HPV L1 Vaccine in Combination with Imiquimod and Metformin for the Treatment of Locally Advanced and Metastatic Cervical, Vaginal and Vulvar Cancers Undergoing Chemoradiation

Inclusion Criteria

• Participants must have histologically confirmed locally advanced or metastatic cervical carcinoma (stage IB2-IVB), vaginal, or vulvar carcinoma (stage II-IVB), AND not be considered a primary surgical candidate. Patients offered neoadjuvant therapy may be enrolled if they respond and receive chemoradiation
• Participants must have measurable disease, defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as ≥ 10 mm (≥ 1 cm) with CT scan, magnetic resonance imaging (MRI), or calipers by clinical exam. Radiological evaluation shall occur within approximately 30 days prior to enrollment initiation and start of radiation
• Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
• Participants must be ≥ 18 years of age
• Absolute neutrophil count ≥ 1,500/uL (within 28 days of registration)
• Platelets ≥ 100,000/uL (within 28 days of registration)
• Hemoglobin ≥ 9 g/dL (within 28 days of registration)
• Serum creatinine ≤ 1.5 x upper limit of normal (ULN) or calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault equation (within 28 days of registration)
• Total bilirubin ≤ 1.5 x ULN (≤ 2.0 in patients with known Gilbert syndrome) OR direct bilirubin ≤ 1 x ULN (within 28 days of registration)
• Aspartate aminotransferase and alanine aminotransferase ≤ 2.5 x ULN unless liver metastases are present, in which case they must be ≤ 5 x ULN (within 28 days of registration)
• Participants receiving corticosteroids may continue as long as their dose is stable for least 4 weeks prior to initiating protocol therapy
• Participant must agree to not donate blood during the study or for 90 days after the last dose of study treatment
• Female participants of childbearing potential must have a negative serum pregnancy test within 14 days prior to registration. Pregnancy test should be repeated within 7 days before CT simulation if more than 14 days has passed since the previous pregnancy test. (If serum test is falsely positive, pregnancy can be excluded by appropriate pelvic imaging.) Patient must agree to abstain from activities that could result in pregnancy from screening through completion of 7 days of pelvic radiotherapy. Females of non-childbearing potential is defined as follows (by other than medical reasons): ≥ 45 years of age and has not had menses for > 1 year, post-hysterectomy, post-bilateral oophorectomy, post external beam radiation of 6 Gy to the pelvis, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by a physical exam or imaging
• Participants must agree to not breastfeed during the study and for 180 days after the last dose of study treatment
• Participants must be able to understand the study procedures and agree to participate in the study by providing written informed consent
• Participants must be eligible for chemoradiation treatment in the opinion of the treating investigator
• Participants who are HIV+ must have CD4 counts > 200/dL and demonstrate documented highly active antiretroviral therapy (HAART) compliance. Participant must have CT (chest/abdomen/pelvis) or PET-CT, within 56 days of registration
• Participants must be newly diagnosed
• Standard chemoradiation using EBRT and brachytherapy is permitted for cervical or vaginal carcinoma, and chemoradiation with EBRT for vulvar carcinoma. A lesion must be readily accessible for intratumoral tumor injection
• ECOG performance status ≤ 2 (Karnofsky ≥ 60%)
• For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
• Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
• Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression
• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
• Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better
• The effects of HPV L1 capsid vaccine in combination with imiquimod and metformin on the developing human fetus are unknown. For this reason, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• The trial medications are not anticipated to interact with concomitant medications, so medications interacting through CYP450 or P-glycoprotein do not exclude the patient from enrollment
• Participants must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria

• Patients who are receiving any other investigational agents
• Patients who have untreated, new or progressive brain metastases or leptomeningeal disease
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to agents used in study
• Patients with uncontrolled intercurrent illness
• Patients with psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because cervical carcinoma or vulva carcinoma patients have undergone treatment rendering the patient infertile. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with cervical carcinoma or vulva carcinoma, breastfeeding should be discontinued