Clinical Trials /

Treatment of High-Grade Pre-Neoplastic Cervical Lesions (CIN 2/3)

NCT02864147

Description:

This is a randomized Phase II, three arm control trial in patients with Cervical Intraepithelial Neoplasia (CIN) 2/3 high grade cervical dysplasia. Patients with CIN 2/3 meeting eligibility criteria will have cervical biopsy specimens centrally reviewed by study pathologist to confirm diagnosis. HPV DNA test and HPV 16/18 genotyping will be performed from endocervical cytobrush samples to determine HPV status associated with the dysplasia. Patients who have CIN 2/3 with HPV+ disease will be enrolled in this study. Patients will be randomized to one of three arms: observation only (control), imiquimod only, imiquimod + 9-valent HPV vaccine.

Related Conditions:
  • High Grade Cervical Intraepithelial Neoplasia
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Treatment of High-Grade Pre-Neoplastic Cervical Lesions (CIN 2/3)
  • Official Title: Treatment of High-Grade Pre-Neoplastic Cervical Lesions (CIN 2/3) Using a Novel "Prime and Pull" Strategy

Clinical Trial IDs

  • ORG STUDY ID: 1603017415
  • NCT ID: NCT02864147

Conditions

  • Cervical Intraepithelial Neoplasia
  • Cervical Dysplasia

Interventions

DrugSynonymsArms
9-valent HPV vaccineimiquimod + 9-valent HPV vaccine
Imiquimodimiquimod + 9-valent HPV vaccine

Purpose

This is a randomized Phase II, three arm control trial in patients with Cervical Intraepithelial Neoplasia (CIN) 2/3 high grade cervical dysplasia. Patients with CIN 2/3 meeting eligibility criteria will have cervical biopsy specimens centrally reviewed by study pathologist to confirm diagnosis. HPV DNA test and HPV 16/18 genotyping will be performed from endocervical cytobrush samples to determine HPV status associated with the dysplasia. Patients who have CIN 2/3 with HPV+ disease will be enrolled in this study. Patients will be randomized to one of three arms: observation only (control), imiquimod only, imiquimod + 9-valent HPV vaccine.

Detailed Description

      The primary objectives of this study are as follows:

        -  To determine treatment efficacy defined as histologic regression to CIN 1 or less at
           weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in the HPV Vaccine +
           Imiquimod group compared to control,

        -  To determine treatment efficacy defined as histologic regression to CIN 1 or less at
           weeks 20-24 (4 to 8 weeks after the end of imiquimod treatment) in the Imiquimod group
           compared to control.

      The secondary objectives of this study are as follows:

        -  To assess complete regression (i.e., histologic remission) at weeks 20-24 (4 to 8 weeks
           after the end of imiquimod treatment) in each group,

        -  To assess HPV clearance in each group,

        -  To assess treatment tolerability.

      In addition to the primary and secondary objectives of this study, there additional
      exploratory/correlative objectives. The exploratory/correlative objectives are as follows:

        -  To assess T cell infiltration in post-treatment cervical biopsies and endocervical
           cytobrush samples,

        -  To assess HPV16 E7 immunity in CD4/CD8 T cells.
    

Trial Arms

NameTypeDescriptionInterventions
imiquimod + 9-valent HPV vaccineExperimentalParticipants randomized to the imiquimod + 9-valent HPV vaccine group will receive instruction on imiquimod self application (16 week course) at the baseline visit. In addition, all women (regardless of age) will be administered a dose of the HPV vaccine on day of enrollment (regardless of previous HPV vaccination history). Women previously unvaccinated will receive an additional booster dose at 8 weeks.
  • 9-valent HPV vaccine
  • Imiquimod
imiquimod onlyActive ComparatorParticipants randomized to the imiquimod only group will receive instruction on imiquimod self application (16 week course) at the baseline visit.
  • Imiquimod
observation only (control)No InterventionParticipants randomized to the control group will only be observed and will receive no intervention.

    Eligibility Criteria

            Inclusion Criteria:
    
              -  Patients must have untreated cervical biopsy-proven, CIN 2/3 ectocervical lesion(s).
    
              -  Patients must have satisfactory colposcopy with visualization of the entire
                 transformation zone or a negative endocervical curettage if colposcopy is
                 unsatisfactory.
    
              -  Patients must be high-risk HPV+ as determined by commercially available DNA
                 hybridization test which tests for 13 high-risk HPV types.
    
              -  All patients must have a histologic diagnosis of CIN 2,3 cervical lesion(s) confirmed
                 by a study pathologist within past 4-10 weeks.
    
              -  Patients must have signed an approved informed consent.
    
              -  Patients of childbearing potential must have a negative serum pregnancy test within 7
                 days prior to the study entry and be practicing an effective form of contraception.
    
              -  Patients must be fluent in speaking English or Spanish.
    
            Exclusion Criteria:
    
              -  Patients with unsatisfactory colposcopy* (unable to visualize entire transformation
                 zone) or evidence of endocervical disease defined as CIN 2/3 diagnosed on endocervical
                 curettage.
    
                 *Patients with unsatisfactory colposcopy but negative endocervical curettage are
                 eligible
    
              -  Patients known to have untreated cervical biopsy-proven CIN 2/3 present for more than
                 10 weeks.
    
              -  Patients with a history of invasive cervical cancer
    
              -  Patients with a history of other invasive malignancies, with the exception of
                 non-melanoma skin cancers are excluded if there is any evidence of other malignancy
                 being present within the last five years. Patients are also excluded if their previous
                 cancer treatment contraindicates this protocol therapy.
    
              -  Patients who have a significant history of cardiac disease, i.e., uncontrolled
                 hypertension, unstable angina, uncontrolled congestive heart failure, or uncontrolled
                 arrhythmias within 6 months of registration (NYHA classification III-IV).
    
              -  Patients with any unstable medical issue (including cardiac issues as above, active
                 treatment for pulmonary embolism, CVA, renal or hepatic insufficiency, active
                 infection/sepsis requiring IV antibiotics).
    
              -  Patients who have an uncontrolled seizure disorder, or active neurological disease.
    
              -  Patients known to be seropositive for HIV and active hepatitis, even if liver function
                 studies are in the normal range. Patients otherwise immunocompromised will also be
                 excluded (chronic steroid use, taking immunosuppressive medications).
    
              -  Known hemorrhagic diathesis or active bleeding disorder.
    
              -  Pregnant or breastfeeding patients.
    
              -  Patients who have had a total hysterectomy (removal of uterus and cervix) or
                 trachelectomy (removal of cervix).
    
              -  Patients with a known hypersensitivity to imiquimod. Patients with a known
                 hypersensitivity to any prophylactic HPV vaccine or severe allergic reactions to yeast
                 (vaccine component).
    
              -  Patients who have received their first dose of HPV vaccine < 4 weeks ago or their
                 second dose < 12 weeks ago.
    
              -  Known hypersensitivity or prior intravaginal treatment with Imiquimod.
          
    Maximum Eligible Age:N/A
    Minimum Eligible Age:18 Years
    Eligible Gender:Female
    Healthy Volunteers:No

    Primary Outcome Measures

    Measure:Incidence of Objective Response
    Time Frame:Between weeks 20 and 24 (approximately week 22)
    Safety Issue:
    Description:The major parameters of objective response to be assessed include treatment efficacy defined as histologic regression of cervical dysplasia to CIN 1 or less after the end of imiquimod treatment, HPV clearance and treatment tolerance. Objective response will be categorized as 'yes' or 'no' and included in the evaluations are the following criteria: Histologic regression (HR): Histologic regression of all index lesions to CIN 1 or less after end of imiquimod treatment period. Histologic remission (HM): Complete regression of cervical dysplasia at all index biopsy sites after end of imiquimod treatment period. Persistent Disease (PR): One or more index lesions persists with CIN 2,3 high grade dysplasia or new lesions are identified colposcopically and histologically confirmed to be CIN 2,3. Progressive Disease (PD): Worsening histology of an index lesion.

    Secondary Outcome Measures

    Measure:Incidence of HPV Clearance
    Time Frame:Between weeks 20 and 24 (approximately week 22)
    Safety Issue:
    Description:HPV Clearance will be categorized as 'yes' or 'no' and the evaluations are the following criteria: HPV clearance will be measured by both the Roche cobas HPV Test utilized by pathology concomitant with the pap test at final study visit which assesses for presence of 14 high risk HPV types as well as HPV 16/18 genotyping performed by Santin Lab.

    Details

    Phase:Phase 2
    Primary Purpose:Interventional
    Overall Status:Recruiting
    Lead Sponsor:Yale University

    Last Updated