phase 1 trial of ipilimumab and gvax in patients with metastatic castration-resistant prostate cancer

Conditions: Prostate Cancer

Summary: 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.

Eligibility criteria:
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

Keywords: gvax ipilimumab prostate cancer