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

This study has been completed.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier:
NCT00550589
First received: October 26, 2007
Last updated: July 25, 2013
Last verified: July 2013
  Purpose

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.


Condition Intervention Phase
Anal Cancer
Precancerous Condition
Drug: cidofovir
Genetic: DNA methylation analysis
Genetic: gene expression analysis
Genetic: polymerase chain reaction
Procedure: biopsy
Procedure: histopathologic examination
Phase 2

Study Type: Interventional
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

Resource links provided by NLM:


Further study details as provided by AIDS Malignancy Clinical Trials Consortium:

Primary Outcome Measures:
  • 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 ]

Secondary Outcome Measures:
  • Human Papilloma Virus (HPV) DNA Type and HPV Strain Variant in Perianal HSIL and Normal Perianal Tissue [ Time Frame: Baseline and 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
  • Correlation of Clinical Regression of Perianal HSIL With Clearance of HPV DNA [ Time Frame: 6 weeks after treatment discontinuation ] [ Designated as safety issue: No ]
  • Identification of HPV-DNA Types Present in the Anus and Cervix in Order to Compare Them With HPV-DNA Present in the Perianus [ Time Frame: Baseline ] [ Designated as safety issue: No ]
  • 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 ]
  • 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 ]

Enrollment: 33
Study Start Date: September 2007
Study Completion Date: February 2010
Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cidofovir
1.0% topical cidofovir cream
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
Genetic: gene expression analysis
punch biopsy collected at baseline, after cycle 1, and 6 weeks after treatment discontinuation
Genetic: 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
Procedure: histopathologic examination
Evaluated at baseline and 6 weeks after treatment discontinuation

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.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00550589

Locations
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
Sponsors and Collaborators
AIDS Malignancy Clinical Trials Consortium
Investigators
Study Chair: Elizabeth Stier, MD Boston Medical Center
Principal Investigator: Joel Palefsky, MD University of California, San Francisco
  More Information

Additional Information:
Publications:
Responsible Party: AIDS Malignancy Clinical Trials Consortium
ClinicalTrials.gov Identifier: NCT00550589     History of Changes
Other Study ID Numbers: CDR0000570720, U01CA121947, AMC-046
Study First Received: October 26, 2007
Results First Received: May 24, 2011
Last Updated: July 25, 2013
Health Authority: United States: Federal Government
United States: Food and Drug Administration
United States: Institutional Review Board

Keywords provided by AIDS Malignancy Clinical Trials Consortium:
high-grade squamous intraepithelial lesion
stage 0 anal cancer

Additional relevant MeSH terms:
Precancerous Conditions
Uterine Cervical Dysplasia
Digestive System Diseases
Gastrointestinal Diseases
Intestinal Diseases
Anus Diseases
Rectal Diseases
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Anus Neoplasms
Rectal Neoplasms
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Neoplasms
Cidofovir
Antiviral Agents
Anti-Infective Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 21, 2014