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

This study is not yet open for participant recruitment. (see Contacts and Locations)
Verified March 2014 by AIDS Malignancy Clinical Trials Consortium
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier:
NCT02059499
First received: February 7, 2014
Last updated: March 14, 2014
Last verified: March 2014
  Purpose

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 Intervention Phase
Anal Intraepithelial Neoplasia
High-grade Squamous Intraepithelial Lesion
HIV Infection
Drug: imiquimod
Drug: fluorouracil
Other: questionnaire administration
Other: laboratory biomarker analysis
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (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

Resource links provided by NLM:


Further study details as provided by AIDS Malignancy Clinical Trials Consortium:

Primary Outcome Measures:
  • Proportion of participants achieving complete response (Arm A and B) [ Time Frame: At week 20 ] [ Designated as safety issue: No ]
    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.

  • Proportion of participants with spontaneous regression (Arm C) [ Time Frame: At week 20 ] [ Designated as safety issue: No ]
    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.

  • Presence of intra-anal HSIL on cytology or histology [ Time Frame: At week 20 ] [ Designated as safety issue: No ]
    Perianal HSIL will be descriptively reported separately, as well as combined.


Secondary Outcome Measures:
  • 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 ] [ Designated as safety issue: Yes ]
    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.

  • Proportion of participants achieving complete response or spontaneous regression [ Time Frame: Up to week 44 ] [ Designated as safety issue: No ]
    Proportions will be compared across sites using the stratified Mantel-Haenszel-Cochran test at the two-sided 0.05 alpha level.

  • Number of quadrants with HSIL found on biopsies [ Time Frame: Up to week 48 ] [ Designated as safety issue: No ]
    Will be compared between arms treating the response as an ordinal variable.

  • Proportion of patients achieving complete or partial responses [ Time Frame: Up to week 44 ] [ Designated as safety issue: No ]
    The proportion of patients achieving complete or partial responses with imiquimod or fluorouracil will be compared to observation only.

  • Persistence of HPV type specific infections [ Time Frame: At week 20 ] [ Designated as safety issue: No ]
    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.

  • Presence of intra-anal HSIL on cytology or histology [ Time Frame: At week 44 ] [ Designated as safety issue: No ]
    Perianal HSIL will be descriptively reported separately, as well as combined. Results for the observation arm will be stratified into cross-over treatment groups.


Estimated Enrollment: 150
Study Start Date: March 2014
Estimated Study Completion Date: December 2016
Estimated Primary Completion Date: June 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.

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.

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.

  Eligibility

Ages Eligible for Study:   27 Years and older
Genders Eligible for Study:   Both
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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02059499

Locations
United States, California
UCSF-Mount Zion Not yet 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         
United States, New York
Weill Medical College of Cornell University Not yet recruiting
New York, New York, United States, 10065
Contact: Timothy J. Wilkin    212-746-7202    tiw2001@med.cornell.edu   
Principal Investigator: Timothy J. Wilkin         
Sponsors and Collaborators
AIDS Malignancy Clinical Trials Consortium
Investigators
Principal Investigator: Timothy Wilkin AIDS Associated Malignancies Clinical Trials Consortium
  More Information

No publications provided

Responsible Party: AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier: NCT02059499     History of Changes
Other Study ID Numbers: AMC-088, NCI-2013-02288, AMC-088, AMC-088, U01CA121947
Study First Received: February 7, 2014
Last Updated: March 14, 2014
Health Authority: United States: Data and Safety Monitoring Board
United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Additional relevant MeSH terms:
HIV Infections
Acquired Immunodeficiency Syndrome
Neoplasms
Uterine Cervical Dysplasia
Carcinoma in Situ
Lentivirus Infections
Retroviridae Infections
RNA Virus Infections
Virus Diseases
Sexually Transmitted Diseases, Viral
Sexually Transmitted Diseases
Immunologic Deficiency Syndromes
Immune System Diseases
Slow Virus Diseases
Precancerous Conditions
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Fluorouracil
Imiquimod
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antimetabolites, Antineoplastic
Antineoplastic Agents
Therapeutic Uses
Immunosuppressive Agents

ClinicalTrials.gov processed this record on August 01, 2014