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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details. Identifier: NCT03196180
Recruitment Status : Recruiting
First Posted : June 22, 2017
Last Update Posted : October 7, 2019
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
This 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.

Condition or disease Intervention/treatment Phase
Cervical Intraepithelial Neoplasia Grade 2/3 Cervical Squamous Cell Carcinoma In Situ Cervical Squamous Intraepithelial Neoplasia 2 High Grade Cervical Intraepithelial Neoplasia Drug: Imiquimod Other: Laboratory Biomarker Analysis Drug: Topical Fluorouracil Phase 1

Detailed Description:


I. Assess feasibility 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.


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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 12 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Feasibility Trial of Alternating Intravaginal Application of 5-Fluorouracil and Imiquimod for Treatment of High-Grade Cervical Squamous Intraepithelial Lesions
Actual Study Start Date : September 30, 2019
Estimated Primary Completion Date : August 31, 2020
Estimated Study Completion Date : August 31, 2020

Resource links provided by the National Library of Medicine

Intervention Details:
  • Drug: Imiquimod
    Given intravaginally
    Other Names:
    • Aldara
    • R 837
    • S 26308
    • Zyclara
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Topical Fluorouracil
    Given intravaginally
    Other Names:
    • Actino-Hermal
    • Arumel
    • Carac
    • Cytosafe
    • Efudex
    • Efurix
    • Fiverocil
    • Fluoroplex
    • Flurox
    • Timazin
    • Tolak

Primary Outcome Measures :
  1. Incidence of adverse events as graded by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 16 weeks ]
    Will assess the number of participants experiencing the dose limiting toxicity (DLT). DLT is defined as grade 2 or greater toxicity (or grade 1 toxicity of any genital lesion [blisters, ulcerations, or pustule]) that is possibly, probably, or definitely related and lasts for more than 5 days. Descriptive statistics of the type and frequency of all adverse events will be generated, including 95% confidence intervals. The adverse event rate and tolerability rate will be reported along with their 95% confidence intervals.

Secondary Outcome Measures :
  1. Response to intravaginal 5-FU and imiquimod defined as histologic regression and clearance of high-risk human papilloma virus (HR-HPV) [ Time Frame: At end of study visit (4-6 weeks after the last agent application) ]
    The response and type-specific HR-HPV clearance will be reported along with their 95% confidence intervals.

  2. Type specific human papillomavirus (HPV) clearance [ Time Frame: At end of study visit (4-6 weeks after the last agent application) ]
    The overall response and type-specific HR-HPV clearance will be reported along with their 95% confidence intervals.

  3. Change in expression of biomarkers of local immune activation after treatment with self-administered intravaginal topical fluorouracil and imiquimod [ Time Frame: Baseline to up to end of study visit (4-6 weeks after last agent application) ]
    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) mRNA 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.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 45 Years   (Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No

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
  • 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 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; 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) 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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03196180

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United States, North Carolina
UNC Lineberger Comprehensive Cancer Center Recruiting
Chapel Hill, North Carolina, United States, 27599
Contact: Lisa Rahangdale    919-843-7851   
Principal Investigator: Lisa Rahangdale         
Sponsors and Collaborators
National Cancer Institute (NCI)
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Principal Investigator: Lisa Rahangdale The University of Arizona Medical Center-University Campus

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Responsible Party: National Cancer Institute (NCI) Identifier: NCT03196180     History of Changes
Other Study ID Numbers: NCI-2017-01079
NCI-2017-01079 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
UAZ2016-08-02 ( Other Identifier: Banner University Medical Center - Tucson )
UAZ2016-08-02 ( Other Identifier: DCP )
N01CN00031 ( U.S. NIH Grant/Contract )
P30CA023074 ( U.S. NIH Grant/Contract )
First Posted: June 22, 2017    Key Record Dates
Last Update Posted: October 7, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Carcinoma in Situ
Cervical Intraepithelial Neoplasia
Squamous Intraepithelial Lesions of the Cervix
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Uterine Cervical Dysplasia
Precancerous Conditions
Uterine Cervical Diseases
Uterine Diseases
Genital Diseases, Female
Molecular Mechanisms of Pharmacological Action
Antimetabolites, Antineoplastic
Antineoplastic Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Adjuvants, Immunologic
Interferon Inducers