Phase I/IIa Trial of Folate Binding Protein Vaccine in Ovarian Cancer

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 multicenter, phase I/IIa 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 ovarian, endometrial, fallopian, or peritoneal 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 one month 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. Up to 15 patients will be
vaccinated at the OBD.

Additionally, the E39-vaccinated patients will be randomized to receive either E39 or J65 (an
attenuated version of E39) as a booster to promote long-term E39-specific immunity. The
clinical endpoints are long-term FBP immunity, time to recurrence from date of enrollment and
5-year survival rate. Those individuals who are eligible to receive the vaccine, but who
decline and all HLA-A2- patients will be followed clinically as matched controls for disease
recurrence/progression

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 5 years 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 December 2014 followed by a
five-year follow-up period. The duration of the trial is expected to be seven years.

Inclusion Criteria:

Patients will be included in the study based on the following criteria. (Enrollment may
commence 1 month from completion of standard primary therapies and up to two years after
completion of treatment.)

1. Ovarian or endometrial, fallopian and peritoneal cancer

2. Completion of primary first-line therapies (i.e., surgery, chemotherapy, immunotherapy
and radiation therapy as appropriate per standard of care for patient's specific
cancer)

3. Stage I-IV but no evidence of disease (NED) after completion of primary therapies

4. Post-menopausal or rendered surgically infertile

5. HLA-A2+ patients will receive the vaccine; HLA-A2- patients will be eligible to
participate in the control group

6. Good performance status (Karnofsky > 60%, ECOG ≤ 2)

7. CBC, CMP, and CA-125 within 2 months of enrollment

8. Capable of informed consent

Exclusion Criteria:

Patients will be excluded from the study based on the following criteria:

1. Receiving immunosuppressive therapy to include chemotherapy, steroids, or methotrexate

2. Not post-menopausal or not rendered surgically infertile

3. Pregnancy

4. In poor health (Karnofsky < 60%, ECOG > 2)

5. Tbili > 1.5, creatinine > 2, hemoglobin < 10, platelets < 50,000, WBC < 2,000

6. Active interstitial lung disease; asthma requiring more than as needed bronchodilators
for management; or other autoimmune lung disease

7. Involved in other experimental protocols (except with permission of the other study PI
and completion of the other study dosing regimen)

8. History of autoimmune disease