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

HIV Infection Clinical Trial

Official 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 in HIV-infected Men and Women

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT02059499
• Other study ID #: AMC-088
• Secondary ID: NCI-2013-02288AM
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: December 28, 2015
• Est. completion date: May 21, 2024

Study information

• Verified date: January 2024
• Source: AIDS Malignancy Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 91
• Est. completion date: May 21, 2024
• Est. primary completion date: December 5, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 21 Years and older

Eligibility

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)

Related Conditions & MeSH terms

• Anal Intraepithelial Neoplasia
• High-grade Squamous Intraepithelial Lesion
• HIV Infection
• Squamous Intraepithelial Lesions of the Cervix

Intervention

Drug:
• imiquimod
Given intra-anally
• fluorouracil
Given intra-anally

Other:
• questionnaire administration
Ancillary studies
• laboratory biomarker analysis
Correlative studies

Locations

Country	Name	City	State
Puerto Rico	University of Puerto Rico	San Juan
United States	Emory University	Atlanta	Georgia
United States	Boston Medical Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	UCLA CARE Center	Los Angeles	California
United States	Louisiana State University Health Sciences Center - New Orleans	New Orleans	Louisiana
United States	Cornell Clinical Trials Unit, New York Presbyterian Hospital	New York	New York
United States	Laser Surgery Care	New York	New York
United States	Weill Medical College of Cornell University	New York	New York
United States	UCSF-Mount Zion	San Francisco	California
United States	University of California, San Francisco	San Francisco	California
United States	Benaroya Research Institute at Virginia Mason Medical Center	Seattle	Washington
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (4)

Lead Sponsor	Collaborator
AIDS Malignancy Consortium	National Cancer Institute (NCI), The Emmes Company, LLC, University of Arkansas

Countries where clinical trial is conducted

United States,  Puerto Rico, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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
Primary	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
Primary	Presence of intra-anal HSIL on cytology or histology	Perianal HSIL will be descriptively reported separately, as well as combined.	At week 20
Secondary	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
Secondary	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
Secondary	Number of quadrants with HSIL found on biopsies	Will be compared between arms treating the response as an ordinal variable.	Up to week 48
Secondary	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
Secondary	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
Secondary	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