title: Phase I study of U3-1287, a fully human anti-HER3 monoclonal antibody, in patients with advanced solid tumors.
abstract: OBJECTIVE
  HER3 is a key dimerization partner for other HER family members, and its expression is associated with poor prognosis. This first-in-human study of U3-1287 (NCT00730470), a fully human anti-HER3 monoclonal antibody, evaluated its safety, tolerability, and pharmacokinetics in patients with advanced solid tumor.
  
  
  METHODS
  The study was conducted in 2 parts: part 1--sequential cohorts received escalating doses (0.3-20 mg/kg) of U3-1287 every 2 weeks, starting 3 weeks after the first dose; part 2--additional patients received 9, 14, or 20 mg/kg U3-1287 every 2 weeks, based on observed tolerability and pharmacokinetics from part 1. Recommended phase II dose, adverse event rates, pharmacokinetics, and tumor response were determined.
  
  
  RESULTS
  Fifty-seven patients (part 1: 26; part 2: 31) received U3-1287. As no dose-limiting toxicities were reported, the maximum-tolerated dose was not reached. The maximum-administered dose was 20 mg/kg every 2 weeks. The most frequent adverse events related to U3-1287 were fatigue (21.1%), diarrhea (12.3%), nausea (10.5%), decreased appetite (7.0%), and dysgeusia (5.3%). No patient developed anti-U3-1287 antibodies. In these heavily pretreated patients, stable disease was maintained 9 weeks or more in 19.2% in part 1 and 10 weeks or more in 25.8% in part 2.
  
  
  CONCLUSIONS
  U3-1287 treatment was well tolerated, and some evidence of disease stabilization was observed. Pharmacokinetic data support U3-1287 dosing of 9 to 20 mg/kg every 2 to 3 weeks. Combination studies of U3-1287 are ongoing.
authors.affiliation: Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201, USA. lorussop@karmanos.org
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: Moacyr
authors.initials: M
authors.lastname: Oliveira
authors.forename: Naiyer
authors.initials: N
authors.lastname: Rizvi
authors.forename: Lisa
authors.initials: L
authors.lastname: Malburg
authors.forename: Vicki
authors.initials: V
authors.lastname: Keedy
authors.forename: Lorrin
authors.initials: L
authors.lastname: Yee
authors.forename: Catherine
authors.initials: C
authors.lastname: Copigneaux
authors.forename: Thore
authors.initials: T
authors.lastname: Hettmann
authors.forename: Chi-Yuan
authors.initials: CY
authors.lastname: Wu
authors.forename: Agnes
authors.initials: A
authors.lastname: Ang
authors.forename: Abdel-Baset
authors.initials: AB
authors.lastname: Halim
authors.forename: Robert A
authors.initials: RA
authors.lastname: Beckman
authors.forename: Darrin
authors.initials: D
authors.lastname: Beaupre
authors.forename: Jordan
authors.initials: J
authors.lastname: Berlin
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D015415:Biomarkers / Q000378:metabolism; D000080908:Broadly Neutralizing Antibodies; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D011379:Prognosis; D020893:Receptor, ErbB-3 / Q000037:antagonists & inhibitors; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D057134:Antibodies, Neutralizing; D000970:Antineoplastic Agents; D015415:Biomarkers; D000080908:Broadly Neutralizing Antibodies; C585471:patritumab; D020893:Receptor, ErbB-3