HPV Vaccine, Imiquimod, and Metformin Combination Trial

Inclusion Criteria:

• Participants must have histologically confirmed locally advanced or metastaticcervical carcinoma (Stage IB2-IVB), vaginal, or vulvar carcinoma (Stage II-IVB), ANDnot be considered a primary surgical candidate. Patients offered neoadjuvant therapymay be enrolled if they respond and receive chemoradiation.

• Participants must have measurable disease, per Recist criteria. See Section 12 (Measurement of Effect) for the evaluation of measurable disease. Radiologicalevaluation shall occur within approximately 30 days prior to enrollment initiationand start of radiation.

• Participants must have an Eastern Cooperative Oncology Group (ECOG) performancestatus of ≤ 2

• Participants must be ≥ 18 years of age

• Participants must have adequate organ function within 28 days of registration,defined as follows: - Absolute neutrophil count ≥ 1,500/µL - Platelets ≥ 100,000/µL

• Hemoglobin ≥ 9 g/dL - Serum creatinine ≤ 1.5 x upper limit of normal (ULN) - Totalbilirubin ≤ 1.5 x ULN (≤2.0 in patients with known Gilberts syndrome) OR directbilirubin ≤ 1 x ULN - Aspartate aminotransferase and alanine aminotransferase ≤ 2.5x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN

• Participants receiving corticosteroids may continue as long as their dose is stablefor at least 4 weeks prior to initiating protocol therapy.

• Participant must agree to not donate blood during the study or for 90 days after thelast dose of study treatment.

• Female participants of childbearing potential must have a negative serum pregnancytest within 14 days prior to registration. Females of non-childbearing potential isdefined as follows (by other than medical reasons): - ≥45 years of age and has nothad menses for >1 year, post-hysterectomy, post-bilateral oophorectomy, postexternal beam radiation of 6 Gy to the pelvis, or post-tubal ligation.

• Participants must agree to not breastfeed during the study.

• Participants must be able to understand the study procedures and agree toparticipate in the study by providing written informed consent

• Participants must be eligible for chemoradiation treatment in the opinion of thetreating investigator.

• Participants who are HIV+ must have CD4 counts >200/dL and demonstratedocumented Highly active antiretroviral therapy (HAART) compliance m. Participantmust have CT (chest/abdomen/pelvis) or PET-CT, within 56 days of registration.

• Participants must be newly diagnosed.

• Standard chemoradiation using external beam radiation therapy (EBRT) andbrachytherapy is permitted for cervical or vaginal carcinoma, and chemoradiationwith EBRT for vulvar carcinoma. A lesion must be readily accessible for intratumoraltumor injection.

• ECOG performance status ≤2 (Karnofsky ≥60%, see Appendix A).

• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBVviral load must be undetectable on suppressive therapy, if indicated.

• Patients with a history of hepatitis C virus (HCV) infection must have been treatedand cured. For patients with HCV infection who are currently on treatment, they areeligible if they have an undetectable HCV viral load.

• Patients with treated brain metastases are eligible if follow-up brain imaging aftercentral nervous system (CNS)-directed therapy shows no evidence of progression.

• Patients with a prior or concurrent malignancy whose natural history or treatmentdoes not have the potential to interfere with the safety or efficacy assessment ofthe investigational regimen are eligible for this trial.

Exclusion Criteria:

• Patients who are receiving any other investigational agents.

• Patients who have untreated, new or progressive brain metastases or leptomeningealdisease.

• History of allergic reactions attributed to compounds of similar chemical orbiologic composition to agents used in study.

• Patients with uncontrolled intercurrent illness.

• Patients with psychiatric illness/social situations that would limit compliance withstudy requirements.

• Pregnant women are excluded from this study because cervical carcinoma or vulvacarcinoma patients have undergone treatment rendering the patient infertile. Becausethere is an unknown but potential risk for adverse events in nursing infantssecondary to treatment of the mother with cervical carcinoma or vulva carcinoma,breastfeeding should be discontinued.