Chemoprevention of Anal Neoplasia Arising Secondary to Anogenital Human Papillomavirus Infection in Persons With HIV Infection.

National Institute of Allergy and Infectious Diseases (NIAID)

Status and phase: Completed; Phase 1

Conditions: Anus Neoplasms; HIV Infections

Treatments: Drug: Interferon alfa-2a; Drug: Isotretinoin

Study type: Interventional

Funder types: Industry; NIH

Identifiers

NCT00000764

11193 (Registry Identifier)

ACTG 216

Details and patient eligibility

About

PRIMARY: In Phase I, to define a broadly tolerable dose of isotretinoin that can be used in combination with interferon alfa-2a (IFN alfa-2a). In Phase II, to determine trends in efficacy of isotretinoin alone or in combination with IFN alfa-2a as chemoprevention (preventing progression or recurrence) of anal intraepithelial neoplasia ( AIN ) / squamous intraepithelial lesions ( SIL ) in patients with HIV infection.

SECONDARY: To evaluate the effects of isotretinoin alone or in combination with IFN alfa-2a on immune function markers, human papillomavirus (HPV) type, and HPV DNA levels.

Patients with HIV infection have a significant risk of recurrence following local ablation of intraepithelial neoplasia; thus, anogenital epithelial may become an increasingly important cause of morbidity, and possibly mortality, as the HIV epidemic matures. Clinical studies of non-HIV-infected subjects have established that synthetic retinoids inhibit the progression of epithelial preneoplastic conditions and some neoplastic states.

Full description

Patients with HIV infection have a significant risk of recurrence following local ablation of intraepithelial neoplasia; thus, anogenital epithelial may become an increasingly important cause of morbidity, and possibly mortality, as the HIV epidemic matures. Clinical studies of non-HIV-infected subjects have established that synthetic retinoids inhibit the progression of epithelial preneoplastic conditions and some neoplastic states.

In the Phase I portion of the study, 20 patients per site each receive isotretinoin in escalating doses. If a patient experiences grade 2 or worse toxicity (or grade 3 or worse hypertriglyceridemia), dose is reduced to the previously tolerated dose for the remainder of the 6 week period. Patients are then reassessed for anal neoplasia; those with no progression and no grade 2 or worse toxicity receive an additional 6 weeks of isotretinoin in combination with interferon alfa-2a. For Phase II of the study, a separate group of patients who have undergone ablative therapy are randomized to one of three arms (26 patients/arm): isotretinoin alone at the dose tolerated by at least 60 percent of patients in Phase I; isotretinoin plus interferon alfa-2a; or observation only. Treatment continues for 48 weeks.

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria

Concurrent Medication:

Allowed:

• PCP prophylaxis (required for patients with CD4 count < 200 cells/mm3).
• Chemoprophylaxis for candidiasis and herpes simplex.
• Metronidazole for up to 14 days.
• Erythropoietin.

Patients must have:

• HIV seropositivity.
• NO active opportunistic infection requiring treatment with prohibited drugs.
• Phase I - Current grade 1 AIN (i.e., low grade SIL) OR treated or untreated grade 2 or 3 AIN (i.e., high grade SIL).

Phase II - Prior histologically confirmed grade 2 or 3 AIN / high grade SIL, with ablative therapy within the past 30-90 days.

• Capability of complying with study protocol.

NOTE:

• The terms condyloma, grade 1 AIN, and low grade SIL are interchangeable. Grade 2 or 3 AIN is interchangeable with high grade SIL.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Active medical problems for which the patient is undergoing evaluations or for which prohibited therapy is required.
• Other active malignancies requiring systemic therapy.
• Significant symptomatic cardiac disease.

NOTE:

• Patients with malignancies being managed with local therapy (e.g., Kaposi's sarcoma, basal cell carcinoma) may enroll at the discretion of the site investigator.

Concurrent Medication:

Excluded:

• G-CSF (filgrastim).
• Myelosuppressive antibiotics (except co-trimoxazole for PCP prophylaxis).
• Corticosteroids.
• Biologic response modifiers.
• Cytotoxic chemotherapy.

Concurrent Treatment:

Excluded:

• Radiation therapy.

Patients with the following prior conditions are excluded:

History of ventricular arrhythmias or myocardial infarction.

Prior Medication:

Excluded within 20 days prior to study entry:

• G-CSF (filgrastim).
• Myelosuppressive antibiotics (except co-trimoxazole for PCP prophylaxis).
• Corticosteroids.
• Biologic response modifiers.
• Cytotoxic chemotherapy.

Prior Treatment:

Excluded within 20 days prior to study entry:

• Radiation therapy.

Excluded within 14 days prior to study entry:

• Transfusion.

Active substance abuse or illegal drug use (alcohol consumption is strongly discouraged).