title: A phase I/II study of erlotinib in combination with the anti-insulin-like growth factor-1 receptor monoclonal antibody IMC-A12 (cixutumumab) in patients with advanced non-small cell lung cancer.
abstract: BACKGROUND
  This phase I/II study evaluated the safety and antitumor effect of the combination of erlotinib with cixutumumab, a recombinant fully humanized anti-insulin-like growth factor-1 receptor IgG1 monoclonal antibody, in advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with advanced NSCLC were treated in an initial safety-lead and drop-down cohorts using erlotinib 150 mg/d with cixutumumab 6 or 5 mg/kg on days 1, 8, 15, and 22 in 28-day cycles (cohorts 1 and 2). Emerging pharmacokinetic data led to an additional cohort (3 + 3 design) with cixutumumab at 15 mg/kg on day 1 in 21-day cycles (cohort 3).
  
  
  RESULTS
  Eighteen patients entered the study (6 at 6 mg/kg, 8 at 5 mg/kg, and 4 at 15 mg/kg), with median age of 65 years. Four of six patients at 6 mg/kg experienced dose-limiting toxicities (DLTs), whereas at 5 mg/kg, one of eight patients experienced DLT but three of eight patients still required a dose delay during cycle 1. At 15 mg/kg every 21 days, two of four patients experienced DLTs. In all cohorts, DLTs were either G3 rash or fatigue. Five patients had stable disease as best response and 14 patients had progressive disease. The median progression-free survival was 39 days (range 21-432+ days). Biomarkers analyses showed a trend toward better progression-free survival seen with higher free baseline insulin-like growth factor-1 levels as seen with other insulin-like growth factor-1R inhibitors.
  
  
  CONCLUSIONS
  The combinations of cixutumumab at 6 mg/kg every 7 days and 15 mg/kg every 21 days and full-dose erlotinib are not tolerable in unselected patients with NSCLC, as measured by DLT. Cixutumumab at 5 mg/kg every 7 days was tolerable per DLT, but dose delays were common. Efficacy in unselected patients with NSCLC seems to be low.
authors.affiliation: University of Colorado Cancer Center, Aurora, Colorado 80045, USA. andrew.weickhardt@ucdenver.edu
authors.forename: Andrew
authors.initials: A
authors.lastname: Weickhardt
authors.forename: Robert
authors.initials: R
authors.lastname: Doebele
authors.forename: Ana
authors.initials: A
authors.lastname: Oton
authors.forename: Janice
authors.initials: J
authors.lastname: Lettieri
authors.forename: DeLee
authors.initials: D
authors.lastname: Maxson
authors.forename: Michele
authors.initials: M
authors.lastname: Reynolds
authors.forename: Amy
authors.initials: A
authors.lastname: Brown
authors.forename: Mary K
authors.initials: MK
authors.lastname: Jackson
authors.forename: Grace
authors.initials: G
authors.lastname: Dy
authors.forename: Araba
authors.initials: A
authors.lastname: Adjei
authors.forename: Gerald
authors.initials: G
authors.lastname: Fetterly
authors.forename: Xian
authors.initials: X
authors.lastname: Lu
authors.forename: Wilbur
authors.initials: W
authors.lastname: Franklin
authors.forename: Marileila
authors.initials: M
authors.lastname: Varella-Garcia
authors.forename: Fred R
authors.initials: FR
authors.lastname: Hirsch
authors.forename: Murry W
authors.initials: MW
authors.lastname: Wynes
authors.forename: Hagop
authors.initials: H
authors.lastname: Youssoufian
authors.forename: Alex
authors.initials: A
authors.lastname: Adjei
authors.forename: D Ross
authors.initials: DR
authors.lastname: Camidge
mesh_terms: D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000556:secondary; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011799:Quinazolines / Q000627:therapeutic use*; D017526:Receptor, IGF Type 1 / Q000037:antagonists & inhibitors*; D012189:Retrospective Studies; D016896:Treatment Outcome
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C557414:cixutumumab; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D017526:Receptor, IGF Type 1