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

Phase 2

Completed

• Conditions: Precancerous Condition; Anal Cancer
• Interventions: Drug: cidofovir; Genetic: DNA methylation analysis; Genetic: gene expression analysis; Genetic: polymerase chain reaction; Procedure: biopsy; Procedure: histopathologic examination

• Registration Number: NCT00550589
• Lead Sponsor: AIDS Malignancy Consortium

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.

Study Timeline

• Study Start: 2007-09
• Study First Submitted: 2007-10-26
• Study First Submitted QC: 2007-10-26
• Study First Posted: 2007-10-30
• Primary Completion: 2010-02
• Study Completion: 2010-02
• Disposition First Submitted: 2011-05-10
• Disposition First Submitted QC: 2011-05-20
• Disposition First Posted: 2011-05-23
• Results First Submitted: 2011-05-24
• Results First Submitted QC: 2011-05-24
• Results First Posted: 2011-06-22
• Status Verified: 2015-11
• Last Update Submitted: 2015-11-17
• Last Update Posted: 2015-12-21

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 33

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Cidofovir	biopsy	1.0% topical cidofovir cream
Cidofovir	DNA methylation analysis	1.0% topical cidofovir cream
Cidofovir	polymerase chain reaction	1.0% topical cidofovir cream
Cidofovir	histopathologic examination	1.0% topical cidofovir cream
Cidofovir	gene expression analysis	1.0% topical cidofovir cream
Cidofovir	cidofovir	1.0% topical cidofovir cream

Primary Outcome Measures

Name	Time	Method
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	Every 2 weeks on study, 6 weeks after treatment discontinuation	Number of study patients who had a serious adverse event

Secondary Outcome Measures

Name	Time	Method
Correlation of Clinical Regression of Perianal HSIL With Clearance of HPV DNA	6 weeks after treatment discontinuation	Number of patients who cleared HPV among those who had a complete or partial response
Identification of HPV-DNA Types Present in the Anus	Baseline	Number of patients with HPV16 type present in the anus from anal swab or cytobrush at baseline
Human Papilloma Virus (HPV) DNA Type in Perianal HSIL and Normal Perianal Tissue	Baseline	Number of patients with HPV16 at baseline in perianal HSIL and normal perianal tissue
Identification of Abnormally Methylated Genes in Perianal Dysplasia	Baseline, after cycle 1, and 6 weeks after treatment discontinuation	Identification of abnormally methylated genes in perianal dysplasia
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

Trial Locations

Locations (8)

UCLA Clinical AIDS Research and Education (CARE) Center; 🇺🇸 Los Angeles, California, United States

Boston University Cancer Research Center; 🇺🇸 Boston, Massachusetts, United States

Benaroya Research Institute at Virginia Mason Medical Center; 🇺🇸 Seattle, Washington, United States

Beth Israel Deaconess Medical Center; 🇺🇸 Boston, Massachusetts, United States

UCSF Helen Diller Family Comprehensive Cancer Center; 🇺🇸 San Francisco, California, United States

Laser Surgery Care; 🇺🇸 New York, New York, United States

New York Weill Cornell Cancer Center at Cornell University; 🇺🇸 New York, New York, United States

Montefiore Medical Center; 🇺🇸 Bronx, New York, United States