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

• ClinicalTrials.gov Identifier: NCT00550589
• Recruitment Status: Completed
• First Posted: October 30, 2007
• Results First Posted: June 22, 2011
• Last Update Posted: December 21, 2015
• Sponsor: AIDS Malignancy Consortium
• Collaborators: National Cancer Institute (NCI); The Emmes Company, LLC
• Information provided by (Responsible Party): AIDS Malignancy Consortium

Tracking Information

• First Submitted Date: October 26, 2007
• First Posted Date: October 30, 2007
• Results First Submitted Date: May 24, 2011
• Results First Posted Date: June 22, 2011
• Last Update Posted Date: December 21, 2015
• Study Start Date: September 2007
• Actual Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 22, 2015)

• Proportion of Patients With Regression of Perianal High-grade Squamous Intraepithelial Lesions (HSIL) [ Time Frame: 6 weeks after treatment discontinuation ]
• 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 ]
  Number of study patients who had a serious adverse event

Original Primary Outcome Measures (submitted: October 26, 2007)

• Regression rate of perianal high-grade squamous intraepithelial lesions (HSIL)
• Safety and tolerability of topical cidofovir as assessed by NCI CTCAE v3.0

Current Secondary Outcome Measures (submitted: September 22, 2015)

• Human Papilloma Virus (HPV) DNA Type in Perianal HSIL and Normal Perianal Tissue [ Time Frame: Baseline ]
  Number of patients with HPV16 at baseline in perianal HSIL and normal perianal tissue
• Correlation of Clinical Regression of Perianal HSIL With Clearance of HPV DNA [ Time Frame: 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 [ Time Frame: Baseline ]
  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 [ Time Frame: 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 [ Time Frame: 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 [ Time Frame: Baseline, after cycle 1, and 6 weeks after treatment discontinuation ]

Original Secondary Outcome Measures (submitted: October 26, 2007)

• Human papilloma virus (HPV) DNA type and HPV strain variant in perianal HSIL and normal perianal tissue
• Correlation of clinical regression of perianal HSIL with clearance of HPV DNA
• Identification of HPV-DNA types present in the anus and cervix in order to compare them with HPV-DNA present in the perianus
• Identification of abnormally methylated genes in perianal dysplasia
• Distribution of abnormally methylated genes among HSIL, low-grade squamous intraepithelial lesions, and normal perianal skin
• Changes in gene expression in perianal HSIL after exposure to cidofovir as assessed by RNA microarray analysis

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cidofovir in Treating HIV-Infected Patients With High-Grade Squamous Intraepithelial Lesions of the Skin Near the Anus
• Official Title: Phase IIA Trial of 1% Topical Cidofovir for Treatment of High-Grade Perianal Squamous Intraepithelial Lesions in HIV-Infected Men and Women

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 Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Anal Cancer
• Precancerous Condition

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
• 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

Study Arms

Experimental: Cidofovir

1.0% topical cidofovir cream

Interventions:

• Drug: cidofovir
• Genetic: DNA methylation analysis
• Genetic: gene expression analysis
• Genetic: polymerase chain reaction
• Procedure: biopsy
• Procedure: histopathologic examination

• 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.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: October 26, 2007): 33
• Original Enrollment: Same as current
• Actual Study Completion Date: February 2010
• Actual Primary Completion Date: February 2010 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years to 120 Years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00550589
• Other Study ID Numbers: AMC-046; U01CA121947 ( U.S. NIH Grant/Contract ); CDR0000570720 ( Other Identifier: NCI )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: AIDS Malignancy Consortium
• Original Responsible Party: Not Provided
• Current Study Sponsor: AIDS Malignancy Consortium
• Original Study Sponsor: AIDS Associated Malignancies Clinical Trials Consortium

Collaborators

• National Cancer Institute (NCI)
• The Emmes Company, LLC

Investigators

• Study Chair: Elizabeth Stier, MD; Boston Medical Center
• Principal Investigator: Joel Palefsky, MD; University of California, San Francisco

• PRS Account: AIDS Malignancy Consortium
• Verification Date: November 2015