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

NCT02059499 | Completed Phase 3 Results DMC

• 3 other identifiers: AMC-088NCI-2013-02288U01CA121947
• Study Type: interventional
• Target: 91
• Locations: 2 countries
• Sites: 13

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.

Conditions

Anal Intraepithelial Neoplasia; High-grade Squamous Intraepithelial Lesion; HIV Infection

Outcome Measures

Primary Outcomes (8)

• 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 Outcomes (9)

• 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.

  Up to week 44

• Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population

  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.

  Up to week 20

• Amount of Drug Consumed in 5-FU and Imiquimod Arm by Week 16

  Week 16

• Percentage of Participants Achieving Complete or Partial Response in 5-FU vs Observation Using ITT Population

  At 44 weeks

Study Arms (3)

Arm A (imiquimod)

EXPERIMENTAL

Patients apply imiquimod intra-anally QD for 16 weeks.

Drug: imiquimod; Other: questionnaire administration; Other: laboratory biomarker analysis

Arm B (fluorouracil)

EXPERIMENTAL

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.

Drug: fluorouracil; Other: questionnaire administration; Other: laboratory biomarker analysis

Arm C (observation)

NO INTERVENTION

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

imiquimod DRUG

Given intra-anally

Also known as: Aldara, IMQ, R 837

Arm A (imiquimod)

fluorouracil DRUG

Given intra-anally

Also known as: 5-fluorouracil, 5-Fluracil, 5-FU

Arm B (fluorouracil)

questionnaire administration OTHER

Ancillary studies

Arm A (imiquimod); Arm B (fluorouracil)

laboratory biomarker analysis OTHER

Correlative studies

Arm A (imiquimod); Arm B (fluorouracil)

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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
• 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)

Sponsors & Collaborators

• AIDS Malignancy Consortium: lead
• National Cancer Institute (NCI): collaborator
• The Emmes Company, LLC: collaborator
• University of Arkansas: collaborator

Study Sites (13)

UCLA CARE Center

Los Angeles, California, 90035, United States

Location

UCSF-Mount Zion

San Francisco, California, 94115, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Emory University

Atlanta, Georgia, 30303, United States

Location

Louisiana State University Health Sciences Center - New Orleans

New Orleans, Louisiana, 70112, United States

Location

Boston Medical Center

Boston, Massachusetts, 02118, United States

Location

Laser Surgery Care

New York, New York, 10011, United States

Location

Cornell Clinical Trials Unit, New York Presbyterian Hospital

New York, New York, 10065, United States

Location

Weill Medical College of Cornell University

New York, New York, 10065, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

Wake Forest University Health Sciences

Winston-Salem, North Carolina, 27157, United States

Location

Benaroya Research Institute at Virginia Mason Medical Center

Seattle, Washington, 98101, United States

Location

University of Puerto Rico

San Juan, 00936-3027, Puerto Rico

Location

Related Publications (1)

• Pedersen TB, Pachler FR, Rosenberg J, Andresen K. Interventions for anal canal intraepithelial neoplasia. Cochrane Database Syst Rev. 2025 Aug 13;8(8):CD009244. doi: 10.1002/14651858.CD009244.pub3.

  PMID: 40801169 DERIVED

MeSH Terms

Conditions

Squamous Intraepithelial Lesions; HIV Infections

Interventions

Imiquimod; Fluorouracil

Condition Hierarchy (Ancestors)

Morphological and Microscopic Findings; Pathological Conditions, Signs and Symptoms; Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Intervention Hierarchy (Ancestors)

Aminoquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Uracil; Pyrimidinones; Pyrimidines; Heterocyclic Compounds, 1-Ring

Results Point of Contact

• Title: Dr Himanshu Joshi, MBBS, MPH, PhD (Assistant Professor)
• Organization: AMC Statistical Center

himanshu.joshi@mountsinai.org

212-259-9635

Study Officials

• Timothy Wilkin

  AIDS Associated Malignancies Clinical Trials Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 7, 2014
• First Posted: February 11, 2014
• Study Start: December 28, 2015
• Primary Completion: December 5, 2023
• Study Completion: May 2, 2024
• Last Updated: July 23, 2025
• Results First Posted: May 20, 2025

Record last verified: 2025-07

Locations

US (12); PR (1)