title: A phase I study of anti-kinase insert domain-containing receptor antibody, IMC-1C11, in patients with liver metastases from colorectal carcinoma.
abstract: OBJECTIVE
  Angiogenesis plays an important role in colorectal cancer progression. Stimulation of vascular endothelial growth factor receptor (VEGFR), a transmembrane glycoprotein, results in endothelial mitogenesis. Within this family of receptors, VEGFR 2/kinase-insert-domain-containing receptor (KDR) appear to be principally up-regulated during tumorigenesis. A chimeric anti-KDR antibody, IMC-1C11, blocks VEGFR-KDR interaction and inhibits VEGFR-induced endothelial cell proliferation. This trial seeks to assess the safety, tolerability and feasibility of targeting an important pathway in tumorigenesis.
  
  
  METHODS
  In a dose-escalation, single-agent study of IMC-1C11, we enrolled 14 patients with colorectal carcinoma and hepatic metastases. Safety-, pharmacokinetic-, immunogenicity-, and magnetic resonance imaging-assessed alteration of vascular effects of IMC-1C11 were evaluated in this trial. IMC-1C11 was infused weekly at 0.2 mg/kg (n = 3), 0.6 mg/kg (n = 4), 2.0 mg/kg (n = 3), and 4.0 mg/kg (n = 4) for 4 weeks, which constituted a cycle.
  
  
  RESULTS
  No grade-3 or -4 IMC-1C11-related toxicities were observed. Minor grade-1 bleeding events were observed in four patients [0.2 mg/kg (n = 1) and 0.6 mg/kg (n = 3)]. Each resolved quickly and required no intervention. The starting dose of IMC-1C11 was selected to achieve a C(max) of approximately 5 micro g/ml. This concentration prevented KDR phosphorylation in vitro. Pharmacokinetic analysis demonstrated that the plasma t(1/2) and C(max) were dose dependent with a plasma t(1/2) of 67 +/- 3 h at the 4-mg/kg dose level. Human antichimeric antibodies were detected in 7 of 14 patients. The antibodies to IMC-1C11 inhibited the circulation of the agent in two patients. One patient had prolonged stable disease for seven cycles (28 weeks). The mean changes in tumor-influx volume-transfer constant k(in) (min(-1)) and enhancement factor after 4 weeks of therapy were significantly decreased compared with pretreatment values in 11 patients.
  
  
  CONCLUSIONS
  IMC-1C11 was both safe and well tolerated. Drug levels of IMC-1C11 were reliably predicted. Further clinical investigation of anti-VEGFR/KDR agents is warranted.
authors.affiliation: Department of Medicine, Division of Hematology/Oncology, Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, Alabama 35294-3300, USA. James.Posey@ccc.uab.edu
authors.forename: James A
authors.initials: JA
authors.lastname: Posey
authors.forename: Thian C
authors.initials: TC
authors.lastname: Ng
authors.forename: Baolian
authors.initials: B
authors.lastname: Yang
authors.forename: M B
authors.initials: MB
authors.lastname: Khazaeli
authors.forename: Mark D
authors.initials: MD
authors.lastname: Carpenter
authors.forename: Floyd
authors.initials: F
authors.lastname: Fox
authors.forename: Mike
authors.initials: M
authors.lastname: Needle
authors.forename: Harlan
authors.initials: H
authors.lastname: Waksal
authors.forename: Albert F
authors.initials: AF
authors.lastname: LoBuglio
mesh_terms: D000328:Adult; D000368:Aged; D000906:Antibodies / Q000737:chemistry*; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology*; D002455:Cell Division; D002478:Cells, Cultured; D015179:Colorectal Neoplasms / Q000473:pathology*; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000166:cytology; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism*; D007700:Kinetics; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000556:secondary*; D008279:Magnetic Resonance Imaging; D008297:Male; D008875:Middle Aged; D010477:Perfusion; D017434:Protein Structure, Tertiary; D013997:Time Factors; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000276:immunology*
chemical_list: D000906:Antibodies; D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; C480573:IMC1C11; D036341:Intercellular Signaling Peptides and Proteins; D040301:Vascular Endothelial Growth Factor Receptor-2