Phase Ib Trial of Folate Binding Protein Vaccine in Ovarian Cancer

• Safety and Local/Systemic Toxicity [ Time Frame: Duration of the vaccine series ] [ Designated as safety issue: Yes ]
  Standard local and systemic toxicities will be collected and graded per the National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03 toxicity scale. For the vaccine series (one vaccine/month for six months), patients will be monitored closely for one hour after vaccine inoculation with questioning, serial exams and vital signs every 15 minutes to observe for a hypersensitivity reaction. Patients will also return to the clinic 48-72 hours after each inoculation for questioning regarding systemic toxicity and to examine and measure inoculation site local reactions.
  
  

• Disease-free survival [ Time Frame: Disease-free survival up to 36 months ] [ Designated as safety issue: No ]
  Disease-free survival (DFS) for all patients regardless of randomization will be determined by the patients' own physicians at the individual study sites during routine follow-up screening. This will occur every three months for the first 24 months after diagnosis and then every six months for an additional 36 months.
  
  

In this study, investigators intend to assess the safety and document local and systemic toxicity to the folate binding protein (FBP) peptide vaccine E39 + GM-CSF given in the adjuvant setting. Investigators also intend to determine the maximum tolerated dose (MTD) and optimal biologic dose (OBD) for the peptide vaccine, as well as evaluate the in vivo cellular immune response to the vaccine. Time to recurrence in the vaccinated patients vs. matched controls will be tracked.

The primary endpoints are the safety and optimal dosing of the vaccine to induce an in vivo peptide-specific immune response. The clinical endpoint is time to recurrence from date of enrollment.

The study will be a multi-center, phase Ib trial of the FBP peptide E39 + GM-CSF. The target study population is female civilian and military health care beneficiaries over the age of 18 years with a diagnosis of FBP+ ovarian or endometrial cancer who have undergone primary surgical and medical therapies, are post-menopausal or have surgically induced menopause, and are currently without evidence of disease. Disease-free subjects after standard of care multi-modality therapy will be screened and HLA typed since the E39 vaccine is specific for HLA-A2+ patients (approximately 40% of the US population). HLA-A2-patients will be followed as prospective clinically matched controls for recurrence.

HLA-A2+ patients who meet all other eligibility criteria will be tested for biomarkers that indicate progression/recurrence of ovarian and advanced uterine cancer FBP. FBP+ and HLA-A2+ patients will be vaccinated with the FBP peptide (E39) and GM-CSF. HLA-A2-negative patients and those individuals who are eligible to receive the vaccine but who decline will be followed clinically as matched controls for disease recurrence/progression.

Treatment will begin within 14 days of the subject enrollment in the study and confirmation of eligibility. The 1 ml by volume vaccine will be administered intradermally in 0.5 mL inoculums at two different sites within 5 cm of each other. A total of six vaccinations will be given every 3-4 weeks and will be administered in the same lymph node draining area. The dose escalation scheme is for three patients to receive each of the doses: 100, 500, and 1,000 mcg of peptide. Patients will be enrolled consecutively. An additional three patients may receive a given a dose depending on the presence of dose limiting toxicity (DLT). Prior to the fourth vaccination, each patient will be assessed for liver, renal, and hematopoietic function. If organ function is stable and no DLT is seen, then the patient will continue with the series. After the last patient in a given dose group has completed the third inoculation and organ function is proven stable, then the next dose group will be initiated. Optimal biologic dose (OBD) is defined as the minimum dose of the vaccine that gives the most optimal and lasting in vivo immunologic response to the vaccinated peptide. Six patients will be vaccinated at the OBD.

Subjects will be followed for safety issues, immunologic response and clinical recurrence. Subjects will be monitored 48-72 hours after each inoculation for reaction to the inoculation as well as documentation of any adverse effects experienced. Immunologic response will be documented with both ex vivo phenotypic and functional assays as well as in vivo delayed type hypersensitivity (DTH) reactions. All patients will be followed for a total of 36 months to document disease-free status.

The investigators intend to enroll up to 60 patients will be enrolled study-wide (15-24 in the vaccine arm, up to 36 in the control arm). With accrual beginning in April 2012 enrollment of the last patient is anticipated to occur in April 2014 followed by a three-year follow-up period. The duration of the trial is expected to be five years.