Phase I dose-escalation trial of tremelimumab in combination with bicalutamide in patients with recurrent prostate cancer.

Abstract

174 Background: Antibodies targeting CTLA-4 have demonstrated anti-tumor efficacy in human clinical trials. The mechanism of this effect is presumably in part mediated by the expansion of tumor-specific T cells. Androgen deprivation (AD), the cornerstone of treatment for patients with metastatic prostate cancer, has been demonstrated to cause prostate tissue apoptosis and lymphocytic inflammation. We hypothesized that treatment with AD, followed by an anti-CTLA-4 antibody, could have benefit by augmenting a tumor-specific immune response elicited with AD. We report the initial results from the dose-escalation portion of a phase I trial evaluating tremelimumab in combination with high-dose bicalutamide. Methods: Eligible patients were those with clinical stage D0 prostate cancer (rising serum PSA but no evidence of metastatic disease). Subjects were treated in two courses, 3 months apart, in which they received bicalutamide 150 mg daily for 28 days and tremelimumab on day 29. Patients were treated in cohorts of six, defined by tremelimumab dose (3 mg/kg, 6 mg/kg, 10 mg/kg, 15 mg/kg). The primary endpoint of the trial was safety. Secondary endpoints included measures of PSA kinetics and identification of a maximum tolerated dose (MTD). Results: Eleven patients were enrolled and completed the dose-escalation portion of the trial and at least one year of follow up. Dose-limiting toxicities (DLTs) were observed in 2/5 subjects treated at 6 mg/kg, and included grade 3 diarrhea and a grade 3 skin rash. One of six subjects treated at 3 mg/kg tremelimumab required hospitalization for colitis. No other grade 3 or grade 4 events were observed. Common grade 1/2 events included fatigue, hot flashes, diarrhea, abdominal discomfort, rash, pruritis, and gynecomastia. Two patients experienced a prolongation in PSA doubling time detectable months after completing treatment. Conclusions: Tremelimumab, administered at 3 mg/kg every 3 months in combination with AD, was found to be the MTD and with reasonable safety in this population. The identification of patients with prolonged stable disease following treatment suggests that future studies could explore repetitive administration of this combination. [Table: see text]