title: Phase 1b study of motesanib, an oral angiogenesis inhibitor, in combination with carboplatin/paclitaxel and/or panitumumab for the treatment of advanced non-small cell lung cancer.
abstract: OBJECTIVE
  Motesanib is a small-molecule antagonist of vascular endothelial growth factor receptor 1, 2, and 3, platelet-derived growth factor receptor, and Kit. This phase 1b study assessed the safety, maximum tolerated dose (MTD), and pharmacokinetics, and explored the objective response of motesanib plus carboplatin/paclitaxel and/or the fully human anti-epidermal growth factor receptor monoclonal antibody panitumumab in advanced non-small cell lung cancer (NSCLC).
  
  
  METHODS
  Patients with unresectable NSCLC received sequentially escalating doses of motesanib [50, 125 mg once daily; 75 mg twice daily] orally continuously plus carboplatin/paclitaxel (arm A; first line) or panitumumab (arm B; first and second line) once every 21-day cycle or 125 mg once daily plus carboplatin/paclitaxel and panitumumab (arm C; first line).
  
  
  RESULTS
  Forty-five patients received motesanib. Three dose-limiting toxicities occurred: grade 4 pulmonary embolism (n = 1; arm A, 50 mg once daily) and grade 3 deep vein thrombosis (n = 2; arm A, 125 mg once daily; arm C). The MTD was 125 mg once daily. Common motesanib-related adverse events were fatigue (60% of patients), diarrhea (53%), hypertension, (38%), anorexia (27%), and nausea (22%). Three cases of cholecystitis occurred but only in the 75-mg twice-daily schedule, which was subsequently discontinued. At 125 mg once daily, motesanib pharmacokinetics were not markedly changed with carboplatin/paclitaxel coadministration; however, exposure to paclitaxel was moderately increased. The objective response rates were 17%, 0%, and 17% in arms A, B, and C, respectively.
  
  
  CONCLUSIONS
  Treatment with motesanib was tolerable when combined with carboplatin/paclitaxel and/or panitumumab, with little effect on motesanib pharmacokinetics at the 125-mg once daily dose level. This dose is being investigated in an ongoing phase 3 study in NSCLC.
authors.affiliation: The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. gblumens@mdanderson.org
authors.forename: George R
authors.initials: GR
authors.lastname: Blumenschein
authors.forename: Karen
authors.initials: K
authors.lastname: Reckamp
authors.forename: G Joe
authors.initials: GJ
authors.lastname: Stephenson
authors.forename: Timothy
authors.initials: T
authors.lastname: O'Rourke
authors.forename: Gregory
authors.initials: G
authors.lastname: Gladish
authors.forename: Jesse
authors.initials: J
authors.lastname: McGreivy
authors.forename: Yu-Nien
authors.initials: YN
authors.lastname: Sun
authors.forename: Yining
authors.initials: Y
authors.lastname: Ye
authors.forename: Mandy
authors.initials: M
authors.lastname: Parson
authors.forename: Alan
authors.initials: A
authors.lastname: Sandler
mesh_terms: D000328:Adult; D000368:Aged; D020533:Angiogenesis Inhibitors / Q000008:administration & dosage*; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D016190:Carboplatin / Q000008:administration & dosage; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D005260:Female; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000188:drug therapy*; D008297:Male; D008875:Middle Aged; D009536:Niacinamide / Q000009:adverse effects / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000627:therapeutic use; D009841:Oligonucleotides; D017239:Paclitaxel / Q000008:administration & dosage; D000077544:Panitumumab; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D020533:Angiogenesis Inhibitors; D000911:Antibodies, Monoclonal; D007211:Indoles; D009841:Oligonucleotides; D009536:Niacinamide; D000077544:Panitumumab; D016190:Carboplatin; D040262:Receptors, Vascular Endothelial Growth Factor; C519562:imetelstat; D017239:Paclitaxel