Fh. Valone et al., PHASE IA IB TRIAL OF BISPECIFIC ANTIBODY MDX-210 IN PATIENTS WITH ADVANCED BREAST OR OVARIAN-CANCER THAT OVEREXPRESSES THE PROTOONCOGENE HER-2/NEU/, Journal of clinical oncology, 13(9), 1995, pp. 2281-2292
Purpose: MDX-210 is a bispecific antibody that binds simultaneously to
type I Fc receptors for immunoglobulin G (IgG) (Fc gamma RI) and to t
he 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 overexp
ressed HER-S/neo were eligible for treatment. Cohorts of three patient
s 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 to
lerated, with most patients experiencing transient grade 1 to 2 fevers
, malaise, and hypotension only. Two patients experienced transient gr
ade 3 hypotension at 10.0 mg/m(2). Transient monocytopenia and lymphop
enia 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) satura
ted 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 i
s greater than the concentration for optimal monocyte/macrophage activ
ation in vitro. Elevated plasma levels of the monocyte products tumor
necrosis factor alpha (TNF alpha), interleukin-6 (IL-6), granulocyte c
olony-stimulating factor (G-CSF), and neopterin were observed with max
imal levels at doses greater than or equal to 7.0 mg/m(2), Localizatio
n of MDX-210 in tumor tissue was demonstrated in two patients. One par
tial and one mixed tumor response were observed among 10 assessable pa
tients. Conclusion: MDX-210 is immunologically active at well-tolerate
d doses, The MTD and OBD is 7 to 10 mg/m(2). (C) 1995 by American Soci
ety of Clinical Oncology.