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: Active, not recruiting
• 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: 19 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
Proportion of participants achieving complete response (Arm A and B)	For each treatment comparison (imiquimod vs observation and fluorouracil vs observation) the proportions will be compared across sites using stratified Mantel-Haenszel-Cochran tests at the one-sided 0.025 alpha level.	At week 20
Proportion of participants with spontaneous regression (Arm C)	For each treatment comparison (imiquimod vs observation and fluorouracil vs observation) the proportions will be compared across sites using stratified Mantel-Haenszel-Cochran tests at the one-sided 0.025 alpha level.	At week 20
Presence of intra-anal HSIL on cytology or histology	Perianal HSIL will be descriptively reported separately, as well as combined.	At week 20

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	To examine the tolerability and safety of the three arms, descriptive statistics for adverse events will be computed. Adverse events will be summarized at the event level and participant level according to severity. Adverse events will be stratified according to those reported at or before week 20 and after week 20. Proportions and their exact 95% confidence intervals will be calculated. Summary statistics will be computed for the amount of study drug taken.	Up to week 44
Proportion of participants achieving complete response or spontaneous regression	Proportions will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.	Up to week 44
Number of quadrants with HSIL found on biopsies	Will be compared between arms treating the response as an ordinal variable.	Up to week 48
Proportion of patients achieving complete or partial responses	The proportion of patients achieving complete or partial responses with imiquimod or fluorouracil will be compared to observation only.	Up to week 44
Persistence of HPV type specific infections	The frequency and proportion of HPV types present at baseline that are no longer detected at week 20 will be reported. The frequency and proportion of new HPV infections detected at week 20 that were not present at baseline will also be reported. Proportions and their exact binomial 95% confidence intervals will be calculated.	At week 20
Presence of intra-anal HSIL on cytology or histology	Perianal HSIL will be descriptively reported separately, as well as combined. Results for the observation arm will be stratified into cross-over treatment groups.	At week 44

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 (Estimated): May 21, 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): January 22, 2024
• Last Update Submitted That Met QC Criteria: January 19, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Uterine Cervical Diseases; Uterine Diseases; Precancerous Conditions; Uterine Cervical Dysplasia; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases; Genital Diseases, Female; Squamous Intraepithelial Lesions of the Cervix; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Adjuvants, Immunologic; Interferon Inducers; Fluorouracil; Imiquimod
• 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