Trial of Autologous, Hapten-Modified Vaccine, OVAX, in Patients With Relapsed Stage III or IV Ovarian Cancer

OVax®: A Feasibility Study Using a DNP-Modified Autologous Ovarian Tumor Cell Vaccine as Therapy in Ovarian Cancer Patients After Relapse:

To determine if a vaccine made from the patient's own tumor tissue can stimulate an immune response against the patient's tumor cells. To determine the safety of the vaccine.

To study the toxicity, safety and DTH response of DNP-modified autologous ovarian tumor cell vaccine and the DTH response to unmodified ovarian tumor cells in patients with relapsed ovarian cancer:

• To determine the tolerability and toxicity of the treatment regimen
• To determine whether O-Vax induces a DTH response to autologous, DNP-modified ovarian cancer cells
• To determine whether O-Vax induces a DTH response to autologous, unmodified ovarian cancer cells

Study Population: Patients with recurrent epithelial ovarian cancer whose therapeutic tumor surgery provides a mass which yields adequate tumor cells for vaccine preparation and delayed-type hypersensitivity (DTH) testing

Study Design: A Phase I/IIa double-blind, three-dose, multi-center study

Investigational Product: O-Vax: DNP-modified autologous ovarian tumor cell vaccine

Dosage Form: Cell suspension

Route of Administration: Intradermal

Dosage and Treatment Schedule: Prior to enrollment in the study, one dose of 5 x 106 modified and one dose of 5 x 106 unmodified autologous ovarian cancer cells will be administered, to establish a negative DTH response at baseline. Three dosing regimens will be used: 5 x 105, 2.5 x 106, or 5 x 106 DNP-modified autologous ovarian tumor cells. An initial dose of DNP-modified autologous ovarian tumor cells* followed by cyclophosphamide then weekly doses of DNP-modified autologous ovarian tumor cells mixed with Bacillus of Calmette and Guérin (BCG) for 6 weeks, and completed with one dose of DNP-modified autologous ovarian tumor cells mixed with BCG as a 6 month booster if adequate cells

• count determined prior to aliquoting for cryopreservation

Endpoints: Treatment-emergent and related adverse events, serious adverse events, and Grade 3 and 4 laboratory abnormalities

Other Parameters:

• Delayed-type hypersensitivity skin reactions for assessing the induction of immune responses to DNP-modified and unmodified autologous ovarian tumor cells
• CA-125 levels
• Survival
• Exploratory analysis incorporating in vitro analysis of lymphocytes separated from patient blood samples

Duration of Treatment: Up to 6 months

Duration of Subject Participation in Study: Three months from the patient's last vaccine

Duration of Follow-up: Survival information will be collected via phone or visit on a quarterly basis for each patient beginning 30 days after the last scheduled visit

Number of Subjects Required to Meet Protocol Objectives: 42 evaluable subjects

Number of Study Centers: 4-5

Number of Individual Blood Draws: 13 draws over nine months

Volume of Blood Drawn: 11 Draws of 30 mL/draw (total 360 mL) and two draws of 50mL in heparinized tubes

Inclusion Criteria:

Screening Phase

• Stage III or IV adenocarcinoma of ovary
• Candidate for surgery to excise the tumor
• Signed informed consent for tumor acquisition

Treatment Phase

• At least 18 years of age
• Standard surgical debulking to maximum extent possible
• Adequate amount of tumor tissue obtained from surgical debulking to prepare a series of vaccines and skin test materials.
• Administration of intraperitoneal chemotherapy following surgical debulking Intraperitoneal drug to consist of a taxane (paclitaxel or docetaxel) Dose of taxane: paclitaxel=60-75 mg/m2 / weekly x 4 or docetaxel = 25 mg/m2 - weekly x 4
• Vaccines and DTH materials pass lot release
• Minimum of 2 weeks and maximum of 6 weeks following last dose of intraperitoneal chemotherapy
• Immunocompetent, as determined by anergy panel performed 1 week after last dose of intraperitoneal chemotherapy (baseline PPD+ patients allowed)
• Expected survival of at least 6 months
• Karnofsky performance status ³ 80
• Signed informed consent for protocol participation

Exclusion Criteria:

• Alkaline phosphatase > 2.5 x ULN
• Total bilirubin > 2.0 mg/dL
• Creatinine > 2.0 mg/dL
• Hemoglobin < 10.0 g/dL
• WBC < 3,000 /mm3
• Platelet count < 100,000/mm3
• Major field radiotherapy within 6 months prior to participation in the study
• Brain metastases, unless successfully treated at least 6 months prior to entry
• Prior immunotherapy (interferons, tumor necrosis factor, other cytokines [e.g., interleukins], biological response modifiers, or monoclonal antibodies) within 4 weeks prior to participation in the study
• Prior splenectomy
• Concurrent use of systemic steroids (Note: Topical steroid therapies [applied to the skin] are not contraindicated for participation in the study, provided these are not applied to either arm. Inhaled aerosol steroids are not contraindicated for participation in the study.)
• Concurrent use of immunosuppressive drugs
• Concurrent use of antitubercular drugs (isoniazid, rifampin, streptomycin)
• Other malignancy within 5 years except curatively treated non-melanomatous skin cancer and curatively treated carcinoma in situ of the uterine cervix
• Concurrent autoimmune diseases, e.g., systemic lupus erythematosus, multiple sclerosis or ankylosing spondylitis
• Concurrent medical condition that would preclude compliance or immunologic response to study treatment
• Concurrent serious infection or other serious medical condition
• Receipt of any investigational medication within 4 weeks prior to participation in the study
• Known gentamicin sensitivity
• Anergic, defined by the inability to make a DTH to at least one of the following: candida, mumps, tetanus, trichophyton (based upon availability), or PPD
• Vaccine lot release failure