Cidofovir in Treating HIV-Infected Patients With High-Grade Squamous Intraepithelial Lesions of the Skin Near the Anus

Study Overview
=================
Brief Summary
-----------------
RATIONALE: High-grade squamous intraepithelial lesions of the skin near the anus are caused by the human papillomavirus (HPV). Antiviral drugs,, such as cidofovir, act against viruses and may stop these lesions from becoming cancer. PURPOSE: This phase II trial is studying the side effects and how well topical cidofovir works in treating HIV-infected patients with high-grade squamous intraepithelial lesions of the skin near the anus.

Detailed Description
-----------------
OBJECTIVES: Primary To evaluate the safety and tolerability of topical cidofovir in HIV-infected patients with perianal high-grade squamous intraepithelial lesions (HSIL). To estimate the regression rate of perianal HSIL in patients treated with this regimen. Secondary To determine the human papilloma virus (HPV) DNA types and HPV strain variants present in perianal HSIL and normal perianal tissue. To determine if clinical regression of perianal HSIL is associated with clearance of HPV DNA. To identify the HPV DNA types present in the anus and cervix and compare them with the HPV DNA present in the perianus in order to determine if the HPV types associated with the perianal lesions are the same as those infecting the anus and cervix. To determine if there are abnormally methylated genes in perianal HSIL compared with normal perianal tissue and if these genes are the same or different from those that have been previously identified in anal and cervical dysplasia. To determine whether methylated genes are changed after treatment with cidofovir. To characterize differences in gene expression in perianal HSIL compared with normal perianal tissue. To examine changes in gene expression in perianal HSIL after exposure to cidofovir using RNA microarray analysis and confirm results with real-time polymerase chain reaction. To correlate pretreatment CD4 count, viral load, lesion size, methylation pattern, and/or HPV type and strain with the clinical efficacy of topical cidofovir. OUTLINE: This is a multicenter study. Patients apply topical cidofovir to the perianus once daily on days 1-5. Patients undergo punch biopsy of pretreatment lesional biopsy sites on day 14. Beginning 2-4 weeks after biopsy, patients receive course 2 of cidofovir therapy. Subsequent treatment repeats every 14 days for up to 6 courses* in the absence of disease progression or unacceptable toxicity. NOTE: *Patients receive a total of 6 courses of study therapy. Patients undergo collection of tumor and normal tissue for histopathological and molecular correlative studies. Punch biopsies are obtained at baseline, after the first course of therapy, and at 6 weeks after completion of therapy. Tissue samples are examined for histopathology, human papilloma virus (HPV)DNA typing, DNA methylation, and gene expression (via RNA microarray analysis and polymerase chain reaction). After completion of study therapy, patients are followed at 6 weeks.

Official Title
-----------------
Phase IIA Trial of 1% Topical Cidofovir for Treatment of High-Grade Perianal Squamous Intraepithelial Lesions in HIV-Infected Men and Women

Conditions
-----------------
Anal Cancer, Precancerous Condition

Intervention / Treatment
-----------------
* Drug: cidofovir
* Genetic: DNA methylation analysis
* Genetic: gene expression analysis
* Genetic: polymerase chain reaction
* Procedure: biopsy
* Procedure: histopathologic examination


Participation Criteria
=================
Eligibility Criteria
-----------------
DISEASE CHARACTERISTICS: Histologically confirmed perianal high-grade squamous intraepithelial lesions (HSIL) within the past 12 weeks The perianal skin (i.e., perianus) is defined as extending radially 5 cm from the anal verge Lesions must cover a surface area of ≥ 3 square centimeters Lesions extending outside the perianus (e.g., vulvar lesions on the posterior perineum bordering the perianus) are allowed Serologic documentation of HIV infection AND meets 1 of the following criteria: Has been on stable highly active anti-retroviral therapy (HAART) for ≥ 12 weeks prior to study entry Has a CD4 count of > 200/mm³ AND is not receiving anti-retroviral therapy OR is currently receiving a non-HAART* anti-retroviral regimen with no plans to initiate HAART within the next 12 weeks NOTE: * A non-HAART regimen is considered to be a therapy that does not include a protease inhibitor or a non-nucleoside reverse transcriptase inhibitor No untreated invasive cancer of the lower genital tract No concurrent neoplasia requiring cytotoxic therapy PATIENT CHARACTERISTICS: Karnofsky performance status 70-100% Life expectancy ≥ 3 months Hemoglobin ≥ 8 g/dL ANC ≥ 1,000/mm³ Platelet count ≥ 75,000/mm³ Creatinine < 1.5 times upper limit of normal (ULN) Total or conjugated (direct) bilirubin ≤ 2.5 times ULN AST and ALT ≤ 3 times ULN Not pregnant or nursing Negative pregnancy test Fertile patients must use effective contraception during and for 3 months after completion of study therapy No acute, opportunistic infection other than oral thrush, yeast vaginitis, or genital herpes within the past 14 days PRIOR CONCURRENT THERAPY: See Disease Characteristics Recovered from prior ablative or surgical treatment of perianal dysplasia At least 4 weeks since prior topical treatment for perianal dysplasia If any prior treatment caused significant trauma to ther area, healing should occur prior to starting treatment More than 14 days since prior acute treatment for infection (other than for oral thrush, yeast vaginitis, or genital herpes) or other serious medical illness No concurrent corticosteroids other than replacement doses No other concurrent investigational drugs except IND-approved anti-retroviral agents No concurrent systemic cytotoxic chemotherapy

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 120 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cidofovir<br>1.0% topical cidofovir cream | Drug: cidofovir<br>* 1.0% topical cream self-applied once daily for 5 consecutive days, with no treatment for the remaining 9 days (a treatment cycle). Subjects will receive up to 6 cycles of treatment.<br>Genetic: DNA methylation analysis<br>* formalin fixed biopsy collected at baseline and 6 weeks after treatment discontinuation<br>Genetic: gene expression analysis<br>* punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation<br>Genetic: polymerase chain reaction<br>* performed on punch biopsy specimens collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation<br>Procedure: biopsy<br>* punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation<br>Procedure: histopathologic examination<br>* Evaluated at baseline and 6 weeks after treatment discontinuation<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Proportion of Patients With Regression of Perianal High-grade Squamous Intraepithelial Lesions (HSIL) |  | 6 weeks after treatment discontinuation | 
| Safety and Tolerability of Topical Cidofovir as Assessed by NCI CTCAE v3.0 | Number of study patients who had a serious adverse event | Every 2 weeks on study, 6 weeks after treatment discontinuation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Human Papilloma Virus (HPV) DNA Type in Perianal HSIL and Normal Perianal Tissue | Number of patients with HPV16 at baseline in perianal HSIL and normal perianal tissue | Baseline | 
| Correlation of Clinical Regression of Perianal HSIL With Clearance of HPV DNA | Number of patients who cleared HPV among those who had a complete or partial response | 6 weeks after treatment discontinuation | 
| Identification of HPV-DNA Types Present in the Anus | Number of patients with HPV16 type present in the anus from anal swab or cytobrush at baseline | Baseline | 
| Identification of Abnormally Methylated Genes in Perianal Dysplasia | Identification of abnormally methylated genes in perianal dysplasia | Baseline, after cycle 1, and 6 weeks after treatment discontinuation | 
| Distribution of Abnormally Methylated Genes Among HSIL, Low-grade Squamous Intraepithelial Lesions, and Normal Perianal Skin |  | Baseline, after cycle 1, and 6 weeks after treatment discontinuation | 
| Changes in Gene Expression in Perianal HSIL After Exposure to Cidofovir as Assessed by RNA Microarray Analysis |  | Baseline, after cycle 1, and 6 weeks after treatment discontinuation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
high-grade squamous intraepithelial lesion, stage 0 anal cancer