Imiquimod, Fluorouracil, or Observation in Treating HIV-Positive Patients With High-Grade Anal Squamous Skin Lesions

PRIMARY OBJECTIVES:

I. To assess the efficacy of intra-anal imiquimod 2.5% for treatment of anal high-grade
squamous intraepithelial lesions (HSIL) compared to observation only.

II. To assess the efficacy of intra-anal topical 5-fluorouracil (fluorouracil) 5% for
treatment of anal HSIL compared to observation only.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of intra-anal imiquimod 2.5% and topical
5-fluorouracil 5%.

II. To compare the efficacy of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5%.

III. To assess for partial response of intra-anal imiquimod 2.5% or topical 5-fluorouracil 5%
as compared to observation only.

IV. To evaluate the effect of intra-anal imiquimod 2.5% and topical 5-fluorouracil 5% on
human papilloma virus (HPV) persistence.

V. To evaluate anal HSIL outcomes at week 44. VI. To evaluate the effect of behavioral
patterns including tobacco smoking and sexual activity on treatment efficacy, tolerability
and HPV.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A: Patients apply imiquimod intra-anally once daily (QD) for 16 weeks.

ARM B: Patients apply fluorouracil intra-anally twice daily (BID) on days 1-5. Treatment
repeats every 2 weeks for 8 courses in the absence of disease progression or unacceptable
toxicity.

ARM C: Patients receive no treatment. Patients who still have HSIL at week 20 and who agree
to randomization may cross-over to Arm A or B.

After completion of study treatment, patients are followed up at weeks 20, 24, 26, 32, 40,
and 44.

Inclusion Criteria:

- HIV-positive; documentation of HIV infection must be based on a federally approved,
licensed HIV test performed in conjunction with screening (enzyme linked immunosorbent
assay [ELISA], western blot, or other test); alternatively, this documentation may
include a record that another physician has documented that the patient has HIV based
on prior ELISA and western blot; an approved antibody test will be used to confirm
diagnosis; if the physician is treating a patient with combination antiretroviral
therapy (cART) with a history of HIV positivity based on an approved antibody test
then repeat antibody confirmation is not necessary

- Biopsy-proven HSIL (anal intraepithelial neoplasia 2 (AIN2) and/or AIN3) of the anal
canal at either the squamocolumnar junction or distal anus, documented within 60 days
prior to enrollment, but not less than 1 week prior to enrollment

- HSIL occupies at least 25% of the circumference of the anal canal at either the
squamocolumnar junction or distal anus on high-resolution anoscopy (HRA) at screening
or entry based on available biopsy results and visual appearance

- Anal HSIL lesions are visible at study entry and no lesions are suspicious for
invasive cancer

- Ability to understand and willing to provide informed consent

- Participants must, in the opinion of the Investigator, be capable of complying with
the requirements of this protocol including self-administration of study treatment

- Karnofsky performance status of >= 70%

- Cluster of differentiation (CD)4 count >= 200 within 120 days prior to enrollment or
plasma HIV-1 ribonucleic acid (RNA) < 200 copies/mL within 120 days prior to
enrollment

- For females, cervical cytology (if having a cervix) and gynecologic evaluation within
12 months prior to enrollment

- Absolute neutrophil count (ANC) > 750 cells/mm^3 within 90 days prior to enrollment

- Hemoglobin >= 9.0 g/dL within 90 days prior to enrollment

- Platelet count >= 75,000/mm^3 within 90 days prior to enrollment

Exclusion Criteria:

- History of anal cancer

- Prior intra-anal use of topical 5-fluorouracil 5% or imiquimod 2.5%, 3.75% or 5% at
any point, or use of perianal imiquimod 2.5%, 3.75% or 5% or topical 5-fluorouracil 5%
within 6 months prior to enrollment

- Extensive concurrent perianal or lower vulvar HSIL or condyloma requiring a different
treatment modality than the study treatment, or treatment that cannot be deferred in
observation arm, per examining provider

- Condyloma occupying more than 50% of the circumference of the anal canal or that
obscures a satisfactory exam

- Ongoing use of anticoagulant therapy other than aspirin or nonsteroidal
anti-inflammatory drugs (NSAIDs)

- Acute treatment for an infection (excluding fungal infection of the skin and sexually
transmitted infections) or other serious medical illness within 14 days prior to study
entry

- Malignancy requiring systemic therapy; note: Kaposi's sarcoma limited to the skin is
not exclusionary unless requiring systemic chemotherapy

- Concurrent systemic corticosteroids, cytokines, and immunomodulatory therapy (e.g.
interferons)

- Prior history of HPV vaccination

- Treatment for anal or perianal HSIL, low-grade squamous intraepithelial lesion (LSIL)
or condyloma within 4 months of entry; please note that infrared coagulation (IRC) or
electrocautery of a biopsy site to stop bleeding does not constitute treatment

- Female participants who are pregnant or breastfeeding; women of childbearing potential
must have a negative urine or serum pregnancy test within 72 hours prior to initiating
study treatment; all women of childbearing potential must be willing to comply with an
acceptable birth control regimen to prevent pregnancy while receiving treatment and
for 3 months after treatment is discontinued as determined by the Investigator;
post-menopausal women must be amenorrheic for at least 12 months to be considered of
non-childbearing potential; (note: a woman of childbearing potential is one who is
biologically capable of becoming pregnant; this includes women who are using
contraceptives or whose sexual partners are either sterile or using contraceptives)