PHASE IA/IB TRIAL OF BISPECIFIC ANTIBODY MDX-210 IN PATIENTS WITH ADVANCED BREAST OR OVARIAN-CANCER THAT OVEREXPRESSES THE PROTOONCOGENE HER-2/NEU

Purpose: MDX-210 is a bispecific antibody that binds simultaneously to type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to the HER-2/neu oncogene protein product. MDX-210 effectively directs Fc gamma RI-positive effector cells such as monocytes and macrophages to phagocytose or kill tumor cells that overexpress HER-2/neo. The goals of this phase la/lb trial were to determine the maximum-tolerated dose (MTD) and/or the optimal biologic dose (OBD) of MDX-210. Patients and Methods: Patients with advanced breast or ovarian cancer that overexpressed HER-S/neo were eligible for treatment. Cohorts of three patients received a single intravenous (IV) infusion of MDX-210 at increasing dose levels from 0.35 to 10.0 mg/m(2). Results: Treatment was well tolerated, with most patients experiencing transient grade 1 to 2 fevers, malaise, and hypotension only. Two patients experienced transient grade 3 hypotension at 10.0 mg/m(2). Transient monocytopenia and lymphopenia developed at 1 to 2 hours, but no other hematologic changes were observed. Doses of MDX-210 greater than or equal to 3.5 mg/m(2) saturated greater than or equal to 80% of monocyte Fc gamma RI and produced peak plasma concentrations greater than or equal to 1 mu g/mL, which is greater than the concentration for optimal monocyte/macrophage activation in vitro. Elevated plasma levels of the monocyte products tumor necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte colony-stimulating factor (G-CSF), and neopterin were observed with maximal levels at doses greater than or equal to 7.0 mg/m(2), Localization of MDX-210 in tumor tissue was demonstrated in two patients. One partial and one mixed tumor response were observed among 10 assessable patients. Conclusion: MDX-210 is immunologically active at well-tolerated doses, The MTD and OBD is 7 to 10 mg/m(2). (C) 1995 by American Society of Clinical Oncology.