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

Primary Purpose

Cervical Intraepithelial Neoplasia, Cervical Dysplasia

Status
Completed
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
9-valent HPV vaccine
Imiquimod
Sponsored by
Yale University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Cervical Intraepithelial Neoplasia

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)FemaleDoes not accept healthy volunteers

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 10 weeks.
  • Patients must have signed an approved informed consent.
  • Patients of childbearing potential must have a negative urine pregnancy test within 7 days prior to the study entry and be practicing an effective form of contraception.
  • Patients must be at least 18 years of age based on previous and current cervical cancer screening guidelines.
  • 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 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 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).
  • 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 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

Sites / Locations

  • Smilow Cancer Hospital at Yale New Haven

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Active Comparator

No Intervention

Arm Label

imiquimod + 9-valent HPV vaccine

imiquimod only

observation only (control)

Arm Description

Participants 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.

Participants randomized to the imiquimod only group will receive instruction on imiquimod self application (16 week course) at the baseline visit.

Participants randomized to the control group will only be observed and will receive no intervention.

Outcomes

Primary Outcome Measures

Incidence of Objective Response
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

Incidence of HPV Clearance
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.

Full Information

First Posted
August 4, 2016
Last Updated
September 6, 2023
Sponsor
Yale University
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1. Study Identification

Unique Protocol Identification Number
NCT02864147
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
Study Type
Interventional

2. Study Status

Record Verification Date
September 2023
Overall Recruitment Status
Completed
Study Start Date
July 2016 (undefined)
Primary Completion Date
May 24, 2022 (Actual)
Study Completion Date
November 22, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Yale University

4. Oversight

Data Monitoring Committee
Yes

5. Study Description

Brief Summary
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Cervical Intraepithelial Neoplasia, Cervical Dysplasia

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
Participant
Allocation
Randomized
Enrollment
134 (Actual)

8. Arms, Groups, and Interventions

Arm Title
imiquimod + 9-valent HPV vaccine
Arm Type
Experimental
Arm Description
Participants 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.
Arm Title
imiquimod only
Arm Type
Active Comparator
Arm Description
Participants randomized to the imiquimod only group will receive instruction on imiquimod self application (16 week course) at the baseline visit.
Arm Title
observation only (control)
Arm Type
No Intervention
Arm Description
Participants randomized to the control group will only be observed and will receive no intervention.
Intervention Type
Drug
Intervention Name(s)
9-valent HPV vaccine
Intervention Description
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.
Intervention Type
Drug
Intervention Name(s)
Imiquimod
Intervention Description
At the baseline visit, this group will be instructed about the correct method of self-application of imiquimod 6.25mg as a vaginal suppository and receive a 16 week course of the drug.
Primary Outcome Measure Information:
Title
Incidence of Objective Response
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.
Time Frame
Between weeks 20 and 24 (approximately week 22)
Secondary Outcome Measure Information:
Title
Incidence of HPV Clearance
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.
Time Frame
Between weeks 20 and 24 (approximately week 22)

10. Eligibility

Sex
Female
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
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 10 weeks. Patients must have signed an approved informed consent. Patients of childbearing potential must have a negative urine pregnancy test within 7 days prior to the study entry and be practicing an effective form of contraception. Patients must be at least 18 years of age based on previous and current cervical cancer screening guidelines. 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 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 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). 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 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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alessandro D Santin, MD
Organizational Affiliation
Yale University School of Medicine Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Oncology
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Sangini S Sheth, MD, MPH
Organizational Affiliation
Yale University School of Medicine Department of Obstetrics, Gynecology & Reproductive Sciences, Division of Gynecologic Specialties
Official's Role
Principal Investigator
Facility Information:
Facility Name
Smilow Cancer Hospital at Yale New Haven
City
New Haven
State/Province
Connecticut
ZIP/Postal Code
06510
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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

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