Topical or Ablative Treatment in Preventing Anal Cancer in Patients With HIV and Anal High-Grade Squamous Intraepithelial Lesions

PRIMARY OBJECTIVES:

I. To determine the effectiveness of treating anal HSIL to reduce the incidence of anal
cancer in human immunodeficiency virus (HIV)-infected men and women.

SECONDARY OBJECTIVES:

I. Determine safety of infrared coagulation, electrocautery, imiquimod, 85% trichloroacetic
acid and 5-fluorouracil (fluorouracil) treatments for anal HSIL.

II. Compare quality of life measures between arms.

TERTIARY OBJECTIVES:

I. Determine the human papilloma virus (HPV) type in cancer and compare to that of overlying
HSIL and HSIL biopsies collected concurrently that did not progress to cancer.

II. Determine the strain variant of HPV 16 in participants who progressed to anal cancer and
compare to participants with HSIL biopsies who did not progress to cancer.

III. Determine the HPV integration site in overlying anal cancer to that of HSIL overlying
the cancer and HSIL biopsies collected concurrently that did not progress to cancer.

IV. Perform gene expression array analysis comparing expression in anal cancer with HSIL
overlying the cancer; perform gene expression array analysis comparing expression in HSIL
biopsies that progressed to cancer with non-progressing HSIL biopsies at other locations;
perform similar analyses comparing expression in HSIL biopsies that progressed to cancer with
the same lesion at earlier time points prior to progression.

V. Characterize genetic changes in anal cancers compared with HSIL overlying the cancer;
characterize genetic changes in HSIL biopsies that progressed to cancer compared with
non-progressing HSIL biopsies at other locations; characterize genetic changes HSIL biopsies
that progressed to cancer with the same lesion at earlier time points prior to progression.

VI. Identify host and viral biomarkers of progression from HSIL to cancer. VII. Evaluate
medical history and behavioral risk factors for HSIL progression to cancer.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients are directed to receive either topical or ablative treatment at the
discretion of the clinician. Patients receiving topical treatment apply imiquimod
intra-anally, peri-anally or both thrice weekly for up to 16 weeks, fluorouracil twice daily
for 5 days every 2 weeks for up to 16 weeks, or trichloroacetic acid every 3 weeks up to 12
weeks. Patients receiving ablative treatment using infrared coagulation,
hyfrecation/electrocautery, or laser. Patients may undergo excision under anesthesia if the
clinician believes none of the other treatment approaches will be effective. The number and
timing of such treatments will be at the discretion of the investigator. Patients with
persistent HSIL should continue a protocol-approved treatment or a new protocol treatment
should be considered.

ARM II: Patients undergo active monitoring with examinations every 6 months. Every 12 months,
patients undergo biopsies of visible lesions. Patients have cytology performed at every
visit.

After completion of study treatment, patients are followed up every 6 months for up to 5
years.

Inclusion Criteria:

- HIV-1 infection, as documented by any federally approved, licensed HIV test performed
in conjunction with screening (or enzyme-linked immunosorbent assay [ELISA], test kit,
and confirmed by western blot or other approved test); alternatively, this
documentation may include a record that another physician has documented that the
participant has HIV infection based on prior ELISA and western blot, or other approved
diagnostic tests; 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

- No history of treatment or removal of HSIL

- No history of anal cancer or signs of anal cancer at baseline, and no history of
penile, vulvar, vaginal or cervical cancer

- Biopsy-proven HSIL at baseline

- At least one focus of HSIL must be identified that is not within a condyloma that may
be treated after enrollment into the study

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

- Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

- Life expectancy of greater than 5 years

- Absolute neutrophil count: >= 750/mm^3

- Platelets: >= 75,000/mm^3

- Hemoglobin >= 9.0 g/dL

- Women of childbearing potential must have a negative urine pregnancy test within 7
days of initiating study treatment if they have been randomized to the treatment arm;
all women of childbearing potential must agree to use a reliable birth control method
(oral contraceptive pills, intrauterine device, Nexplanon, DepoProvera, or permanent
sterilization, etc., or another acceptable method as determined by the investigator)
during the entire period of the trial (5 years), and must not intend to become
pregnant during study participation and for 3 months after treatment is discontinued;
all participants must be willing to comply with an acceptable birth control regimen as
determined by the Investigator

- Men randomized to the treatment arm should not father a baby while in this study; men
who could father a child should use at least two forms of birth control for 3 months
after stopping all study treatment

- Ability to understand and the willingness to sign a written informed consent document

- Participant is willing to be randomized and able to comply with the protocol

- Clinician is comfortable with either following patient for up to 5 years without
therapy or treating patient for up to 5 years

Exclusion Criteria:

- Inability to provide informed consent

- Patients who are receiving any other immunomodulatory investigational agents within
the 4 weeks before randomization enrollment, other than investigational antiretroviral
agents for HIV

- History of anal cancer, penile, vulvar, vaginal or cervical cancer

- History of prior treatment or removal of anal HSIL

- Participant has symptoms related to HSIL and would benefit more from immediate
treatment than from entry into the study and potential for randomization to active
monitoring arm

- Current systemic chemotherapy or radiation therapy that potentially causes bone marrow
suppression that would preclude safe treatment of HSIL

- History of HPV vaccination, or intention to receive an HPV vaccine during study
participation

- Prior pelvic radiation therapy that would preclude radiation therapy if anal cancer
develops

- Warts so extensive that they preclude the clinician from determining the extent and
location of HSIL

- Participant plans to relocate away from the study site during study participation