Topical Fluorouracil and Imiquimod in Treating Patients With High-Grade Cervical Intraepithelial Neoplasia

PRIMARY OBJECTIVES:

I. Assess safety and tolerability of self-administered weekly intravaginal topical
fluorouracil (5-fluorouracil [5-FU]) and imiquimod used on alternating weeks for 16 weeks in
women with biopsy confirmed high grade cervical intraepithelial lesions.

SECONDARY OBJECTIVES:

I. Describe the response to intravaginal 5-FU and imiquimod. II. Describe type-specific human
papillomavirus (HPV) clearance after treatment with intravaginal 5-FU and imiquimod.

III. Measure biomarkers of local immune activation.

OUTLINE: This is a phase I, dose escalation study of imiquimod.

Patients receive topical fluorouracil intravaginally via applicator at weeks 1, 3, 5, 7, 9,
11, 13, and 15 and imiquimod intravaginally via applicator at weeks 2, 4, 6, 8, 10, 12, 14,
and 16. Patients who are menstruating will delay application until the end of the menstrual
cycle.

After completion of study treatment, patients are followed up within 8 months.

Inclusion Criteria:

- Women with biopsy confirmed high grade cervical intraepithelial lesions (diagnosis
confirmed by positive p16 immunohistochemistry staining) within 12 weeks of baseline
visit

- Karnofsky >= 70%

- Leukocytes >= 3,000/microliter

- Absolute neutrophil count >= 1,500/microliter

- Platelets >= 100,000/microliter

- Creatinine within normal institutional limits

- Urinalysis within normal institutional limits

- Participants must have a negative human immunodeficiency virus (HIV) antibody/antigen
test and negative Chlamydia (C.) trachomatis/Neisseria (N.) gonorrhea nucleic acid
amplification test (NAAT)

- Agree to use an effective form of contraception; women of child-bearing potential and
men must agree to use adequate dual methods of contraception (hormonal method of birth
control, intrauterine device, or tubal ligation - plus condoms) or abstinence prior to
study entry and for the duration of study participation; should a woman become
pregnant or suspect she is pregnant while participating in this study, she should
inform her study physician immediately

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

Exclusion Criteria:

- Women treated previously with 5-fluorouracil or imiquimod or other medications for
high-grade squamous intraepithelial lesions will be excluded from the study

- Concurrent vaginal, vulvar, anal lesions or symptomatic infections

- Pregnant or planning pregnancy within the next 6 months, or breastfeeding;
breastfeeding should be discontinued if the mother is treated with 5-fluorouracil

- Inability to speak or read English or Spanish

- Prior hysterectomy

- Use of anticoagulant medications

- Subjects who have a known immunocompromised condition (HIV+, use of immunosuppressive
medications or systemic steroids, organ transplant recipients)

- Evidence of invasive anal, vulva, vaginal, or cervical carcinoma; prior loop
electrosurgical excision procedure (LEEP) or ablative treatment within 6 months prior
to study entry; other invasive malignancies, with the exception of non-melanoma skin
cancer, within the last 5 years

- Pathologic findings consistent with

- atypical endometrial cells or serious glandular-cell atypia (atypical glandular
cells, favor neoplasia cytology diagnosis)

- evidence of cervical carcinoma on Pap smear or biopsy

- more than two cervical quadrants of cervical intraepithelial neoplasia grade 3
(CIN 3) as visualized by colposcopy

- nonvisual squamous columnar junction on colposcopy with no concurrent
endocervical sampling performed

- Use of other investigational agents within 6 months prior to enrollment

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to 5-fluorouracil or imiquimod

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
infection (other than human papilloma virus [HPV]), symptomatic congestive heart
failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements