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Cidofovir

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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.

cidofovir

formalin fixed biopsy collected at baseline and 6 weeks after treatment discontinuation

DNA methylation analysis

punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation

gene expression analysis

performed on punch biopsy specimens collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation

polymerase chain reaction

biopsy

Evaluated at baseline and 6 weeks after treatment discontinuation

histopathologic examination

Elizabeth Stier, MD

Joel Palefsky, MD

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.

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.

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

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

Number of study patients who had a serious adverse event

Number of patients with HPV16 at baseline in perianal HSIL and normal perianal tissue

Number of patients who cleared HPV among those who had a complete or partial response

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

National Cancer Institute (NCI)

The Emmes Company, LLC

AIDS Malignancy Consortium

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

Jeannette Lee

Proportion of Patients With Regression of Perianal High-grade Squamous Intraepithelial Lesions (HSIL)

Safety and Tolerability of Topical Cidofovir as Assessed by NCI CTCAE v3.0

Number of patients with tissue samples available at baseline

Human Papilloma Virus (HPV) DNA Type in Perianal HSIL and Normal Perianal Tissue

1.0% topical cidofovir cream

cidofovir: 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.

DNA methylation analysis: formalin fixed biopsy collected at baseline and 6 weeks after treatment discontinuation

gene expression analysis: punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation

polymerase chain reaction: performed on punch biopsy specimens collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation

biopsy: punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation

histopathologic examination: Evaluated at baseline and 6 weeks after treatment discontinuation

Participants who had a partial or complete response and for whom pre and post-treatment HPV data were available

Correlation of Clinical Regression of Perianal HSIL With Clearance of HPV DNA

Number of patients with anal swabs or cytobrush results at baseline

Identification of HPV-DNA Types Present in the Anus

The lab analysis of genes was not performed

Identification of Abnormally Methylated Genes in Perianal Dysplasia

Distribution of Abnormally Methylated Genes Among HSIL, Low-grade Squamous Intraepithelial Lesions, and Normal Perianal Skin

The gene expression analysis was not done

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Cidofovir in Treating HIV-Infected Patients With High-Grade Squamous Intraepithelial Lesions of the Skin Near the Anus	NCT00550589	Anal Cancer Precancerous Co...	cidofovir DNA methylation... gene expression... polymerase chai... biopsy histopathologic...	18 Years - 120 Years	AIDS Malignancy Consortium
Cidofovir in Treating HIV-Infected Patients With High-Grade Squamous Intraepithelial Lesions of the Skin Near the Anus	NCT00550589	Anal Cancer Precancerous Co...	cidofovir DNA methylation... gene expression... polymerase chai... biopsy histopathologic...	18 Years - 120 Years	AIDS Malignancy Consortium

Spots Global Cancer Trial Database for stage 0 anal cancer