Phase 1 Trial of Ipilimumab and GVAX in Patients With Metastatic Castration-resistant Prostate Cancer

A Phase 1 Dose Escalation Trial of Ipilimumab in Combination With CG1940 and CG8711 in Patients With Metastatic Hormone-Refractory Prostate Cancer

Ipilimumab, an antibody that blocks cytotoxic T-lymphocyte antigen 4, and GVAX have demonstrated anti-tumor activity in prostate cancer. Pre-clinical studies with this combination have demonstrated potent synergy. The purpose of this study is to investigate, using a phase-I 3+3 dose escalation design followed by an expansion cohort, the safety and efficacy of combined treatment with GVAX and ipilimumab in castration-resistant metastatic prostate cancer (CRPC) patients.

A promising immunotherapeutic approach in prostate cancer is whole-cell vaccination. Irradiated allogeneic tumor cells expressing GM-CSF generate a long-lasting and specific anti-tumor immunity in preclinical models. Results from several phase I and II trials showed Prostate GVAX (GVAX) to be well tolerated and suggested improved survival. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) is a crucial immune checkpoint molecule that down-regulates T-cell activation and proliferation. Ipilimumab, a fully human monoclonal antibody (IgG1) that blocks CTLA-4, promotes antitumor immunity, and has been demonstrated in two phase III trials to improve overall survival in metastatic melanoma patients. Pre-clinical studies of the anti-CTLA-4 antibody in combination with GM-CSF secreting tumor cell vaccines demonstrated a potent synergy. In this phase I study the investigators examine in CRPC patients whether ipilimumab can be safely combined with GVAX. In addition, the investigators will treat an additional 16 patients at a dose level of 3•0 mg/kg to determine the safety profile and antitumor effects of GVAX and ipilimumab in patients with CRPC.

Inclusion Criteria:

• Males age 18-80 years
• Histologic diagnosis of adenocarcinoma of the prostate
• Metastatic prostate cancer deemed to be unresponsive or refractory to hormone therapy
• Detectable metastases by bone scan, CT scan or MRI
• Two consecutive rising PSA values obtained at least two weeks apart and both obtained at least 4-6 weeks after discontinuation of hormone therapy. Second PSA value must be > 5.0 ng/mL. LHRH agonist should not be discontinued.
• Testosterone < 50 ng/dL. Must have had orchiectomy or is currently receiving an LHRH agonist.
• WBC > 3.0 x 109/L, ANC > 1.5 x 109/L, hemoglobin > 6.2 mmol/L, and platelets > 100 x 109/L
• Serum creatinine < 177 umol/L Bilirubin < 1.5 times the upper limit of normal AST < 3 times the upper limit of normal
• ECOG performance status 0-2
• Life expectancy of at least 6 months
• If sexually active, willing to use barrier contraception during the treatment phase of the protocol
• The ability to understand and willingness to sign a written informed consent

Exclusion Criteria:

• Transitional cell, small cell, neuroendocrine, or squamous cell prostate cancer
• Bone pain severe enough to require routine narcotic analgesia use
• Clinical evidence of brain metastases or history of brain metastases
• Seropositive for HIV, Hepatitis B antigen positive and/or Hepatitis C viremic
• Prior chemotherapy or immunotherapy for prostate cancer
• Radiation therapy within 4 weeks of the first treatment
• Surgery within 4 weeks of the first treatment. Must have recovered from all side effects.
• Flutamide within 4 weeks of the first treatment Megesterol acetate (Megace), finasteride (Proscar), bicalutamide (Casodex),nilutamide, aminoglutethimide, ketoconazole or diethylstilbestrol within 6 weeks of the first treatment.
• Systemic corticosteroid use within 4 weeks of the first treatment
• History of autoimmune disease
• History of another malignancy, except for the following: adequately treated basal cell or squamous cell skin cancer, superficial bladder cancer, adequately treated Stage I or II cancer currently in complete remission or any other cancer that has been in complete remission for at least 5 years