Cervical Dysplasia, Cervical Intraepithelial Neoplasia
Conditions
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.
Interventions
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.
DRUGImiquimod
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.
Sponsors
Yale University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Subject)
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Objective Response | Between weeks 20 and 24 (approximately week 22) | 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
| Measure | Time frame | Description |
|---|---|---|
| Incidence of HPV Clearance | Between weeks 20 and 24 (approximately week 22) | 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Observation Only (Control) Participants randomized to the control group will only be observed and will receive no intervention. | 45 |
| Imiquimod Only Participants randomized to the imiquimod only group will receive instruction on imiquimod self application (16 week course) at the baseline visit.
Imiquimod: 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. | 45 |
| Imiquimod + 9-valent HPV Vaccine 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.
9-valent HPV vaccine: 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.
Imiquimod: 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. | 43 |
| Total | 133 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 | 0 |
| Overall Study | Lost to Follow-up | 0 | 4 | 0 |
| Overall Study | Opted for excisional procedures | 0 | 0 | 3 |
| Overall Study | Physician Decision | 0 | 0 | 1 |
| Overall Study | Pregnancy | 4 | 0 | 0 |
| Overall Study | Withdrawal by Subject | 3 | 2 | 1 |
Baseline characteristics
| Characteristic | Observation Only (Control) | Imiquimod Only | Imiquimod + 9-valent HPV Vaccine | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 45 Participants | 45 Participants | 43 Participants | 133 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 5 Participants | 5 Participants | 19 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 35 Participants | 36 Participants | 38 Participants | 109 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 4 Participants | 0 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 2 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 8 Participants | 4 Participants | 16 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 6 Participants | 1 Participants | 12 Participants |
| Race (NIH/OMB) White | 33 Participants | 28 Participants | 34 Participants | 95 Participants |
| Region of Enrollment United States | 45 participants | 45 participants | 43 participants | 133 participants |
| Sex: Female, Male Female | 45 Participants | 45 Participants | 43 Participants | 133 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 45 | 0 / 43 |
| other Total, other adverse events | 5 / 45 | 38 / 45 | 36 / 43 |
| serious Total, serious adverse events | 0 / 45 | 0 / 45 | 1 / 43 |
Outcome results
Primary
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.
Time frame: Between weeks 20 and 24 (approximately week 22)
Population: Complete case analysis.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imiquimod + 9-valent HPV Vaccine | Incidence of Objective Response | Histologic regression (HR) | 32 Participants |
| Imiquimod + 9-valent HPV Vaccine | Incidence of Objective Response | Histologic remission (HM) | 0 Participants |
| Imiquimod + 9-valent HPV Vaccine | Incidence of Objective Response | Persistent Disease (PR) | 6 Participants |
| Imiquimod + 9-valent HPV Vaccine | Incidence of Objective Response | Progressive Disease (PD) | 0 Participants |
| Imiquimod Only | Incidence of Objective Response | Progressive Disease (PD) | 0 Participants |
| Imiquimod Only | Incidence of Objective Response | Histologic regression (HR) | 36 Participants |
| Imiquimod Only | Incidence of Objective Response | Persistent Disease (PR) | 2 Participants |
| Imiquimod Only | Incidence of Objective Response | Histologic remission (HM) | 0 Participants |
| Observation Only (Control) | Incidence of Objective Response | Progressive Disease (PD) | 0 Participants |
| Observation Only (Control) | Incidence of Objective Response | Histologic remission (HM) | 0 Participants |
| Observation Only (Control) | Incidence of Objective Response | Persistent Disease (PR) | 8 Participants |
| Observation Only (Control) | Incidence of Objective Response | Histologic regression (HR) | 30 Participants |
p-value: 0.043Fisher Exact
p-value: 0.384Fisher Exact
Secondary
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.
Time frame: Between weeks 20 and 24 (approximately week 22)
Population: Complete case analysis- 2 participants in imiquimod + 9-valent HPV vaccine were not assessed at follow up.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Imiquimod + 9-valent HPV Vaccine | Incidence of HPV Clearance | HPV Negative | 18 Participants |
| Imiquimod + 9-valent HPV Vaccine | Incidence of HPV Clearance | HPV Positive | 18 Participants |
| Imiquimod Only | Incidence of HPV Clearance | HPV Negative | 24 Participants |
| Imiquimod Only | Incidence of HPV Clearance | HPV Positive | 14 Participants |
| Observation Only (Control) | Incidence of HPV Clearance | HPV Negative | 19 Participants |
| Observation Only (Control) | Incidence of HPV Clearance | HPV Positive | 19 Participants |
p-value: 0.177Fisher Exact
p-value: 0.592Fisher Exact