title: Safety, pharmacokinetics and pharmacodynamics of the anti-A33 fully-human monoclonal antibody, KRN330, in patients with advanced colorectal cancer.
abstract: OBJECTIVE
  The objective of this first-in-human trial included the safety, maximum tolerated dose (MTD), pharmacokinetics, immunogenicity and antitumour effects of KRN330, a novel fully-human monoclonal antibody directed against A33, a membrane bound glycoprotein uniformly expressed in 95% of colorectal cancers.
  
  
  METHODS
  Patients with advanced or metastatic colorectal cancer (CRC) refractory to standard therapy were eligible. Twenty-nine patients received weekly intravenous KRN330 (0.1-10mg/kg) for a minimum of 4 weeks in a standard 3+3 design, and nine patients received q2 week doses at 3mg/kg with pre- and post-biopsies to evaluate tumour binding and safety on this schedule.
  
  
  RESULTS
  The most common KRN330 related adverse events (all grades) were nausea (66%), diarrhoea (61%) and vomiting (47%). The MTD was 3mg/kg weekly, with dose-limiting grade 3 gastrointestinal toxicities at 10mg/kg and the intermediate dose level of 6 mg/kg. Pharmacokinetics of KRN330 was linear. Stable disease was reported in 12/38 patients (32%), with a median duration of 155 days. There was no evidence of human anti-human antibodies, and immunohistochemistry on biopsy samples demonstrated that KRN330 remained bound to tumour 2 weeks after dosing.
  
  
  CONCLUSIONS
  KRN330 is safe and tolerable at the MTD of 3mg/kg once weekly in patients with advanced CRC. Dosing on alternate weeks is supported by tumour binding. The long treatment durations and lack of immunogenicity warrant further investigation of KRN330 in combination.
authors.affiliation: Sarah Cannon Research Institute/Tennessee Oncology, PLLC, Nashville, TN 37203, USA. jinfante@tnonc.com
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Infante
authors.forename: Johanna C
authors.initials: JC
authors.lastname: Bendell
authors.forename: Laura Williams
authors.initials: LW
authors.lastname: Goff
authors.forename: Suzanne F
authors.initials: SF
authors.lastname: Jones
authors.forename: Emily
authors.initials: E
authors.lastname: Chan
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Sudo
authors.forename: Howard A
authors.initials: HA
authors.lastname: Burris
authors.forename: Jordan D
authors.initials: JD
authors.lastname: Berlin
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D019540:Area Under Curve; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008562:Membrane Glycoproteins / Q000276:immunology*; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009325:Nausea / Q000139:chemically induced; D009362:Neoplasm Metastasis; D013997:Time Factors; D016896:Treatment Outcome; D014839:Vomiting / Q000139:chemically induced
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C104258:GPA33 protein, human; D008562:Membrane Glycoproteins; C581257:KRN-330