for trial conduct by signing the site subaward agreement for the grant and the AMC 
Adherence Statement for site membership; clinical investigators also certify compliance in 
completing the protocol signature page for each protocol active at the site, and Form FDA-1572 
for CTEP investigator registration, and also for AMC IND studies sponsored by AMC 
investigators or industry sponsors. Protocol compliance with AE identification, assessment and 
reporting requirements is assessed by the AMC ODMC using several methods: 1) programmed 
system checks and messages to instruct the site to complete routine and/or expedited reporting 
when certain criteria are reported in the clinical data entry system; 2) programmed data reports 
provided to the protocol chairs that identify reports requiring expedited AE reporting; 3) remote 
review of data entry or data reports to ensure compliance with protocol and NCI AE reporting 
requirements; 4) AMC medical monitor review described in the section above; and, 5) routine site 
audits by reviewing the site’s source documentation. 
The clinical data entry systems used for AMC studies include the Oncology Patient Enrollment 
Network, OPEN for enrollment, and Medidata Rave for clinical data entry for enrolled 
participants; trials activated before September 1, 2020 or that involve only AMC international sites 
may be reported in AdvantageEDC/Advantage eClinical, a web-based data entry and enrollment 
system. These data entry systems are programmed to notify the site investigator, protocol chair, 
AMC medical monitor, and AMC ODMC via email in the event that a site reports an AE that 
meets expedited reporting criteria to NCI and/or FDA. Additional reporting conditions may be 
programmed depending on the sponsor reporting requirements of a given protocol (e.g., adverse 
events of special interest [AESI]). 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 AEs on a routine 
basis to identify AEs reported by sites that require expedited reporting. The protocol chair, AMC 
SWG chairs, AMC group chair, and IND sponsors have general oversight for assuring that routine 
and expedited adverse reporting requirements are met by the responsible parties. 
For studies monitored by CTEP using the Data Mapping Utility (DMU), cumulative protocol- and 
patient-specific data will be submitted weekly to CTEP electronically via the DMU. For trials 


 
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monitored by the NCI’s Clinical Data Update System (CDUS), AE information is transmitted 
electronically to NCI on a quarterly basis. For trials monitored by NCI’s Clinical Trials Monitoring 
Service (CTMS), AE information is transmitted electronically to NCI every two weeks. 
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 temporary or permanent suspension of a trial, or major modification to the 
protocol is under consideration, the protocol chair will convene the AMC ODMC, AMC Statistical 
Center, and SWG chair by conference call to discuss the options. Suspension actions will also be 
reviewed by the AMC Executive Committee for program oversight and direct communication of 
the action with the OHAM program directors. For phase III trials, closure decisions are typically 
rendered by the AMC DSMB; if the trial in question is under AMC DSMB oversight but rendered 
by the AMC investigators, the AMC DSMB will be notified of the suspension and the reason. 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), with copy to OHAM 
Directors, when studies are temporarily or permanently closed. In the event of major trial 
modification, CTEP 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 the 
applicable clinical data entry system for the trial. 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. Submitted data entry forms are reviewed for compliance with the 
protocol and data entry instructions according to the AMC ODMC’s standards for data quality 
processes. AMC ODMC staff routinely interacts with site staff to resolve any data submission 
problems. 
In accordance with NCI guidelines, the AMC ODMC conducts audits at the AMC sites to evaluate 
compliance with regulatory issues, and to review data for specific cases by checking source 
documents. These reports are sent to the site principal investigator and to the NCI. In the event 
that major violations are identified, sites are asked to provide a written corrective and preventative 
action plan 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 to implement remedial action(s) for 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 IX: PARTICIPANT APPLICATION INSTRUCTIONS AND DIARY FOR 
IMIQUIMOD (ZYCLARA) 
Instructions for Inserting Imiquimod 2.5% Cream 
You have been randomized to receive topical Imiquimod cream once a day at night for 16 weeks. 
Please follow the directions below for the topical cream you have been given. 
On weeks 1 and 2, you will apply one actuation (pump) daily and it will be divided as shown 
below; after two weeks this will be increased to two actuations, or one per side.  
 
 
 
1. Imiquimod Pump 
2. Apply one actuation (pump) to either 
right or left finger. 
3. Divide this dose in half to one 
finger on the left and right hand. 
 


 
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4. Apply one finger inside the anus and 
spread the cream as far as you can reach 
from side to side. Repeat with opposite 
hand. 
5. Alternatively, remove plunger from 
syringe and pump the cream into the top. 
 
6. Insert left finger to the first joint 
and spread the cream evenly as far 
as you can reach; repeat on right 
side. 
Repeat this once a day; at the 
two-week follow-up visit the 
clinician may instruct you to 
increase this to two actuations 
a day (one to each side). 
Inform the study staff of any 
severe side effects. 


 
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Store the bottle of Imiquimod upright at room temperature. 
 
 
If instructed to also treat the outside 
(perianus) 
apply 
an 
additional 
actuation around the anal opening.  
Record on the diary each application. 
 
Inform the study staff of any severe 
side effects. 


 
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PROTOCOL AMC-088 IMIQUIMOD PARTICIPANT DIARY 
2.5% TOPICAL IMIQUIMOD FOR TREATMENT OF HIGH-GRADE ANAL SQUAMOUS 
INTRAEPITHELIAL LESIONS IN HIV-INFECTED MEN AND WOMEN 
Only the recipient of the study treatment should complete this card. Study 
personnel may write on this card to document their interview and 
clarification of information recorded by the participant. However, all 
primary information should be the subject’s; all entries by study 
personnel should be dated and initialed. Study personnel who annotate 
this record should sign the last page of this document and print their name 
clearly. 
 
Study cycle: 2 weeks 
Today’s date:  _____/_____/_________ 
Subject ID:  ______ - ______ - ______ 
 
STUDY PARTICIPANTS MUST BRING THIS COMPLETED DIARY 
CARD AND ALL STUDY DRUG CONTAINERS TO EACH STUDY VISIT 
DURING TREATMENT ADMINISTRATION. 
Complete this card every day for the first 14 days of the study; day number 1 is 
__________You will complete this card until (_____/_____/_____) and return the card to 
the study site in person at your next visit. 
You may receive a telephone call from the study nurse or coordinator to clarify information 
you have written. Feel free to write any concerns or questions in the boxes at the bottom of 
each page. 
COORDINATORS: Distribute the applicable section(s) of the imiquimod diary(ies) at each 
treatment visit. Please ensure all pages of the diary are provided to the participant at each 
visit when the diary distributed. The diary(ies) must be collected at each visit. 
 


AMC-088 Participant Diary for Imiquimod 2.5% 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
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Starting on your office visit day, please record the date and time of the application of medication and any reactions that occur at the treatment site. Estimate 
the severity of the following reactions AT THE APPLICATION SITE using the following definitions: 
Mild: An awareness of symptoms, easily tolerated 
Moderate: Discomfort is enough to interfere with your usual daily activities. 
Severe: Incapacitating and you are unable to participate in activities that you usually do. 
Week 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date (MM/DD/YY) 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
Applied? 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
Pain or Tenderness 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Bleeding 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Comments 
 
 
 
 
 
 
 


AMC-088 Participant Diary for Imiquimod 2.5% 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
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Starting on your office visit day, please record the date and time of the application of medication and any reactions that occur at the treatment site. Estimate 
the severity of the following reactions AT THE APPLICATION SITE using the following definitions: 
Mild: An awareness of symptoms, easily tolerated 
Moderate: Discomfort is enough to interfere with your usual daily activities. 
Severe: Incapacitating and you are unable to participate in activities that you usually do. 
Week 2 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date (MM/DD/YY) 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
Applied? 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
 Yes   1 pump 
 No   2 pumps 
Pain or Tenderness 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Bleeding 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Comments 
 
 
 
 
 
 
 


AMC-088 Participant Diary for Imiquimod 2.5% 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
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Other Complaints or Illnesses 
Date (month/day/year) 
Severity 
Started 
Last Present 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
Comments or Concerns: 
 
 
 
 
 
 
 
 


AMC-088 Participant Diary for Imiquimod 2.5% 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
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Please list any NEW prescription or over the counter medications or supplements that you took beginning on Day 1 and ending on Day 14 during this cycle. You 
do not have to list your HIV medications or any other drugs that you were taking regularly since the start of the study. 
Name of Medication 
Date (mm/dd/yy) 
Maximum 
Daily Dose 
Reason for Medication 
Started 
Last Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
If during the 14 days you did not take any medications check the box here:  None 
 
Comments or Concerns: 
 
 
 
 
 
 


 
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APPENDIX X: PARTICIPANT APPLICATION INSTRUCTIONS AND DIARY FOR 
EFUDEX (5-FLUOROURACIL 5%) 
Instructions for Inserting 5-FU Cream 
You have been randomized to receive topical 5-FU cream for 16 weeks. Please follow the 
directions below for the topical cream you have been given. 
 
 
 
 
1. Open tube of 5-FU 
 
2. Remove plunger from applicator. 
 
3. Insert opening of tube into top 
of applicator and squeeze a small 
amount into applicator. 


 
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4. Re-insert the plunger until it reaches the 
.5ml mark on the applicator; any excess 
cream can be wiped off. 
 
5. Find a comfortable position ex. 
squatting, lying on side, one leg raised, 
and insert the applicator into the anus 
approx. ½”, then push the plunger until 
it stops.  
 
6. Insert left finger to the first joint and 
spread the cream evenly as far as you 
can reach; repeat on right side. 
 
7. Alternatively, place ½ the 
amount (or .25ml) on your left or 
right finger then follow instruction 
in #6. 


 
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8. Insert any remaining cream 
on the outside into the anus, 
then clean off any excess. 
 
Repeat this procedure for 5 
days, twice a day. Then stop 
for 9 days. Repeat this two 
week cycle for 16 weeks.  
Inform the study staff if you 
have severe side effects. 


 
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PROTOCOL AMC-088 5-FU PARTICIPANT DIARY 
5% TOPICAL 5-FU FOR TREATMENT OF HIGH-GRADE ANAL SQUAMOUS 
INTRAEPITHELIAL LESIONS IN HIV-INFECTED MEN AND WOMEN 
Only the recipient of the study treatment should complete this card. Study 
personnel may write on this card to document their interview and 
clarification of information recorded by the participant. However, all 
primary information should be the subject’s; all entries by study 
personnel should be dated and initialed. Study personnel who annotate 
this record should sign the last page of this document and print their name 
clearly. 
 
Study cycle: 2 weeks 
 
Today’s date:  _____/_____/_________ 
 
Subject ID:  ______ - ______ - ______ 
 
Doses you should apply: ________________________________________________________ 
 
STUDY PARTICIPANTS MUST BRING THIS COMPLETED DIARY CARD AND ALL 
STUDY DRUG CONTAINERS TO EACH STUDY VISIT DURING TREATMENT 
ADMINISTRATION. 
Complete this card every day for the first 14 days of the study; day number 1 is 
__________You will complete this card until (_____/_____/_____) and return the card to 
the study site in person at your next visit. 
You may receive a telephone call from the study nurse or coordinator to clarify information 
you have written. Feel free to write any concerns or questions in the boxes at the bottom of 
each page. 
COORDINATORS: Distribute the applicable section(s) of the imiquimod diaries at each 
treatment visit. Please ensure all pages of the diary are provided to the participant at each 
visit when the diary distributed. The diaries must be collected at each visit. 
 


AMC-088 Participant Diary for 5% Topical 5-FU 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
 
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Starting on your office visit day, please record the date and time of the application of medication and any reactions that occur at the treatment site. Estimate 
the severity of the following reactions AT THE APPLICATION SITE using the following definitions: 
Mild: An awareness of symptoms, easily tolerated 
Moderate: Discomfort is enough to interfere with your usual daily activities. 
Severe: Incapacitating and you are unable to participate in activities that you usually do. 
Cycle ___ Week 1 
Day 1 
Day 2 
Day 3 
Day 4 
Day 5 
Day 6 
Day 7 
Date (MM/DD/YY) 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
Applied? 
AM          PM 
 Yes       Yes 
 No        No 
AM          PM 
 Yes       Yes 
 No        No 
AM          PM 
 Yes       Yes 
 No        No 
AM          PM 
 Yes       Yes 
 No        No 
AM          PM 
 Yes       Yes 
 No        No 
Day Off 
Day Off 
Pain or Tenderness 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Bleeding 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 None 
 None 
 None 
 None 
 None 
 None 
 None 


AMC-088 Participant Diary for 5% Topical 5-FU 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
 
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___________________ 
 Mild 
 Moderate 
 Severe 
 Mild 
 Moderate 
 Severe 
 Mild 
 Moderate 
 Severe 
 Mild 
 Moderate 
 Severe 
 Mild 
 Moderate 
 Severe 
 Mild 
 Moderate 
 Severe 
 Mild 
 Moderate 
 Severe 
Comments 
 
 
 
 
 
 
 
 
 


AMC-088 Participant Diary for 5% Topical 5-FU 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
 
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Starting on your office visit day, please record the date and time of the application of medication and any reactions that occur at the treatment site. Estimate 
the severity of the following reactions AT THE APPLICATION SITE using the following definitions: 
Mild: An awareness of symptoms, easily tolerated 
Moderate: Discomfort is enough to interfere with your usual daily activities. 
Severe: Incapacitating and you are unable to participate in activities that you usually do. 
Cycle ___ Week 2 
Day 8 
Day 9 
Day 10 
Day 11 
Day 12 
Day 13 
Day 14 
Date (MM/DD/YY) 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
____/____/____ 
Applied? 
Day Off 
Day Off 
Day Off 
Day Off 
Day Off 
Day Off 
Day Off 
Pain or Tenderness 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Bleeding 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
 None 
 Mild 
 Moderate 
 Severe 
Other: 
 
___________________ 
 None 
 Mild 
 Moderate 
 None 
 Mild 
 Moderate 
 None 
 Mild 
 Moderate 
 None 
 Mild 
 Moderate 
 None 
 Mild 
 Moderate 
 None 
 Mild 
 Moderate 
 None 
 Mild 
 Moderate 


AMC-088 Participant Diary for 5% Topical 5-FU 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
 
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 Severe 
 Severe 
 Severe 
 Severe 
 Severe 
 Severe 
 Severe 
Comments 
 
 
 
 
 
 
 
 
Other Complaints or Illnesses 
Date (month/day/year) 
Severity 
Started 
Last Present 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 
 Mild     Moderate    Severe 
 
 
 


AMC-088 Participant Diary for 5% Topical 5-FU 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
 
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Comments or Concerns: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Please list any NEW prescription or over the counter medications or supplements that you took beginning on Day 1 and ending on Day 14 during this cycle. You 
do not have to list your HIV medications or any other drugs that you were taking regularly since the start of the study. 
Name of Medication 
Date (mm/dd/yy) 
Maximum 
Daily Dose 
Reason for Medication 
Started 
Last Taken 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


AMC-088 Participant Diary for 5% Topical 5-FU 
 
Cycle ____ 
Subject ID#: _____ - _____ - ______ 
Dates: ____ / ____ / ________ to ____ / ____ / ________ 
 
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If during the 14 days you did not take any medications check the box here:  None 
 
Comments or Concerns: 
 
 
 
 
 


 
 
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APPENDIX XI: PROTOCOL AMC-088 SMOKING STATUS/ RECENT SEXUAL 
HISTORY QUESTIONNAIRE 
Subject ID number: ___________________________ 
Date completed: ________________    Study Week number: ________ 
NOTE TO STAFF: Please answer question #1, then give to subject. It is preferable that the 
questionnaire be self-administered. 
1. 
Was this questionnaire self-administered or interviewer-administered? 
____ Self-administered 
____ Interviewer administered 
Thank you for taking this questionnaire. This form will ask about cigarette smoking. It will also 
ask about sex you may have had in the last 6 months. 
2. 
How often do you currently smoke cigarettes? (Choose one) 
____ Not at all (skip to question 4) 
____ Some days 
____ Every day 
____ I prefer not to answer (skip to question 4) 
3. 
On average over the past 6 months, how many cigarettes have you smoked per day?  (1 
pack equals 20 cigarettes) 
____ 
The next few questions will ask about men or women you may have had sex with in the past 6 
months. Let's review some words so that we agree on what we are talking about. By "having 
sex" we mean oral sex, anal sex, oral-anal sex, or vaginal sex. 
ANAL SEX is when a man puts his penis into someone’s rectum, anus, or butt. 
ORAL SEX is when someone puts his or her mouth or tongue to a woman’s vagina or clitoris 
or on a man’s penis. 
ORAL/ANAL SEX is when someone puts his or her mouth or tongue to someone’s anus (also 
known as rimming). 
VAGINAL SEX is when a man puts his penis in a woman’s vagina. 
1. 
Have you ever had sex with a man (even only once)? 
____ Yes 
____ No (skip to question 8) 
____ I prefer not to answer (skip to question 8) 


 
 
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2. 
Have you ever had sex by having a penis inserted into your anus (even only once)? 
____ Yes 
____ No  
____ I prefer not to answer 
3. 
Have you had sex of any kind with a man in the past 6 months? 
____ Yes 
____ No (skip to question 8) 
____ I prefer not to answer (skip to question 8) 
4. 
How many men have you had sex with in the past 6 months? 
____ 1 
____ 2 to 5 
____ 6 to 10 
____ More than 10 
5. 
With how many men have you had receptive anal sex with in the past 6 months (i.e. have 
sex by putting their penis into your anus)? 
____ 0 (skip to question 7) 
____ 1 
____ 2 to 5  
____ 6 to 10  
____ More than 10 
6. 
How often did your sex partner use a condom during receptive anal sex?  
____ Every time (100%) 
____ Mostly  
____ Half the time 
____ Occasionally 
____ Never (0%) 
7. 
In the past 6 months, how many men put their mouth or tongue on your anus? 
____0 
____1 
____2 to 5 
____6 to 10 
____More than 10 


 
 
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8. 
In the past 6 months, have you had sex with a woman? 
____Yes   
____No (skip to the end of the questionnaire) 
____I prefer not to answer (skip to the end of the questionnaire) 
9. 
In the past 6 months, how many women put their mouth or tongue on your anus? 
____ 0 
____ 1 
____2 to 5 
____ 6 to 10 
____More than 10 
Thank you for taking this questionnaire! 

ICF_001.pdf: 
AMC-088 Protocol (Version 8.0) 02AUG2023 
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NCI Version Date 02AUG2023 
SUMMARY OF CHANGES 
A Randomized, Phase III Study of Intra-anal Imiquimod 2.5% vs. Topical 5-fluorouracil 
5% vs. Observation for the Treatment of High-grade Anal Squamous Intraepithelial 
Lesions in HIV-positive Men and Women 
Version 8.0 
 
NCI Protocol #: AMC-088 
Local Protocol #: AMC-088 
 
NCI Version Date: 02AUG2023 
Protocol Date: 02AUG2023 
 
I. Scientific and Substantive Changes: 
# 
Section 
Comments 
1. 
Why is this 
study being 
done? 
Accrual target was updated from 118 participants to 88 participants 
because of the slow accrual rate. 
 
II. Administrative and Editorial Changes: 
# 
Section 
Comments 
2. 
Global 
The ICF was updated from version 7.0 to version 8.0 and the date was 
updated from 28JAN2022 to 02AUG2023. 


AMC-088 (Version 8.0) 02AUG2023 
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MODEL INFORMED CONSENT 
Study Title for Study Participants: Self-applied 5-fluorouracil Cream compared to Observation 
alone for the Treatment of Anal pre-cancers in HIV-positive Men and Women 
Official Study Title for Internet Search on http://www.ClinicalTrials.gov: A Randomized, 
Phase III Study of Intra-anal Imiquimod 2.5% % vs. Topical 5-fluorouracil 5% vs. Observation 
for the Treatment of High-grade Anal Squamous Intraepithelial Lesions in HIV-positive Men and 
Women 
A Clinical Trial of the AIDS Malignancy Consortium (AMC) 
______________________________________________________________________________ 
WHAT IS THE USUAL APPROACH TO MY ANAL PRE-CANCER, OR HSIL (HIGH 
GRADE SQUAMOUS INTRAEPITHELIAL LESIONS)? 
You are being asked to take part in the study because you are an adult with HIV and you may have, 
or have anal high grade squamous intraepithelial lesions (anal HSIL). Anal HSIL is tissue in the 
anal canal that has been damaged by infection with human papillomavirus (HPV) and is at risk for 
turning into cancer of the anus. Treating anal HSIL has been shown to lower the risk of developing 
anal cancer. 
The standard of care (the accepted standard of treatment) for anal HSIL varies among treatment 
centers. Some of the ways doctors may care for people with anal HSIL include: 
• Remove the anal HSIL lesions with a surgical procedure or other methods. 
WHAT ARE MY OTHER CHOICES IF I DO NOT TAKE PART IN THIS STUDY? 
If you decide not to take part in this study, you have other choices. For example: 
• You may choose to have the usual approach described above. 
• You may choose to take part in a different study, if one is available. 
• You may choose not to be treated for anal pre-cancer. 
• Or you may choose to receive 5-fluorouracil outside of the trial. 
WHY IS THIS STUDY BEING DONE? 
Anal HSIL is more common in men who have sex with men (MSM) and people who are living 
with HIV. Some people with anal HSIL will develop cancer of the anus, and treating anal HSIL 
lowers the chance that anal HSIL will turn into cancer. If anal HSIL turns into cancer, the standard 
treatment is surgery or chemotherapy and radiation. Most treatment of anal HSIL uses destructive 
methods such as electrocautery or surgery.  
This study will study a drug applied directly to the anal skin, also known as topical therapy. We 
want to know if this topical drug is effective at getting rid of anal HSIL. We also want to understand 
how well people are able to tolerate this treatment. The treatment is topical 5-fluorouracil (5FU), 
which is also known as EFUDEX. 5FU is approved for treating actinic keratosis (precancerous 
conditions of the skin not related to HPV), and for superficial basal cell carcinoma (a skin cancer 
not related to HPV). This drug is experimental when used to treat anal HSIL. A prior version of 
this study also included 2.5% imiquimod. This arm was stopped early because this drug was no 
longer available. 


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About 88 people will take part in this study. 
WHAT ARE THE STUDY GROUPS? 
This study has two study group. If you are in the 5FU group, you will be asked to put on gloves 
and apply the cream to the inside of your anus using your finger or syringe. 
• Group 1 will get 5FU. 
• Group 2 will not get any study drug for the first 24 weeks. 
A computer will assign you to one of the study groups by chance. This is called randomization. 
This is done by chance because no one knows if one treatment is better than the others. You have 
an equal chance of being in any group. 
Another way to find out what will happen to you during this study is to read the chart below. Start 
reading at the left side and read across to the right, following the lines and arrows. 
 
 
 
 
 
 
 
HOW LONG WILL I BE IN THIS STUDY? 
If you are eligible and randomized, you will be in the study for up to 44 weeks. 
WHAT EXTRA TESTS AND PROCEDURES WILL I HAVE IF I TAKE PART IN THIS 
STUDY? 
Most of the exams, tests, and procedures you will have are part of the usual approach for anal 
HSIL. However, there are some extra evaluations that you will need to have if you take part in this 
study. 
Before you begin the study: 
We will ask you about your medical history and perform tests to confirm that you can take part. 
Your first visit will include the following unless done recently by a health care provider: 
• Questions about your medical history, including: 
o Information about your HIV diagnosis and anal HSIL. 
o Whether you ever had an HPV vaccine (like Gardasil® or Cervarix®). 
o Your current medications, any history of allergies to medications. 
• Extra tests and procedures: 
o A physical exam. 
You agree 
to take 
part in the 
study 
Randomize 
(The computer will 
randomly put you in 
a study group) 
Group 1 
5FU 
Group 2 
No study drug 
We perform 
tests to see if 
you are right 
for the study 


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o A pregnancy test, if you are a woman who could become pregnant. Women also need to 
have a routine gynecologic exam within the last year. 
o An anal cytology (Pap test) to test for abnormal cells in the anus. The researcher will insert 
a swab (similar to a Q-tip™) into your anus. The end of the swab will be rubbed against 
the skin inside the anus. 
o A rectal exam with a finger to feel for any abnormalities. 
o An anal exam called high resolution anoscopy (HRA) that uses a special microscope and 
dyes to find abnormal areas of the anus. A lubricated plastic anoscope will be inserted into 
your anus. Then, a swab moistened with acetic acid (i.e. vinegar) is placed in your anus so 
that abnormal areas will be visible. The researcher puts the anoscope back into your anus. 
A colposcope (a machine with a magnifying lens) is used to see the skin inside the anus. 
Iodine may be used to help make lesions show up. 
o Biopsies to test anal HSIL. A biopsy cuts out a small piece of the abnormal skin (about the 
size of a sesame seed). Most often no medication to numb the skin is needed. If you feel 
pain, the researcher may inject a small amount of local anesthesia (Lidocaine or another 
anesthetic). 
o Blood will be drawn (about 4 teaspoons) to check your blood cell counts. These tests will 
also measure your T-cells (part of your immune system that helps fight infections) and HIV 
viral load (how much HIV is in your blood). 
o A blood test for HIV unless we have a copy of your HIV test results. 
o We will ask you if you would like to donate blood to the AIDS and Cancer Specimen 
Resource. If you agree, you will sign another consent form. If you don't agree, you can still 
take part in this study. 
If the exams, tests, and procedures show that you can take part in the study, and you choose to take 
part, then you will be randomized to one of the arms described above. 
• If you are in Group 1  (5FU). You will receive 16 weeks of treatment. Please bring back your 
containers of 5FU to every visit, even if they are empty. 
• Four weeks after treatment stops, you will come to the provider’s office for more tests. 
• If you still have anal HSIL, your provider will discuss additional treatment options with you. 
• About 11 months (44 weeks) after you started the study, you will be seen for final tests. 
If you are in Group 2 (no study drug): 
• You will be observed for 20 weeks (about 5 months). 
• If you still have anal HSIL at week 24, you will have the option of receiving 5FU. 
• You will receive 5FU from week 24 to week 40 (up to 16 weeks). 
• About 11 months (44 weeks) after you started the study, you will be seen for final tests. 
Study staff will follow you with HRA, anal biopsies, cytology and questions about how your are 
feeling. You will also undergo anal swabs for HPV testing. These tests are not part of the usual 
approach for anal HSIL. Neither you nor your health care plan/insurance carrier will be billed for 


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the collection of the anal HPV that will be used for this study. The anal HPV test results will not 
be given to you or your doctor. 
A study calendar that shows how often these tests will be done is attached. 
Your privacy is very important and the researchers will make every effort to protect it. Your test 
results will be identified by a unique code and the list that links the code to your name will be kept 
separate from your sample and health information. 
WHAT POSSIBLE RISKS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
If you choose to take part in this study, there is a risk that: 
• You may lose time at work or home and spend more time in the hospital or doctor’s office than 
usual 
• You may be asked sensitive or private questions which you normally do not discuss 
• 5FU may not be better, and could possibly be worse, than doing nothing for your pre-cancer. 
• For all participants, there is a slight chance that HSIL can become cancer, requiring 
more involved treatments. The risk of progression to cancer is low in all arms. However, 
the risk is higher for those in the observation arm than in the 5FU group, since HSIL will 
be followed without treatment for up to 24 weeks. 
• The risk of cancer during the time of no treatment is about 2 out of 1000 people.  The 
risk of cancer with treatment is about 1 out of 1000 people. 
Anal Pap Smear and HPV Test: Insertion of anal swabs may cause some discomfort. Minor 
bleeding (less than a quarter of a teaspoon) occurs occasionally in men and women due to the 
insertion of the swabs. The bleeding stops almost right away. 
HRA: Insertion of an anoscope will likely cause some discomfort. You may feel pressure and the 
urge to have a bowel movement. Putting acetic acid (vinegar) in the anal canal may cause some 
burning and irritation. 
Anal Biopsies: You may have pain with the anal biopsies. You may have some bleeding for up to 
a week after biopsies, especially when you have a bowel movement. There is a rare chance of very 
heavy bleeding that may require extra treatment. There is a very slight risk of infection (<1%). 
Contact the study clinic if you have symptoms of heavy bleeding or infection (fever, redness, or 
swelling). 
Injection of Local Anesthetic (numbing medicine): You may have a pinching or burning feeling 
from the shot of anesthetic. There is a very slight chance of reaction to the numbing medicine 
including rash, flushing, rapid heartbeat, and dizziness. 
Blood Drawing (venipuncture) Risks: In many people, obtaining blood from a vein may cause 
some discomfort. This may include infection, bruising, and/or tenderness at the site where the 
blood is taken, and fainting or feeling faint. 
Questionnaire: You will be asked questions about any sex you have had recently. Some people 
may find these questions embarrassing. 
There is also a risk that you could have side effects from the study drug. Here are important points 
about side effects: 


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• The study doctors do not know who will or will not have side effects. 
• Some side effects may go away soon, some may last a long time, or some may never go away. 
Here are important points about how you and the study doctor can make side effects less of a 
problem: 
• Tell the study doctor if you notice or feel anything different so they can see if you are having 
a side effect. 
• The study doctor may be able to treat some side effects. 
• The study doctor may adjust the study drugs to try to reduce side effects. 
The lists below show the most common and the most serious side effects that researchers know 
about. There might be other side effects that researchers do not yet know about. If important new 
side effects are found, the study doctor will discuss these with you. 
Study Group 1 - Table of Possible Side Effects of 5-FU for this type of cancer: 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving 5-FU, more than 20 and up to 100 may have: 
• Pain, burning, irritation and itching 
• Redness 
• Swelling 
• Ulcerations (i.e., sores on the skin) and bleeding 
• Flaking and crusting of the skin 
• Allergic reactions in the skin 
• Pain, redness and sores on skin near the treatment area (for example on the scrotum 
in men) 
Study Group 1 - In addition to side effects outlined above, people who are in Group 1 may also 
experience the possible side effects of 5FU listed in the Table below. 
COMMON, SOME MAY BE SERIOUS 
In 100 people receiving 5FU more than 20 and up to 100 may have: 
• Scarring of the skin. 
OCCASIONAL, SOME MAY BE SERIOUS 
In 100 people receiving 5FU, from 4 to 20 may have: 
• Emotional upset, insomnia, irritability 
• Medicinal taste 
• Low platelet counts, high white blood cells counts, and other blood count problems. 
• Loss of hair, and other rashes. 
• Red irritated eyes, and irritated nose. 
• It may cause a herpes infection to return. 


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COMMON, SOME MAY BE SERIOUS 
In 100 people receiving 5FU more than 20 and up to 100 may have: 
RARE, AND SERIOUS 
In 100 people receiving 5FU, 3 or fewer may have: 
• There have been miscarriages (loss of a pregnancies), and one birth defect (a serious 
heart condition) in women who have used 5FU during pregnancy. 
Let your study doctor know of any questions you have about possible side effects. You can ask the 
study doctor questions about side effects at any time. 
Reproductive risks: You should not get pregnant, breastfeed, or father a baby while in this study. 
The study drugs used in this study could be very damaging to an unborn baby. Check with the 
study doctor about what types of birth control, or pregnancy prevention, to use while in this study. 
If you are a woman and become pregnant or suspect you are pregnant while participating in this 
study, please inform your treating physician immediately. Women who could get pregnant and 
men who could father a child should use at least two forms of birth control for 3 months after 
stopping all study treatment. 
WHAT POSSIBLE BENEFITS CAN I EXPECT FROM TAKING PART IN THIS STUDY? 
This study has only a small chance of helping you because we do not know if the study drugs are 
effective. This study may help researchers learn things that may help other people in the future. 
CAN I STOP TAKING PART IN THIS STUDY? 
Yes. You can decide to stop at any time. If you decide to stop for any reason, it is important to let 
the study doctor know as soon as possible so you can stop safely. If you stop, you can decide 
whether or not to let the study doctor continue to provide your medical information to the 
organization running the study. 
The study doctor will tell you about new information or changes in the study that may affect your 
health or your willingness to continue in the study. 
The study doctor may take you out of the study: 
• If your health changes and the study is no longer in your best interest. 
• If new information becomes available. 
• If you do not follow the study rules. 
• If the study is stopped by the sponsor, IRB or FDA. 
WHAT ARE MY RIGHTS IN THIS STUDY? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 


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at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
WHAT ARE THE COSTS OF TAKING PART IN THIS STUDY? 
The 5FU will be supplied at no charge while you take part in this study. It is possible that the 5FU 
may not continue to be supplied while you are on the study. Although not likely, if this occurs, 
your study doctor will talk to you about your options. 
Your health plan/insurance company will need to pay for all of the other standard costs of treating 
your pre-cancer while in this study, including the cost of tests, procedures, or medicines to manage 
any side effects, unless you are told that certain tests are supplied at no charge. Before you decide 
to be in the study, you should check with your health plan or insurance company to find out exactly 
what they will pay for. If you do not have health insurance, arrangements may be made by the 
AMC to cover the cost of participation. 
You will be reimbursed $100 per study visit for visits 1, 5 and 10 where anoscopies and biopsies 
are performed.  You will receive $50 for all other visits while taking part in this study. 
WHAT HAPPENS IF I AM INJURED OR HURT BECAUSE I TOOK PART IN THIS 
STUDY? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please 
tell your study doctor. The study sponsors will not offer to pay for medical treatment for injury. 
Your insurance company may not be willing to pay for study-related injury. If you have no 
insurance, you would be responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to receive 
payment for this even though you are in a study. 
WHO WILL SEE MY MEDICAL INFORMATION? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, the researchers will do 
their best to make sure that any information that is released will not identify you. Some of your 
health information, and/or information about your specimen, from this study will be kept in a 
central database for research. Your name or contact information will not be put in the database. 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of these 
organizations are: 
• The AIDS Malignancy Consortium (AMC) 
• Any drug company supporting the study (Valeant Pharmaceuticals) 
• The Institutional Review Board, IRB, is a group of people who review the research with the 
goal of protecting the people who take part in the study. 
• The Food and Drug Administration and the National Cancer Institute in the U.S. 


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WHERE CAN I GET MORE INFORMATION? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at: 1-800-4-CANCER (1-800-422-6237). 
A description of this clinical trial will be available on http://www.ClinicalTrials.gov, as required 
by U.S. Law. This Web site will not include information that can identify you. At most, the Web 
site will include a summary of the results. You can search this Web site at any time. 
WHO CAN ANSWER MY QUESTIONS ABOUT THIS STUDY? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of study 
doctor[s]) at __________________ (insert telephone number). 
OPTIONAL 
SAMPLE 
COLLECTIONS 
FOR 
LABORATORY 
STUDIES 
AND 
DONATION OF LEFTOVER TISSUE SAMPLES TO THE AIDS AND CANCER 
SPECIMEN RESOURCE (ACSR) 
What is the usual approach to donate blood and/or tissue to the ACSR? 
You are being asked to donate blood and/or tissue for future research. You are being asked to 
donate your blood and/or tissue samples to the ACSR because you have HIV infection and are 
being considered for participation in an AIDS Malignancy Consortium (AMC) clinical trial. The 
AMC works with the ACSR to collect donated samples from persons with HIV infection for 
research studies. People who do not take part in an AMC clinical trial can also donate samples to 
the ACSR. 
What are my other choices if I do not take part in this study? 
It is your choice to donate or not donate your blood and/or tissue samples. You may still take part 
in the AMC clinical study if you choose not to donate blood or biopsy samples to the ACSR. You 
may also choose to donate: 
• Blood but not tissue, or 
• Tissue but not blood. 
What is the AIDS and Cancer Specimen Resource? 
The ACSR is a biorepository (biobank) that collects human biological specimens (samples) from 
persons who have HIV or cancers related to HIV/AIDS. The ACSR stores the samples and some 
of the donor’s medical information for use by researchers in future research studies. The National 
Cancer Institute (NCI) has set up the ACSR to assist researchers locate samples needed for their 
studies. 
The ACSR has an independent research panel that approves researchers’ requests to use the 
ACSR’s stored samples for research studies. The ACSR only gives samples and medical 
information to researchers after their projects have been approved. Researchers may use the 
samples to study cancers and other diseases associated with HIV disease. This information may 
help us learn more about the causes of HIV-related diseases and cancers and to develop better 
ways to screen, diagnose, and treat them. 


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Why is this study being done? 
The purpose of this study is to collect samples for the ACSR for future research studies. 
Researchers may study samples from the ACSR in combination with hundreds or thousands of 
other samples to explore how biologic or genetic factors may be related to HIV-related diseases 
and cancer. The information might help doctors in the future to identify who will or will not benefit 
from treatment. The samples may be used to learn more about how HIV-related diseases and 
cancers develop. The samples may also lead to new tests or discoveries. Finally, researchers may 
use the samples to study the genetic material from your cancer tissue and compare it to the material 
from your normal tissue (blood) to try to find the differences that exist. These studies could make 
it possible to identify many of the changes that are associated with diseases such as cancers. It may 
also help us tailor treatments to a patient's unique genetic make-up and/or to the genetic markers 
of the tumors. 
What extra tests and procedures will I have if I take part in this study? 
1. 
If you agree to donate blood, the medical team will draw about 2 tablespoons of blood to 
give to the ACSR. This takes about 10 minutes. 
2. 
If you agree to donate tissue, your leftover tissue biopsy material will be donated to and 
stored by the ACSR. 
3. 
Some of your clinical information will be released to the ACSR and entered into their 
database. The information given to the ACSR will not include your name or any 
information that could personally identify you. 
No extra biopsies will be collected for the ACSR. 
We will only give the ACSR tissue that is left over after making decisions about your treatment or 
diagnosis. The study doctor will not take any extra biopsies just for the ACSR. 
We cannot tell you right now what future research these samples would be used for. Instead, we 
are asking that you give approval to give your samples for future testing without contacting you 
again. The results of whatever research is done on your samples will not be told to you or your 
doctor. The results of the tests will not be placed in your study records. 
How long will ACSR keep my samples? 
Your blood and/or tissue sample will be stored until it is used for research. The samples may be 
stored indefinitely. 
What possible risks can I expect from taking part in this study? 
• Blood Draw: The risks of drawing blood include temporary discomfort from the needle stick, 
bruising, and, rarely, infection. 
• Biopsy: The risks of biopsy include possible need for stitches depending on the size of the 
biopsy. There may be swelling, slight pain and a small amount of blood loss. There is also a 
chance of infection at the site of the biopsy.  
• Confidentiality: The ACSR will receive study samples with code numbers. There will be no 
personal identifiers on the samples. Then the samples will be re-labeled with a barcode and 
stored for future testing. While the ACSR and researchers who study ACSR samples will have 
no information that could identify you, there is a risk that someone could use information from 


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genetic studies to trace your samples back to you. The researchers believe the chance that 
someone will identify you is very small, but the risk may change in the future as people come 
up with new ways of tracing information. In some cases, this information could be used to 
make it harder for you to get or keep a job. There are laws against misuse of genetic 
information, but they may not give full protection. The researchers believe the chance these 
things will happen is very small, but cannot promise that they will not occur. 
Let your study doctor know of any questions you have about these possible risks. You can ask the 
study doctor questions about side effects at any time. 
What possible benefits can I expect from taking part in this study? 
This study is unlikely to help you. This study may help us learn things that may help people in the 
future. 
The information may help to identify those who are at increased risk and those who may benefit 
from targeted treatment and screening. In turn, these studies could help find ways to prevent or 
improve treatments for HIV-related diseases and AIDS-related cancers. 
Can I stop taking part in this study? 
Yes, you may withdraw your samples from the ACSR at any time. You may contact your AMC 
study coordinator if you would like to withdraw your samples. The coordinator can ask in writing 
that your sample be removed from research use and that any identifiable sample and information 
still in their possession be destroyed. However, if any research has already been done using some 
of your samples, the data will be kept and analyzed as part of those studies. 
What are my rights in this study? 
Taking part in this study is your choice. No matter what decision you make, and even if your 
decision changes, there will be no penalty to you. You will not lose medical care or any legal 
rights. 
For questions about your rights while in this study, call the ________________________ (insert 
name of center) Institutional Review Board at __________________ (insert telephone number). 
(Note to Local Investigator: Contact information for patient representatives or other individuals 
at a local institution who are not on the IRB or research team but take calls regarding clinical 
trial questions can also be listed here.) 
What are the costs of taking part in this study? 
There will be no cost to you for donating your samples to the ACSR. You will not be paid for 
taking part in this study. 
What happens if I am injured or hurt because I took part in this study? 
If you are injured or hurt as a result of taking part in this study and need medical treatment, please 
tell your study doctor. The AMC will not offer to pay for medical treatment for injury. Your 
insurance company may not be willing to pay for study-related injury. If you have no insurance, 
you would be responsible for any costs. 
If you feel this injury was a result of medical error, you keep all your legal rights to seek payment 
for injury even though you are in a study. 


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Who will see my medical information? 
Your privacy is very important to us and the researchers will make every effort to protect it. Your 
information may be given out if required by law. For example, certain states require doctors to 
report to health boards if they find a disease like tuberculosis. However, the researchers will do 
their best to make sure that any information that is released will not identify you. Some of your 
health information, and/or information about your specimen, from this study will be kept in a 
central database for research. Your name or contact information will not be put in the database. 
There are organizations that may inspect your records. These organizations are required to make 
sure your information is kept private, unless required by law to provide information. Some of these 
organizations are: 
• The AIDS Malignancy Consortium (AMC) 
• The Institutional Review Board, IRB, is a group of people who review the research with the 
goal of protecting the people who take part in the study. 
• The Office for Human Research Protections and the National Cancer Institute in the U.S. 
To protect your privacy, the AMC does not keep identifying information that links study 
participants to specific samples. As a result, the AMC and ACSR will not be able to link the results 
from studies that use your samples back to you. Thus, information, including genetic information, 
that researchers may obtain in studies that use your samples may not be directly linked to you and 
will not be placed in your medical record. However, some clinical and basic information obtained 
confidentially from the AMC will be attached with these data. It is possible that findings may one 
day help, for example, people of the same race or sex as you. It also is possible that genetic factors 
might come to be associated with people who have HIV and cancer through these kinds of studies. 
Where can I get more information? 
You may visit the NCI Web site at http://cancer.gov/ for more information about studies or general 
information about cancer. You may also call the NCI Cancer Information Service to get the same 
information at 1-800-4-CANCER (1-800-422-6237). 
Who can answer my questions about this study? 
You can talk to the study doctor about any questions or concerns you have about this study or to 
report side effects or injuries. Contact the study doctor __________________ (insert name of study 
doctor[s]) at __________________ (insert telephone number). 
Please circle your answer to show whether or not you would like to take part in each option: 
1. I agree to donate my blood to the ACSR for future research that may be used to learn 
about, prevent, diagnose, or treat HIV-related diseases and cancer. 
YES 
 
NO 
2. I agree to donate my blood to the ACSR for future research that may include genetic 
testing to learn about, prevent, diagnose, or treat HIV-related diseases and cancer.  
YES 
 
NO 


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3. I agree to donate some of my tissue biopsy material that is not required for my treatment 
or diagnosis to the ACSR for future research that may be used to learn about, prevent, 
diagnose, or treat HIV-related diseases and cancer. 
YES 
 
NO 
4. I agree to donate some of my tissue biopsy material to the ACSR for future research that 
may include genetic testing to learn about, prevent, diagnose, or treat HIV-related 
diseases and cancer.  
YES 
 
NO 
 
 


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MY SIGNATURE AGREEING TO TAKE PART IN THE MAIN STUDY 
I have read this consent form or had it read to me. I have discussed it with the study doctor and my 
questions have been answered. I will be given a signed copy of this form. I agree to take part in 
the main study and any additional studies where I circled ‘yes’.  
 
____________________________________ 
___________________________________ 
Participant’s Signature 
 
 
 
Date of Signature 
 
____________________________________ 
___________________________________ 
Signature of Person(s) conducting the 
 
Date of Signature 
Informed Consent Discussion 
 
 
 


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AMC-088: STUDY CALENDAR FOR VOLUNTEERS 
5-fluorouracil cream to observation alone for the treatment of anal pre-cancers in HIV-
positive Men and Women 
Visit 1 (Baseline Visit, Enrollment, Randomization) 
At this visit, we will ask you about the following information and perform these exams: 
• Any current anal problems and any symptoms you may have related to the anal HSIL 
• Any changes to your medication 
• Pregnancy test if you are female and able to become pregnant 
• A physical exam 
• A rectal exam with a finger to feel for any abnormalities 
• High-resolution anoscopy (HRA) to document the size and location of your lesions. No 
biopsies are obtained 
• It is important that you do not have anal sex or insert anything into the anus, including enemas, 
for 24 hours prior to each visit. 
• A study nurse or doctor will ask you about smoking and recent sexual activity including how 
many sexual partners, use of condoms, and types of sexual activity. 
We will take photographs of your lesions to document their appearance. A computer program will 
randomly assign you to 5FU, or observation group. If you are in the observation arm, your visit is 
complete. If you are in the 5FU arm, study staff will explain how to properly apply the treatment. 
You will be given a study diary to take home with you to help you remember any problems that 
you experience from the study treatment.  
Visits 2, 3, 4 (Week 2, 8, 16) 
At these visits, we will ask you about the following information and perform these exams: 
• You will have a week 2 visit only if you are receiving 5FU. 
• Your medical history will be updated for any changes since your last visit. This includes any 
side effects from the study exam, and any changes in your medication. A brief physical exam 
may be performed. 
• Pregnancy test if you are female and able to become pregnant. 
• A rectal exam with a finger to feel for any abnormalities. 
• High-resolution anoscopy (HRA) at week 8. HRA may also be done at week 2 and 16 if your 
provider feels it is necessary to investigate symptoms you may be experiencing. Anal biopsies 
are only collected if it appears that the HSIL is getting worse. 
• An anal swab for HPV testing will be done at weeks 8 and 16. 
• Your treatment diary will be reviewed, and you should bring in any partially used containers 
of 5FU to be weighed. Empty bottles and tubes must also be returned for weighing. 


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Visit 5 (Week 20) 
At this visit, we will ask you about the following information and perform these exams: 
• Your medical history will be updated for any changes since your last visit. This includes any 
side effects from the study exam, and any changes in your medication. A brief physical exam 
may be performed. 
• Pregnancy test if you are female and able to become pregnant. 
• Anal swabs for cytology and HPV testing will be done. 
• A rectal exam with a finger to feel for any abnormalities. 
• A study nurse or doctor will ask you about smoking and recent sexual activity including how 
many sexual partners, use of condoms, and types of sexual activity. 
• High-resolution anoscopy (HRA) to document the size and location of your lesions. At least 4 
anal biopsies will be done to determine the extent of HSIL. 
Visits 6, 7, 8 and 9 (weeks 24, 26, 32 and 40) 
• For participants randomizedto 5FU, you will receive the results of the cytology and anal 
biopsies. If you still have HSIL, your study providers will discuss options to treat your HSIL 
other than study provided treatments. These treatments are not determined by the study. After 
you stop the study treatment, you will only need to return for Visit 10 at week 44 (not Visits 
6, 7, 8 or 9). 
• For participants randomized to observation, you will receive the results of the cytology and 
anal biopsies. If you still have HSIL, you have the option of being assigned to 5FU. This 
treatment would start at week 24. If you start 5FU at week 24, you will be asked to attend 
Visits 6, 7, 8 and 9. If you do not start 5FU, or if you do not have HSIL, you will only be asked 
to attend Visit 10 (week 44). 
• Visit 6 (Week 24) has the same evaluations as Visit 1 (Baseline) except no HRA will be 
performed. If you agreed to donate blood to the AIDS and Cancer Specimen Resource, we will 
ask you to provide a blood sample again. 
• Visits 7, 8 and 9 (weeks 26, 32 and 40) have the same evaluations as Visits 2, 3 and 4 (weeks 
2, 8 and 16). Anal swabs for HPV testing will be obtained at Visit 8 (week 32) and Visit 9 
(week 40). 
• Your treatment diary will be reviewed, and you should bring in any partially used containers 
of 5FU to be weighed. Empty bottles and tubes must also be returned for weighing. 
Visit 10 (Week 44) 
This will be the final visit for this study. At this visit, we will ask you about the following 
information and perform these exams: 
• Your medical history will be updated for any changes since your last visit. This includes any 
side effects from the study exam, and any changes in your medication. A brief physical exam 
may be performed. 
• Pregnancy test if you are female and able to become pregnant. 


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• Anal swabs for cytology and HPV testing will be done. 
• A rectal exam with a finger to feel for any abnormalities. 
• A study nurse or doctor will ask you about smoking and recent sexual activity including how 
many sexual partners, use of condoms, and types of sexual activity. 
• High-resolution anoscopy (HRA) to document the size and location of your lesions. At least 4 
anal biopsies will be done to determine the extent of HSIL. 
• If your biopsies show HSIL, your study providers will discuss treatment options available to 
you. 
 
 


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AMC-088: AMC CERTIFICATE OF CONFIDENTIALITY 
Self-applied imiquimod gel or 5-fluorouracil cream to observation alone for the treatment of 
anal pre-cancers in HIV-infected Men and Women 
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 turn down 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.