Imiquimod, Fluorouracil, or Observation in Treating HIV-Positive Patients With High-Grade Anal Squamous Skin Lesions

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-infected Men and Women

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.

Study Overview

• Status: Completed
• Conditions: HIV Infection; Anal Intraepithelial Neoplasia; High-grade Squamous Intraepithelial Lesion
• Intervention / Treatment: Other: laboratory biomarker analysis; Other: questionnaire administration; Drug: imiquimod; Drug: fluorouracil

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.

• Study Type: Interventional
• Enrollment (Actual): 91
• Phase: Phase 3

Contacts and Locations

Study Locations

• Puerto Rico
  • San Juan, Puerto Rico, 00936-3027
    • University of Puerto Rico
• United States
  • California
    • Los Angeles, California, United States, 90035
      • UCLA CARE Center
    • San Francisco, California, United States, 94143
      • University of California, San Francisco
    • San Francisco, California, United States, 94115
      • UCSF-Mount Zion
  • Georgia
    • Atlanta, Georgia, United States, 30303
      • Emory University
  • Louisiana
    • New Orleans, Louisiana, United States, 70112
      • Louisiana State University Health Sciences Center - New Orleans
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston Medical Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10065
      • Weill Medical College of Cornell University
    • New York, New York, United States, 10011
      • Laser Surgery Care
    • New York, New York, United States, 10065
      • Cornell Clinical Trials Unit, New York Presbyterian Hospital
  • North Carolina
    • Winston-Salem, North Carolina, United States, 27157
      • Wake Forest University Health Sciences
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute at Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 17 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• HIV-positive; documentation of HIV infection must be based on a federally approved, licensed HIV test performed in conjunction with screening (enzyme linked immunosorbent assay [ELISA], western blot, or other test); alternatively, this documentation may include a record that another physician has documented that the patient has HIV based on prior ELISA and western blot; an approved antibody test will be used to confirm diagnosis; if the physician is treating a patient with combination antiretroviral therapy (cART) with a history of HIV positivity based on an approved antibody test then repeat antibody confirmation is not necessary
• Biopsy-proven HSIL (anal intraepithelial neoplasia 2 (AIN2) and/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 1 week prior to enrollment
• HSIL occupies at least 25% of the circumference of the anal canal at either the squamocolumnar junction or distal anus on high-resolution anoscopy (HRA) at screening or entry based on available biopsy results and visual appearance
• Anal HSIL lesions are visible at study entry and no lesions are suspicious for invasive cancer
• Ability to understand and willing to provide informed consent
• Participants must, in the opinion of the Investigator, be capable of complying with the requirements of this protocol including self-administration of study treatment
• Karnofsky performance status of >= 70%
• Cluster of differentiation (CD)4 count >= 200 within 120 days prior to enrollment or plasma HIV-1 ribonucleic acid (RNA) < 200 copies/mL within 120 days prior to enrollment
• For females, cervical cytology (if having a cervix) and gynecologic evaluation within 12 months prior to enrollment
• Absolute neutrophil count (ANC) > 750 cells/mm^3 within 90 days prior to enrollment
• Hemoglobin >= 9.0 g/dL within 90 days prior to enrollment
• Platelet count >= 75,000/mm^3 within 90 days prior to enrollment

Exclusion Criteria:

• History of anal cancer
• Prior intra-anal use of topical 5-fluorouracil 5% or imiquimod 2.5%, 3.75% or 5% at any point, or use of perianal imiquimod 2.5%, 3.75% or 5% or topical 5-fluorouracil 5% within 6 months prior to enrollment
• 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
• Condyloma occupying more than 50% of the circumference of the anal canal or that obscures a satisfactory exam
• Ongoing use of anticoagulant therapy other than aspirin or nonsteroidal anti-inflammatory drugs (NSAIDs)
• 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 study entry
• Malignancy requiring systemic therapy; note: Kaposi's sarcoma limited to the skin is not exclusionary unless requiring systemic chemotherapy
• Concurrent systemic corticosteroids, cytokines, and immunomodulatory therapy (e.g. interferons)
• Prior history of HPV vaccination
• Treatment for anal or perianal HSIL, low-grade squamous intraepithelial lesion (LSIL) or condyloma within 4 months of entry; please note that infrared coagulation (IRC) or electrocautery of a biopsy site to stop bleeding does not constitute treatment
• 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 initiating study treatment; all women of childbearing potential must be willing to comply with an acceptable birth control regimen to prevent pregnancy while receiving treatment and for 3 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)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Single

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Arm A (imiquimod); Patients apply imiquimod intra-anally QD for 16 weeks.	Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Drug: imiquimod; Given intra-anally; Other Names: Aldara; R 837; IMQ
Experimental: Arm B (fluorouracil); 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.	Other: laboratory biomarker analysis; Correlative studies; Other: questionnaire administration; Ancillary studies; Drug: fluorouracil; Given intra-anally; Other Names: 5-FU; 5-fluorouracil; 5-Fluracil
No Intervention: Arm C (observation); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Participants Achieving Complete Response in 5-FU Arm and Observation Arm Using ITT Population	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. The percentage of participants achieving complete response in the 5-FU and observation arms will be reported and compared across sites, along with the corresponding p-value, using stratified Mantel-Haenszel-Cochran tests at a one-sided alpha level of 0.025.	At week 20
Percentage of Participants Achieving Complete Response (5-FU vs Observation ) Using Per Protocol Population	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. The percentage of participants achieving complete response in the 5-FU and observation arms will be reported, along with the corresponding p-value, using stratified Mantel-Haenszel-Cochran tests to compare results across sites at a one-sided alpha level of 0.025.	At week 20
Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.	Complete response is defined as an absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the percentage of complete response in 5-FU vs Imiquimod arms across sites using stratified CMH test at one-sided 0.05 alpha.	Week 20
Percentage of Participants Achieving Complete Response in 5-FU vs. Imiquimod, Using the PP Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by 5-FU vs Imiquimod across sites using stratified CMH test at one-sided 0.05 alpha using only the participants randomized to imiquimod and 5-FU prior to closure of the imiquimod arm.	Week 20
Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by Observation vs Imiquimod across sites using stratified CMH test at two-sided 0.05 alpha using only the participants randomized to imiquimod and observation prior to closure of the imiquimod arm.	Week 20
Percentage of Participants Achieving Complete Response in Imiquimod vs Observation Arm, Using Per Protocol Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Compare the complete response by Observation vs Imiquimod across sites using stratified CMH test at two-sided 0.05 alpha using only the participants randomized to imiquimod and observation prior to closure of the imiquimod arm.	Week 20
Number of Participants With Peri-anal HSIL Confirmed by Histology Across All Study Arms	Perianal HSIL are HSIL lesions detected in peri-anal region; These lesions will be detected by visual inspection using high resolution anoscopy and biopsy. Number of participants with presence of peri-anal HSIL on histology	At week 20
Number of Participants With Intra-anal HSIL	Intra-anal HSIL lesions are those lesions that are detected in intra-anal region. It will be detected using visual inspection using HRA followed by positive identification of HSIL using biopsy or cytology. Presence of intra-anal HSIL lesions will be descriptively reported across the three arms	At week 20

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Participants Who Experienced an Adverse Event of Grade 1 to 5 by Week 44, Irrespective of Relatedness to the Intervention. AEs Were Stratified According to Those Reported at or Before Week 20 and After Week 20.	Adverse events are graded on a scale from 1 (mild) to 5 (death) as per CTCAE v. 5.0, with higher grades indicating greater severity. The number of participants who experienced an adverse event of grade 1 to 5 by Week 44, regardless of its relatedness to the intervention, will be reported. AEs were stratified according to those reported at or before Week 20 and after Week 20.	Up to week 44
Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as either 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentages will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.	Up to week 20
Percentageof Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.	Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentage of patients achieving complete or partial responses with imiquimod will be compared to observation using participants randomized to imiquimod and observation prior to closure of the imiquimod arm.	Up to week 20
Amount of Drug Consumed in 5-FU and Imiquimod Arm by Week 16	Amount of study drug consumed by measuring the mass of study drug dispensed (weight of study drug container at baseline - weight of study drug at the end of treatment) by study arm (5FU vs imiquimod) by the time of receiving 8 cycle treatment	Week 16
Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population	Complete response is defined as the Complete response is defined as the absence of HSIL histology for all biopsies and the absence of HSIL cytology. Partial response is defined as 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL. Percentage will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.	At 44 weeks
Percentage of Patients Achieving Complete or Partial Response in Imiquimod vs Observation Arm, Using ITT Population Restricted to Those Randomized to Either Treatment Prior to the Closure of the Imiquimod Arm.	The proportion of patients achieving complete or partial responses with imiquimod will be compared to observation using participants randomized to imiquimod and observation prior to closure of the imiquimod arm. Complete response is defined as the absence of HSIL based on central pathology review, if available; otherwise, local biopsy results will be used. Partial Response is defined as: 1) The regression of HSIL histology but HSIL cytology is present, or 2) Reduction in number of octants with HSIL.	Up to week 44
Persistence and New Infections of HPV Type Specific Infections	The proportion of participants with persistent HPV infection, defined as the presence of the same HPV type detected at both baseline and Week 20. The proportion of participants who acquire a new HPV infection at Week 20 that was not detected at baseline is new infection. Persistence and new infection will be assessed separately for each HPV type.	At week 20
Comparison of the Number of hrHPV Genotypes in Each Arm Observed at Baseline vs at Week 20	hrHPV genotypes will be detected in anal swabs specimens processed using polymerase chain reaction (PCR) and reverse line blot analysis. Comparison of mean number of hrHPV genotypes in each arm observed at baseline vs at week 20	week 20
HPV Genotypes Present at Baseline But no Longer Detected at Week 20	Count of HPV genotypes present at baseline but no longer detected at week 20.	20 weeks

Collaborators and Investigators

• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); University of Arkansas; The Emmes Company, LLC
• Investigators: Principal Investigator: Timothy Wilkin, AIDS Associated Malignancies Clinical Trials Consortium

Study record dates

Study Major Dates

• Study Start (Actual): December 28, 2015
• Primary Completion (Actual): December 5, 2023
• Study Completion (Actual): May 2, 2024

Study Registration Dates

• First Submitted: February 7, 2014
• First Submitted That Met QC Criteria: February 10, 2014
• First Posted (Estimated): February 11, 2014

Study Record Updates

• Last Update Posted (Actual): July 23, 2025
• Last Update Submitted That Met QC Criteria: July 11, 2025
• Last Verified: July 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Uterine Diseases; Genital Diseases, Female; Uterine Cervical Dysplasia; Precancerous Conditions; Uterine Cervical Diseases; Squamous Intraepithelial Lesions of the Cervix; Toll-Like Receptor Agonists; Immunomodulating Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Adjuvants, Immunologic; Interferon Inducers; Imiquimod; Fluorouracil
• Other Study ID Numbers: AMC-088 (Other Identifier: CTEP); U01CA121947 (U.S. NIH Grant/Contract); NCI-2013-02288 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED