Topical Fluorouracil and Imiquimod in Treating Patients With High-Grade Cervical Intraepithelial Neoplasia
Topical Fluorouracil and Imiquimod in Treating Patients With High-Grade Cervical Intraepithelial Neoplasia
This early phase I clinical trial studies the side effects of topical fluorouracil and
 imiquimod ointment in treating patients with high-grade cervical intraepithelial neoplasia.
 Topical fluorouracil may kill precancerous cells. Imiquimod ointment may stimulate the immune
 system. Applying topical fluorouracil and imiquimod ointment may cause fewer side effects and
 may be a better way to treat patients with precancerous cervical lesions.
PRIMARY OBJECTIVE:

 I. Assess feasibility, evaluated based on safety and tolerability, of a combination agent
 intervention (once-weekly self-administered intravaginal application of 5-fluorouracil
 alternating with once-weekly provider-applied imiquimod) for treatment of high-grade cervical
 squamous intraepithelial lesions.

 SECONDARY OBJECTIVES:

 I. Assess efficacy of the combination agent intervention on cervical disease regression
 (endpoint based on histologic regression from high-grade lesions to low-grade or no lesions
 and clearance of high risk-human papillomavirus [HPV] detection) between baseline and study
 exit visits.

 II. Assess efficacy of the combination agent intervention on genotype-specific HPV clearance
 between baseline and study exit visits.

 III. Assess efficacy of the combination agent intervention on biomarkers of local immune
 activation (measurement of changes in expression of Toll-like receptors (TLR) and
 T-regulatory cells and the levels of innate, immune mediating and proinflammatory cytokines
 with intravaginal 5-fluorouracil [FU] and imiquimod) between baseline and study exit visits.

 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 squamous intraepithelial lesions
 (i.e., cervical squamous intraepithelial neoplasia 3 [CIN3] lesions, and cervical
 squamous epithelial neoplasia 2 [CIN2] lesions with 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

 -  Serum creatinine =< the upper 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; the effects of intravaginal
 5-fluorocuracil and imiquimod on the developing human fetus at the recommended
 therapeutic dose are unknown; for this reason and because 5- fluorouracil is known to
 be teratogenic, women of child-bearing potential 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; pregnant
 women are excluded from this study because 5-fluorouracil is an antimetabolite with
 the potential for teratogenic effects; because there is an unknown but potential risk
 for adverse events (AEs) in nursing infants secondary to treatment of the mother with
 5-fluorouracil, 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 positive [+], use of
 immunosuppressive medications or systemic steroids, organ transplant recipients) or
 autoimmune conditions (e.g. psoriasis, rheumatoid arthritis or other known autoimmune
 conditions)

 -  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 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

 -  Subjects with known partial or complete dihydropyrimidine dehydrogenase (DPD) enzyme
 deficiency