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

Anal Cancer Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00550589
• Other study ID #: AMC-046
• Secondary ID: U01CA121947CDR00
• Status: Completed
• Phase: Phase 2
• First received: October 26, 2007
• Last updated: November 17, 2015
• Start date: September 2007
• Est. completion date: February 2010

Study information

• Verified date: November 2015
• Source: AIDS Malignancy Consortium
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 33
• Est. completion date: February 2010
• Est. primary completion date: February 2010
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 120 Years

Eligibility

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

Related Conditions & MeSH terms

• Anal Cancer
• Anus Neoplasms
• Precancerous Condition
• Precancerous Conditions
• Squamous Intraepithelial Lesions of the Cervix

Intervention

Drug:
• 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.

Genetic:
• 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

Procedure:
• 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

Locations

Country	Name	City	State
United States	Beth Israel Deaconess Medical Center	Boston	Massachusetts
United States	Boston University Cancer Research Center	Boston	Massachusetts
United States	Montefiore Medical Center	Bronx	New York
United States	UCLA Clinical AIDS Research and Education (CARE) Center	Los Angeles	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	UCSF Helen Diller Family Comprehensive Cancer Center	San Francisco	California
United States	Benaroya Research Institute at Virginia Mason Medical Center	Seattle	Washington

Sponsors (3)

Lead Sponsor	Collaborator
AIDS Malignancy Consortium	National Cancer Institute (NCI), The EMMES Corporation

Country where clinical trial is conducted

United States, 

References & Publications (1)

Stier EA, Goldstone SE, Einstein MH, Jay N, Berry JM, Wilkin T, Lee JY, Darragh TM, Da Costa M, Panther L, Aboulafia D, Palefsky JM. Safety and efficacy of topical cidofovir to treat high-grade perianal and vulvar intraepithelial neoplasia in HIV-positive — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Proportion of Patients With Regression of Perianal High-grade Squamous Intraepithelial Lesions (HSIL)		6 weeks after treatment discontinuation
Primary	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	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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
Secondary	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