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

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.

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.