A phase I study of a HER2/neu bispecific antibody with granulocyte-colony-stimulating factor in patients with metastatic breast cancer that overexpresses HER2/neu

A phase I study of escalating doses of humanized bispecific antibody (bsAb) MDX-H210 with granulocyte-colony-stimulating factor (G-CSF) was conducted in patients with metastatic breast cancer that overexpressed HER2/neu. The main objectives of the study were to define the maximal tolerated dose (MTD ) of MDX-H210 when combined with G-CSF, to measure the pharmacokinetics of MDX-H210 when administered with G-CSF, and to determine the toxicity, biolo gical effects and possible therapeutic effect of MDX-H210 with G-CSF. MDX-H 210 is a F(ab)' x F(ab)' humanized bispecific murine antibody that binds to both HER2/neu and the Fc gamma R1 receptor (CD64), and was administered in travenously weekly for three doses followed by a 2-week break and then thre e more weekly doses. A total of 23 patients were treated, and doses were es calated from 1 mg/m(2) to 40 mg/m(2) with no MTD reached. The toxicity of t he bsAb + G-CSF combination was modest, with no dose-limiting toxicity note d: 19 patients had fevers, 7 patients had diarrhea, and 3 patients had alle rgic reactions that did not limit therapy. The beta-elimination half-life v aried from 4 h to 8 h at doses up to 20 mg/m(2) Significant release of cyto kines interleukin-6, G-CSF, and tumor necrosis factor cl was observed after administration of bsAb. Circulating monocytes disappeared within I h of bs Ab infusion, which correlated with binding of bsAb, noted by flow-cytometri c analysis. Significant levels of human anti-(bispecific antibody) were mea sured in the plasma of most patients by the third infusion. No objective cl inical responses were seen in this group of heavily pre-treated patients.