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

Sponsor
National Cancer Institute (NCI) (NIH)
Overall Status
Active, not recruiting
CT.gov ID
NCT03196180
Collaborator
(none)
13
1
1
37.2
0.3

Study Details

Study Description

Brief Summary

This early phase 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

PRIMARY OBJECTIVE:
  1. 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:
  1. 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.

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

  3. 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 pilot study in women aged 18-45 years with biopsy confirmed high-grade cervical intraepithelial lesions to assess the feasibility of once-weekly intravaginal application of 5-FU and imiquimod used on alternating weeks for 8 to 16 weeks.

Study Design

Study Type:
Interventional
Actual Enrollment :
13 participants
Allocation:
N/A
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 :
Sep 30, 2019
Actual Primary Completion Date :
Nov 4, 2020
Anticipated Study Completion Date :
Nov 4, 2022

Arms and Interventions

Arm Intervention/Treatment
Experimental: Treatment (topical fluorouracil, imiquimod)

The study has two phases: Initiation Phase, which includes applications of 5-FU and imiquimod on alternating weeks for 8 applications. Participants will self-administer intravaginal 5-FU (2 g of 5% 5-fluorouracil, Effudex) once every other week for a total of 4 applications (wks 1, 3, 5, 7). Participants will receive provider-applied commercially available imiquimod cream 5% (12.5 mg imiquimod in 250 mg cream) directly to the cervix once every other week for a total of 4 applications (wks 2, 4, 6, 8). Extension phase, which will include participants from the initiation phase who opt to continue their participation for applications of 5-FU and imiquimod on alternating weeks for 8 additional applications as described in the initiation phase. Patients who are menstruating will delay application until the end of the menstrual cycle.

Drug: Imiquimod
Given intravaginally
Other Names:
  • Aldara
  • R 837
  • S 26308
  • Zyclara
  • Drug: Topical Fluorouracil
    Given intravaginally
    Other Names:
  • Actino-Hermal
  • Arumel
  • Carac
  • Cytosafe
  • Efudex
  • Efurix
  • Fiverocil
  • Fluoroplex
  • Flurox
  • Timazin
  • Tolak
  • Outcome Measures

    Primary Outcome Measures

    1. Feasibility of Intravaginal Use 5-FU and Imiquimod on Alternating Weeks in Women With Biopsy Confirmed High Grade Cervical Squamous Intraepithelial Lesions. [Up to 22 weeks]

      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.

    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) [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 [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 [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) 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.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years to 45 Years
    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

    • 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

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 UNC Lineberger Comprehensive Cancer Center Chapel Hill North Carolina United States 27599

    Sponsors and Collaborators

    • National Cancer Institute (NCI)

    Investigators

    • Principal Investigator: Lisa Rahangdale, UNC Lineberger Comprehensive Cancer Center

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03196180
    Other Study ID Numbers:
    • NCI-2017-01079
    • NCI-2017-01079
    • N01-CN-2012-00031
    • 1712088061
    • UAZ2016-08-02
    • N01CN00031
    • P30CA023074
    First Posted:
    Jun 22, 2017
    Last Update Posted:
    Feb 23, 2022
    Last Verified:
    Jan 1, 2022
    Individual Participant Data (IPD) Sharing Statement:
    Yes
    Plan to Share IPD:
    Yes
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Treatment (Topical Fluorouracil, Imiquimod)
    Arm/Group Description Patients receive once-weekly intravaginal application of 5-fluorouracil and imiquimod used on alternating weeks for 8 to 16 weeks. Imiquimod: Given intravaginally Topical Fluorouracil: Given intravaginally
    Period Title: Overall Study
    STARTED 13
    COMPLETED 11
    NOT COMPLETED 2

    Baseline Characteristics

    Arm/Group Title Treatment (Topical Fluorouracil, Imiquimod)
    Arm/Group Description Patients receive once-weekly intravaginal application of 5-fluorouracil and imiquimod used on alternating weeks for 8 to 16 weeks. Imiquimod: Given intravaginally Topical Fluorouracil: Given intravaginally
    Overall Participants 13
    Age (years) [Mean (Standard Deviation) ]
    Mean (Standard Deviation) [years]
    27
    (4)
    Sex: Female, Male (Count of Participants)
    Female
    13
    100%
    Male
    0
    0%
    Ethnicity (NIH/OMB) (Count of Participants)
    Hispanic or Latino
    2
    15.4%
    Not Hispanic or Latino
    11
    84.6%
    Unknown or Not Reported
    0
    0%
    Race (NIH/OMB) (Count of Participants)
    American Indian or Alaska Native
    0
    0%
    Asian
    1
    7.7%
    Native Hawaiian or Other Pacific Islander
    0
    0%
    Black or African American
    3
    23.1%
    White
    7
    53.8%
    More than one race
    0
    0%
    Unknown or Not Reported
    2
    15.4%
    Region of Enrollment (Count of Participants)
    United States
    13
    100%

    Outcome Measures

    1. Primary Outcome
    Title Feasibility of Intravaginal Use 5-FU and Imiquimod on Alternating Weeks in Women With Biopsy Confirmed High Grade Cervical Squamous Intraepithelial Lesions.
    Description 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.
    Time Frame Up to 22 weeks

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Treatment (Topical Fluorouracil, Imiquimod)
    Arm/Group Description 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. Imiquimod: Given intravaginally Topical Fluorouracil: Given intravaginally
    Measure Participants 13
    Safety
    4
    30.8%
    Tolerability
    1
    7.7%
    2. Secondary Outcome
    Title Response to Intravaginal 5-FU and Imiquimod Defined as Histologic Regression and Clearance of High-risk Human Papilloma Virus (HR-HPV)
    Description The response and type-specific HR-HPV clearance will be reported along with their 95% confidence intervals.
    Time Frame At end of study visit (4-6 weeks after the last agent application)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    3. Secondary Outcome
    Title Type Specific Human Papillomavirus (HPV) Clearance
    Description The overall response and type-specific HR-HPV clearance will be reported along with their 95% confidence intervals.
    Time Frame At end of study visit (4-6 weeks after the last agent application)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description
    4. Secondary Outcome
    Title Change in Expression of Biomarkers of Local Immune Activation After Treatment With Self-administered Intravaginal Topical Fluorouracil and Imiquimod
    Description 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.
    Time Frame Baseline to up to end of study visit (4-6 weeks after last agent application)

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title
    Arm/Group Description

    Adverse Events

    Time Frame 14-22 weeks
    Adverse Event Reporting Description
    Arm/Group Title Treatment (Topical Fluorouracil, Imiquimod)
    Arm/Group Description Patients receive once-weekly intravaginal application of 5-fluorouracil and imiquimod used on alternating weeks for 8 to 16 weeks. Imiquimod: Given intravaginally Topical Fluorouracil: Given intravaginally
    All Cause Mortality
    Treatment (Topical Fluorouracil, Imiquimod)
    Affected / at Risk (%) # Events
    Total 0/13 (0%)
    Serious Adverse Events
    Treatment (Topical Fluorouracil, Imiquimod)
    Affected / at Risk (%) # Events
    Total 0/13 (0%)
    Other (Not Including Serious) Adverse Events
    Treatment (Topical Fluorouracil, Imiquimod)
    Affected / at Risk (%) # Events
    Total 13/13 (100%)
    Gastrointestinal disorders
    Abdominal pain 1/13 (7.7%)
    Pain - Lower abdominal 2/13 (15.4%)
    General disorders
    Fever 1/13 (7.7%)
    Flu like symptoms 1/13 (7.7%)
    Other 2/13 (15.4%)
    Infections and infestations
    Bacterial vaginosis 1/13 (7.7%)
    Candida 1/13 (7.7%)
    Upper respiratory infection 5/13 (38.5%)
    Investigations
    Weight gain 3/13 (23.1%)
    Weight loss 2/13 (15.4%)
    Musculoskeletal and connective tissue disorders
    Myalgia 1/13 (7.7%)
    Nervous system disorders
    Headache 4/13 (30.8%)
    Renal and urinary disorders
    Dysuria 1/13 (7.7%)
    Reproductive system and breast disorders
    Cervical erythema 1/13 (7.7%)
    Cervical friability 1/13 (7.7%)
    Dysmenorrhea/cramping with menses 2/13 (15.4%)
    Dyspareunia 1/13 (7.7%)
    Metrorrhagia 1/13 (7.7%)
    Pain - Pelvic 6/13 (46.2%)
    Pain - Vagina 8/13 (61.5%)
    Postcoital bleeding 1/13 (7.7%)
    Unexplained infrequent bleeding 4/13 (30.8%)
    Vaginal abrasions 1/13 (7.7%)
    Vaginal discharge as observed by clinician 1/13 (7.7%)
    Vaginal erythema 1/13 (7.7%)
    Vaginal discharge by participant report 7/13 (53.8%)
    Vaginal lesions 3/13 (23.1%)
    Vulvar/vaginal itching 5/13 (38.5%)
    Respiratory, thoracic and mediastinal disorders
    Nasal congestion 2/13 (15.4%)
    Vascular disorders
    Hypertension 5/13 (38.5%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    Principal Investigators are NOT employed by the organization sponsoring the study.

    The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.

    Results Point of Contact

    Name/Title Sherry Chow, PhD
    Organization University of Arizona
    Phone 520-626-3358
    Email schow@azcc.arizona.edu
    Responsible Party:
    National Cancer Institute (NCI)
    ClinicalTrials.gov Identifier:
    NCT03196180
    Other Study ID Numbers:
    • NCI-2017-01079
    • NCI-2017-01079
    • N01-CN-2012-00031
    • 1712088061
    • UAZ2016-08-02
    • N01CN00031
    • P30CA023074
    First Posted:
    Jun 22, 2017
    Last Update Posted:
    Feb 23, 2022
    Last Verified:
    Jan 1, 2022