An Early Phase 1 interventional study of Imiquimod and Topical Fluorouracil in Cervical Intraepithelial Neoplasia Grade 2/3, Cervical Squamous Cell Carcinoma In Situ and Cervical Squamous Intraepithelial Neoplasia 2, sponsored by National Cancer Institute (NCI). Completed at 1 site in United States. Open to female participants aged 18 Years to 45 Years. Per ClinicalTrials.gov, last updated 2025-04-08.
Sponsored by National Cancer Institute (NCI) · Early Phase 1, Interventional, and Treatment
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.
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Exclusion Criteria:
Pathologic findings consistent with
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 · Drug: Topical Fluorouracil
Given intravaginally
Also known as: Aldara, R 837, S 26308, Zyclara
Given intravaginally
Also known as: Actino-Hermal, Arumel, Carac, Cytosafe, Efudex, Efurix, Fiverocil, Fluoroplex, Flurox, Timazin, Tolak
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.
Time frame: Up to 22 weeks
Response to Intravaginal 5-FU and Imiquimod Defined as Histologic Regression and Clearance of High-risk Human Papilloma Virus (HR-HPV)
The response will be reported along with their 95% confidence intervals. Response is defined as histologic regression from high-grade lesions to low-grade- or no lesions and clearance of HR-HPV detection between baseline and end of study.
Time frame: At end of study visit (4-6 weeks after the last agent application)
Type Specific Human Papillomavirus (HPV) Clearance
The 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)
Change in Expression of Biomarkers of Local Immune Activation (Cytokines) After Treatment With Self-administered Intravaginal Topical Fluorouracil and Imiquimod
For each biomarker, the mean change of log transformed data and the associated standard deviation will be reported. Will measure 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)
Change in Expression of Biomarkers of Local Immune Activation (Toll Like Receptors (TLRs)) After Treatment With Self-administered Intravaginal Topical Fluorouracil and Imiquimod
For each biomarker, the mean change of log transformed data and the associated standard deviation will be reported. TLR messenger ribonucleic acid expression is normalized by the housekeeping genes and does not have a unit of measure.
Time frame: Baseline to up to end of study visit (4-6 weeks after last agent application)
| Milestone | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Started | 13 |
| Completed | 11 |
| Not completed | 2 |
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.
| Participants | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Safety | 4 |
| Tolerability | 1 |
The response will be reported along with their 95% confidence intervals. Response is defined as histologic regression from high-grade lesions to low-grade- or no lesions and clearance of HR-HPV detection between baseline and end of study.
| percentage of participants | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Response to Intravaginal 5-FU and Imiquimod Defined as Histologic Regression and Clearance of High-risk Human Papilloma Virus (HR-HPV) | 40 (12 to 74) |
The type-specific HR-HPV clearance will be reported along with their 95% confidence intervals.
| percentage of participants | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| HPV16 | 75 (19 to 99) |
| HPV31 | 50 (1 to 99) |
| HPV35 | 100 (3 to 100) |
| HPV39 | 0 (0 to 98) |
| HPV51 | 0 (0 to 84) |
| HPV52 | 75 (19 to 99) |
| HPV56 | 0 (0 to 98) |
| HPV66 | 50 (1 to 99) |
| HPV68 | 100 (16 to 100) |
For each biomarker, the mean change of log transformed data and the associated standard deviation will be reported. Will measure the innate (IFN-alpha2), immune mediating (IFN-gamma, IL-10, IL-12), and pro-inflammatory (IL-1alpha, -1beta, -6, -8, MIP-1alpha, TNF) cytokine.
| log pg/ml | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| IFN-alpha 2 | -0.29 ± 1.49 |
| IFN-gamma | 0.16 ± 0.81 |
| IL-1 alpha | -0.55 ± 1.01 |
| IL-1 beta | -0.15 ± 1.84 |
| IL-6 | -0.84 ± 1.94 |
| IL-8 | -0.16 ± 2.63 |
| IL-12 | 0.15 ± 0.95 |
| IL-13 | -0.53 ± 1.11 |
| MIP-1 alpha | 0.66 ± 0.77 |
| TNF alpha | -0.01 ± 1.99 |
For each biomarker, the mean change of log transformed data and the associated standard deviation will be reported. TLR messenger ribonucleic acid expression is normalized by the housekeeping genes and does not have a unit of measure.
| gene expression level | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| TLR2 | 0.90 ± 2.16 |
| TLR3 | 0.75 ± 4.26 |
| TLR4 | 0.86 ± 1.84 |
| TLR7 | 2.20 ± 1.36 |
| TLR9 | 0.95 ± 4.43 |
Collected over 14-22 weeks. Non-serious events are listed at a 5% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Treatment (Topical Fluorouracil, Imiquimod) | 0/13 (0%) | 0/13 (0%) | 13/13 (100%) |
| Event | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Pain - VaginaReproductive system and breast disorders | 8/13 |
| Vaginal discharge by participant reportReproductive system and breast disorders | 7/13 |
| Pain - PelvicReproductive system and breast disorders | 6/13 |
| Upper respiratory infectionInfections and infestations | 5/13 |
| Vulvar/vaginal itchingReproductive system and breast disorders | 5/13 |
| HypertensionVascular disorders | 5/13 |
| HeadacheNervous system disorders | 4/13 |
| Unexplained infrequent bleedingReproductive system and breast disorders | 4/13 |
| Weight gainInvestigations | 3/13 |
| Vaginal lesionsReproductive system and breast disorders | 3/13 |
| Age, Continuous(years) | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Mean | 27 ± 4 |
| Sex: Female, Male(Participants) | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Female | 13 |
| Male | 0 |
| Ethnicity (NIH/OMB)(Participants) | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| Hispanic or Latino | 2 |
| Not Hispanic or Latino | 11 |
| Unknown or Not Reported | 0 |
| Race (NIH/OMB)(Participants) | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| American Indian or Alaska Native | 0 |
| Asian | 1 |
| Native Hawaiian or Other Pacific Islander | 0 |
| Black or African American | 3 |
| White | 7 |
| More than one race | 0 |
| Unknown or Not Reported | 2 |
| Region of Enrollment(Participants) | Treatment (Topical Fluorouracil, Imiquimod) |
|---|---|
| United States | 13 |
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