Phase I pilot trial of the bispecific antibody MDXH210 (anti-Fc gamma RI Xanti-HER-2/neu) in patients whose prostate cancer overexpresses HER-2/neu

The goal of this study was to evaluate, in patients with prostate cancer, t he toxicity profle acid biologic activity of the bispecific antibody MDXH21 0, which has specificity for the non-ligand-binding site of the high-affini ty immunoglobulin G receptor (Fc gamma RI) and the extracellular. domain of the HER-2/neu photo-oncogene product. Patients with prostate cancer that e xpressed HER-2/neu were entered into a phase I dose-escalation trial of MDX H210. Patients received an intravenous infusion MDXH210 during a period of 2 h three times per week for 2 weeks and were monitored for toxicity. Pharm acokinetic and pharmacodynamic parameters were measured and included the bi ologic end points of monocyte-bound MDXH210, cytokine production, and clini cal response. Seven patients were treated with MDXH210 doses ranging from 1 to 8 mg/m(2). In general, MDXH210 was well tolerated, with only mild infus ion-related malaise, fever, chills, and myalgias. No dose-limiting toxic ef fects were observed. Biologic effects included induction of low plasma conc entrations of tumor necrosis factor-alpha and interleukin-6 observed immedi ately after MDXH210 infusion and 70% saturation of circulating monocyte-ass ociated Fc gamma RT with MDXH210 at a dose level of 4 to 8 mg/m(2). Five of six patients had stable prostate-specific antigen levels during the course of 40 days or more. Circulating plasma HER-2/neu levels decreased by 80% a t days 12 and 29 (p = 0.03 and 0.06, respectively, by the Wilcoxon signed r ank test). MDXH210 can be given safely to patients with HER-2/neu-positive prostate cancer in doses of at least 8 mg/m(2). At the doses studied, biolo gic activity was demonstrated and characterized by binding of MDXH210 to ci rculating monocytes, release of monocyte-derived cytokines, a decrease in c irculating HER-2/neu, and short-term stabilization of prostate-specific ant igen levels.