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

• ClinicalTrials.gov Identifier: NCT02059499
• Recruitment Status: Recruiting
• First Posted: February 11, 2014
• Last Update Posted: July 18, 2022
• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); The Emmes Company, LLC; University of Arkansas
• Information provided by (Responsible Party): AIDS Malignancy Consortium

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Anal Intraepithelial Neoplasia; High-grade Squamous Intraepithelial Lesion; HIV Infection	Drug: imiquimod; Drug: fluorouracil; Other: questionnaire administration; Other: laboratory biomarker analysis	Phase 3

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 150 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: December 28, 2015
• Estimated Primary Completion Date: August 2025
• Estimated Study Completion Date: September 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A (imiquimod); Patients apply imiquimod intra-anally QD for 16 weeks.	Drug: imiquimod; Given intra-anally; Other Names: Aldara; IMQ; R 837; Other: questionnaire administration; Ancillary studies; Other: laboratory biomarker analysis; Correlative studies
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.	Drug: fluorouracil; Given intra-anally; Other Names: 5-fluorouracil; 5-Fluracil; 5-FU; Other: questionnaire administration; Ancillary studies; Other: laboratory biomarker analysis; Correlative studies
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.

Outcome Measures

Primary Outcome Measures :

1. Proportion of participants achieving complete response (Arm A and B) [ Time Frame: At week 20 ]
   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.
2. Proportion of participants with spontaneous regression (Arm C) [ Time Frame: At week 20 ]
   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.
3. Presence of intra-anal HSIL on cytology or histology [ Time Frame: At week 20 ]
   Perianal HSIL will be descriptively reported separately, as well as combined.

Secondary Outcome Measures :

1. Incidence of adverse events, graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to week 44 ]
   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.
2. Proportion of participants achieving complete response or spontaneous regression [ Time Frame: Up to week 44 ]
   Proportions will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.
3. Number of quadrants with HSIL found on biopsies [ Time Frame: Up to week 48 ]
   Will be compared between arms treating the response as an ordinal variable.
4. Proportion of patients achieving complete or partial responses [ Time Frame: Up to week 44 ]
   The proportion of patients achieving complete or partial responses with imiquimod or fluorouracil will be compared to observation only.
5. Persistence of HPV type specific infections [ Time Frame: At week 20 ]
   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.
6. Presence of intra-anal HSIL on cytology or histology [ Time Frame: At week 44 ]
   Perianal HSIL will be descriptively reported separately, as well as combined. Results for the observation arm will be stratified into cross-over treatment groups.

Eligibility Criteria

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

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)

Contacts and Locations

Locations

United States, California

UCLA CARE Center; Recruiting

Los Angeles, California, United States, 90035

Contact: Nikkole Valdez 310-557-9027 nbvaldez@mednet.ucla.edu

Principal Investigator: Ronald Mitsuyasu, MD

UCSF-Mount Zion; Recruiting

San Francisco, California, United States, 94115

Contact: Naomi Jay 415-353-7443 naomi.jay@ucsf.edu

Sub-Investigator: Naomi Jay

Principal Investigator: Joel Palefsky, MD

University of California, San Francisco; Recruiting

San Francisco, California, United States, 94143

Contact: Arezou Sadighi Akha 818-447-5857 Arezou.SadighiAkha@ucsf.edu

Principal Investigator: Naomi Jay, PhD, NP

United States, Florida

University of Miami; Withdrawn

Miami, Florida, United States, 33136

United States, Georgia

Emory University; Recruiting

Atlanta, Georgia, United States, 30303

Contact: Fletcher Neale, CRC II 404-712-3522 mnealej@emory.edu

Principal Investigator: Lisa Flowers, MD

United States, Louisiana

Louisiana State University Health Sciences Center - New Orleans; Recruiting

New Orleans, Louisiana, United States, 70112

Contact: Jim Outland 504-568-7634 joutla@lsuhsc.edu

Principal Investigator: Michael Hagensee, MD

United States, Massachusetts

Boston Medical Center; Recruiting

Boston, Massachusetts, United States, 02118

Contact: Elizabeth Stier, MD 617-414-5101 elstier@bu.edu

Principal Investigator: Elizabeth Stier, MD

United States, New York

Montefiore Medical Center; Recruiting

Bronx, New York, United States, 10461

Contact: Rikin Gandhi, MSRA 718-862-8840 ext 451 rigandhi@montefiore.org

Contact: Akash Shah, MSc, CCRP 718-862-8840 ext 436

Principal Investigator: Rebecca Levine, MD

Laser Surgery Care; Recruiting

New York, New York, United States, 10011

Contact: Krystal Chuang kchuang@lasersurgerycare.com

Principal Investigator: Stephen Goldstone, MD

Cornell Clinical Trials Unit, New York Presbyterian Hospital; Recruiting

New York, New York, United States, 10065

Contact: Christina Megill 212-746-7163

Principal Investigator: Timothy Wilkin, MD, MPH

Weill Medical College of Cornell University; Recruiting

New York, New York, United States, 10065

Contact: Timothy J. Wilkin 212-746-7202 tiw2001@med.cornell.edu

Principal Investigator: Timothy J. Wilkin

United States, North Carolina

Wake Forest University Health Sciences; Recruiting

Winston-Salem, North Carolina, United States, 27157

Contact: Elizabeth Zieser-Misenheimer 336-716-5685 ezieserm@wakehealth.edu

Principal Investigator: Luis Barroso, MD

United States, Texas

Baylor College of Medicine; Withdrawn

Houston, Texas, United States, 77030

United States, Washington

Benaroya Research Institute at Virginia Mason Medical Center; Recruiting

Seattle, Washington, United States, 98101

Contact: Rachel Dowty 206-342-6928 rachel.dowty@virginiamason.org

Principal Investigator: David Aboulafia, MD

Puerto Rico

University of Puerto Rico; Recruiting

San Juan, Puerto Rico, 00936-3027

Contact: Maribel Tirado-Gomez 787-772-8300 ext 1108 maribel.tirado1@upr.edu

Principal Investigator: Humberto Guiot, MD

Sponsors and Collaborators

AIDS Malignancy Consortium

National Cancer Institute (NCI)

The Emmes Company, LLC

University of Arkansas

Investigators

• Principal Investigator: Timothy Wilkin; AIDS Associated Malignancies Clinical Trials Consortium

More Information

• Responsible Party: AIDS Malignancy Consortium
• ClinicalTrials.gov Identifier: NCT02059499
• Other Study ID Numbers: AMC-088; NCI-2013-02288 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); AMC-088 ( Other Identifier: AIDS - Associated Malignancies Clinical Trials Consortium ); AMC-088 ( Other Identifier: CTEP ); U01CA121947 ( U.S. NIH Grant/Contract )
• First Posted: February 11, 2014
• Last Update Posted: July 18, 2022
• Last Verified: July 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Additional relevant MeSH terms:

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