title: A phase-I trial of the epidermal growth factor receptor directed bispecific antibody MDX-447 without and with recombinant human granulocyte-colony stimulating factor in patients with advanced solid tumors.
abstract: BACKGROUND
  MDX-447 is a bispecific antibody directed against the epidermal growth factor receptor (EGFR) and the high affinity Fc receptor (FcgammaRI). Preclinical data suggest that co-administration of granulocyte-colony stimulating factor (G-CSF) may enhance the tumor cytotoxicity of bispecific antibodies.
  
  
  METHODS
  In group 1, patients received MDX-447 intravenously (i.v.) weekly. Dose levels of MDX-447 evaluated in group 1 were 1, 3.5, 7, 10, 15, 20, 30, and 40 mg/m(2). In group 2, patients received MDX-447 IV weekly with G-CSF (3 mcg/kg/day) subcutaneously (days -3 to +2, 5-9, 12-16, etc.). Dose levels of MDX-447 evaluated in group 2 were 1, 3.5, 7, 10, and 15 mg/m(2).
  
  
  RESULTS
  Sixty-four patients with advanced solid tumors were treated. Forty-one patients received MDX-447 alone (group 1); 23 patients received MDX-447 + G-CSF (group 2). Hypotension was the predominant dose-limiting toxicity (DLT) in both treatment groups, with seven patients experiencing >or= grade 3 events. MDX-447 half-life (T(1/2)) ranged from 1.9 to 8.4 h, with no obvious differences between the two treatment groups. MDX-447 binding to neutrophils and peak levels of circulating tumor necrosis factor alpha (TNFalpha) and interleukin-6 (IL-6) were higher in group 2. The MTD for MDX-447 alone was 30 mg/m(2). When G-CSF was given with MDX-447, treatment was not well tolerated and group 2 was closed early because of safety concerns, with the last patient being treated at the 7 mg/m(2) dose level. There were no objective complete or partial responses in either group.
  
  
  CONCLUSIONS
  MDX-447 alone was generally well tolerated, but did not achieve objective tumor responses. The MTD for MDX-447 alone was 30 mg/m(2) weekly. Co-administration of G-CSF with MDX-447 precluded meaningful dose escalation.
authors.affiliation: Division of Solid Tumor Oncology, Head and Neck Medical Oncology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Matthew G
authors.initials: MG
authors.lastname: Fury
authors.forename: Allan
authors.initials: A
authors.lastname: Lipton
authors.forename: Katherine M
authors.initials: KM
authors.lastname: Smith
authors.forename: Corinne B
authors.initials: CB
authors.lastname: Winston
authors.forename: David G
authors.initials: DG
authors.lastname: Pfister
mesh_terms: D000328:Adult; D018033:Antibodies, Bispecific / Q000008:administration & dosage* / Q000009:adverse effects; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000009:adverse effects; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage* / Q000009:adverse effects; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D009369:Neoplasms / Q000188:drug therapy*; D011994:Recombinant Proteins
chemical_list: D018033:Antibodies, Bispecific; D000911:Antibodies, Monoclonal; D016207:Cytokines; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; D066246:ErbB Receptors