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

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.

Study Overview

• Status: Completed
• Conditions: Precancerous Condition; Anal Cancer
• Intervention / Treatment: Drug: cidofovir; Genetic: DNA methylation analysis; Genetic: gene expression analysis; Genetic: polymerase chain reaction; Procedure: biopsy; Procedure: histopathologic examination

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 Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90095-1793
      • UCLA Clinical AIDS Research and Education (CARE) Center
    • San Francisco, California, United States, 94115
      • UCSF Helen Diller Family Comprehensive Cancer Center
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Beth Israel Deaconess Medical Center
    • Boston, Massachusetts, United States, 02118
      • Boston University Cancer Research Center
  • New York
    • Bronx, New York, United States, 10461
      • Montefiore Medical Center
    • New York, New York, United States, 10021
      • New York Weill Cornell Cancer Center at Cornell University
    • New York, New York, United States, 10010
      • Laser Surgery Care
  • Washington
    • Seattle, Washington, United States, 98101
      • Benaroya Research Institute at Virginia Mason Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	Number of study patients who had a serious adverse event	Every 2 weeks on study, 6 weeks after treatment discontinuation

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
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

Collaborators and Investigators

• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); The Emmes Company, LLC
• Investigators: Study Chair: Elizabeth Stier, MD, Boston Medical Center

Publications and helpful links

General Publications

• 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 men and women. AIDS. 2013 Feb 20;27(4):545-51. doi: 10.1097/QAD.0b013e32835a9b16.

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (ACTUAL): February 1, 2010
• Study Completion (ACTUAL): February 1, 2010

Study Registration Dates

• First Submitted: October 26, 2007
• First Submitted That Met QC Criteria: October 26, 2007
• First Posted (ESTIMATE): October 30, 2007

Study Record Updates

• Last Update Posted (ESTIMATE): December 21, 2015
• Last Update Submitted That Met QC Criteria: November 17, 2015
• Last Verified: November 1, 2015

More Information

Terms related to this study

• Keywords: high-grade squamous intraepithelial lesion; stage 0 anal cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Uterine Cervical Diseases; Uterine Diseases; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Rectal Neoplasms; Anus Diseases; Uterine Cervical Dysplasia; Precancerous Conditions; Anus Neoplasms; Squamous Intraepithelial Lesions of the Cervix; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Cidofovir
• Other Study ID Numbers: AMC-046; U01CA121947 (U.S. NIH Grant/Contract); CDR0000570720 (OTHER: NCI)