Cidofovir in Treating HIV-Infected Patients With High-Grade Squamous Intraepithelial Lesions of the Skin Near the Anus
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.
Genetic: DNA methylation analysis
Genetic: gene expression analysis
Genetic: polymerase chain reaction
Procedure: histopathologic examination
|Study Design:||Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
|Official Title:||Phase IIA Trial of 1% Topical Cidofovir for Treatment of High-Grade Perianal Squamous Intraepithelial Lesions in HIV-Infected Men and Women|
- Proportion of Patients With Regression of Perianal High-grade Squamous Intraepithelial Lesions (HSIL) [ Time Frame: 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
- Safety and Tolerability of Topical Cidofovir as Assessed by NCI CTCAE v3.0 [ Time Frame: Every 2 weeks on study, 6 weeks after treatment discontinuation ] [ Designated as safety issue: Yes ]Number of study patients who had a serious adverse event
- Human Papilloma Virus (HPV) DNA Type in Perianal HSIL and Normal Perianal Tissue [ Time Frame: Baseline ] [ Designated as safety issue: No ]Number of patients with HPV16 at baseline in perianal HSIL and normal perianal tissue
- Correlation of Clinical Regression of Perianal HSIL With Clearance of HPV DNA [ Time Frame: 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]Number of patients who cleared HPV among those who had a complete or partial response
- Identification of HPV-DNA Types Present in the Anus [ Time Frame: Baseline ] [ Designated as safety issue: No ]Number of patients with HPV16 type present in the anus from anal swab or cytobrush at baseline
- Identification of Abnormally Methylated Genes in Perianal Dysplasia [ Time Frame: Baseline, after cycle 1, and 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]Identification of abnormally methylated genes in perianal dysplasia
- Distribution of Abnormally Methylated Genes Among HSIL, Low-grade Squamous Intraepithelial Lesions, and Normal Perianal Skin [ Time Frame: Baseline, after cycle 1, and 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
- Changes in Gene Expression in Perianal HSIL After Exposure to Cidofovir as Assessed by RNA Microarray Analysis [ Time Frame: Baseline, after cycle 1, and 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
|Study Start Date:||September 2007|
|Study Completion Date:||February 2010|
|Primary Completion Date:||February 2010 (Final data collection date for primary outcome measure)|
1.0% topical cidofovir cream
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.Genetic: DNA methylation analysis
formalin fixed biopsy collected at baseline and 6 weeks after treatment discontinuationGenetic: gene expression analysis
punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuationGenetic: polymerase chain reaction
performed on punch biopsy specimens collected at baseline, after cycle 1, and 6 weeks after treatment discontinuationProcedure: biopsy
punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuationProcedure: histopathologic examination
Evaluated at baseline and 6 weeks after treatment discontinuation
- 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.
- 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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00550589
|United States, California|
|UCLA Clinical AIDS Research and Education (CARE) Center|
|Los Angeles, California, United States, 90095-1793|
|UCSF Helen Diller Family Comprehensive Cancer Center|
|San Francisco, California, United States, 94115|
|United States, Massachusetts|
|Beth Israel Deaconess Medical Center|
|Boston, Massachusetts, United States, 02215|
|Boston University Cancer Research Center|
|Boston, Massachusetts, United States, 02118|
|United States, New York|
|Montefiore Medical Center|
|Bronx, New York, United States, 10461|
|Laser Surgery Care|
|New York, New York, United States, 10010|
|New York Weill Cornell Cancer Center at Cornell University|
|New York, New York, United States, 10021|
|United States, Washington|
|Benaroya Research Institute at Virginia Mason Medical Center|
|Seattle, Washington, United States, 98101|
|Study Chair:||Elizabeth Stier, MD||Boston Medical Center|
|Principal Investigator:||Joel Palefsky, MD||University of California, San Francisco|