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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Feasibility Trial of Alternating Intravaginal Application of 5-Fluorouracil and Imiquimod for Treatment of High-Grade Cervical Squamous Intraepithelial Lesions

Conditions
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Cervical Intraepithelial Neoplasia Grade 2/3, Cervical Squamous Cell Carcinoma In Situ, Cervical Squamous Intraepithelial Neoplasia 2, High Grade Cervical Intraepithelial Neoplasia

Intervention / Treatment
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* Drug: Imiquimod
* Drug: Topical Fluorouracil


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (topical fluorouracil, imiquimod)<br>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. | Drug: Imiquimod<br>* Given intravaginally<br>* Other names: Zyclara;Drug: Topical Fluorouracil<br>* Given intravaginally<br>* Other names: Tolak;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Feasibility of Intravaginal Use 5-FU and Imiquimod on Alternating Weeks in Women With Biopsy Confirmed High Grade Cervical Squamous Intraepithelial Lesions. | Feasibility is evaluated based on safety and tolerability of the study intervention. For safety, the study assessed the number of participants experiencing the specified adverse events defined as Grade 2 or greater toxicity (or Grade 1 toxicity of any genital lesion (blisters, ulcerations, or pustules)) that is possibly, probably, or definitely related and lasts for more than 5 days. For tolerability, the study assessed the number of participants who were not able to apply at least 50% of the treatment due to the specified adverse events. | Up to 22 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response to Intravaginal 5-FU and Imiquimod Defined as Histologic Regression and Clearance of High-risk Human Papilloma Virus (HR-HPV) | The response and type-specific HR-HPV clearance will be reported along with their 95% confidence intervals. | At end of study visit (4-6 weeks after the last agent application) | 
| Type Specific Human Papillomavirus (HPV) Clearance | The overall response and type-specific HR-HPV clearance will be reported along with their 95% confidence intervals. | At end of study visit (4-6 weeks after the last agent application) | 
| Change in Expression of Biomarkers of Local Immune Activation After Treatment With Self-administered Intravaginal Topical Fluorouracil and Imiquimod | For each biomarker, the mean change and the associated standard deviation will be reported. Will measure the TLR (TLR2, TLR 3, TLR7, TLR8 and TLR9) and T-regulatory cell (Foxp3) messenger ribonucleic acid expression and the innate (IFN-alpha2), immune mediating (IFN-gamma, IL-10, IL-12), and pro-inflammatory (IL-1alpha, -1beta, -6, -8, MIP-1alpha, TNF) cytokine. | Baseline to up to end of study visit (4-6 weeks after last agent application) |