title: 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.
abstract: 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, biological effects and possible therapeutic effect of MDX-H210 with G-CSF. MDX-H210 is a F(ab)' x F(ab)' humanized bispecific murine antibody that binds to both HER2/neu and the FcgammaR1 receptor (CD64), and was administered intravenously weekly for three doses followed by a 2-week break and then three more weekly doses. A total of 23 patients were treated, and doses were escalated from 1 mg/m2 to 40 mg/m2 with no MTD reached. The toxicity of the bsAb + G-CSF combination was modest, with no dose-limiting toxicity noted: 19 patients had fevers, 7 patients had diarrhea, and 3 patients had allergic reactions that did not limit therapy. The beta-elimination half-life varied from 4 h to 8 h at doses up to 20 mg/m2. Significant release of cytokines interleukin-6, G-CSF, and tumor necrosis factor alpha was observed after administration of bsAb. Circulating monocytes disappeared within 1 h of bsAb infusion, which correlated with binding of bsAb, noted by flow-cytometric analysis. Significant levels of human anti-(bispecific antibody) were measured in the plasma of most patients by the third infusion. No objective clinical responses were seen in this group of heavily pre-treated patients.
authors.affiliation: USC/Norris Comprehensive Cancer Center, Los Angeles, CA 90049, USA.
authors.forename: V
authors.initials: V
authors.lastname: Pullarkat
authors.forename: Y
authors.initials: Y
authors.lastname: Deo
authors.forename: J
authors.initials: J
authors.lastname: Link
authors.forename: L
authors.initials: L
authors.lastname: Spears
authors.forename: V
authors.initials: V
authors.lastname: Marty
authors.forename: R
authors.initials: R
authors.lastname: Curnow
authors.forename: S
authors.initials: S
authors.lastname: Groshen
authors.forename: C
authors.initials: C
authors.lastname: Gee
authors.forename: J S
authors.initials: JS
authors.lastname: Weber
mesh_terms: D000328:Adult; D000368:Aged; D000818:Animals; D018033:Antibodies, Bispecific / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D001943:Breast Neoplasms / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D015850:Interleukin-6 / Q000097:blood; D051379:Mice; D008875:Middle Aged; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000096:biosynthesis / Q000276:immunology*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D018033:Antibodies, Bispecific; D016179:Granulocyte Colony-Stimulating Factor; D015850:Interleukin-6; D018719:Erb-b2 Receptor Tyrosine Kinases; D014409:Tumor Necrosis Factor-alpha