title: Phase I-IIa study of BMS-690514, an EGFR, HER-2 and -4 and VEGFR-1 to -3 oral tyrosine kinase inhibitor, in patients with advanced or metastatic solid tumours.
abstract: OBJECTIVE
  BMS-690514 is a potent, reversible oral inhibitor of epidermal growth factor receptor (EGFR/HER-1), HER-2 and -4, and vascular endothelial growth factor receptors (VEGFRs)-1 to -3 offering targeted inhibition of tumour growth and vascularisation in a single agent. This phase I-IIa study was designed to identify the maximum tolerated dose (MTD) and assess safety, antitumour activity, pharmacokinetics and pharmacodynamics of BMS-690514.
  
  
  METHODS
  In phase I, patients with advanced solid tumours received escalating doses of once-daily BMS-690514. In phase IIa, erlotinib-naïve (cohort A) or erlotinib-resistant (cohort B) patients with advanced non-small-cell lung cancer (NSCLC) received BMS-690514 once-daily at the MTD.
  
  
  RESULTS
  In phase I (n=28), the MTD was determined to be 200mg daily. BMS-690514 was rapidly absorbed and highly metabolised after repeated oral administration with minimum drug accumulation. In phase IIa (n=62), the most frequent treatment-related adverse events were diarrhoea and acneiform rash. Adverse events that led to >1 discontinuation were diarrhoea (n=4; 4%) and rash (n=2; 2%). Disease control (≥4months) and objective response rates, respectively, were 43.3% and 3.3% (cohort A) and 22.6% and 3.2% (cohort B). Six of 21 (29%) NSCLC patients with wild-type EGFR achieved disease control versus seven of 10 (70%) patients with EGFR mutations (including T790M). At MTD, BMS-690514 modulated pharmacodynamic biomarkers associated with inhibition of VEGFR- and EGFR-signalling pathways.
  
  
  CONCLUSIONS
  This phase I-IIa study suggests that BMS-690514 has manageable safety profile and antitumour activity in patients with NSCLC at 200mg/d, including those with EGFR mutations conferring resistance to erlotinib.
authors.affiliation: SITEP, Institut Gustave Roussy, South-Paris University, Villejuif, France. soria@igr.fr
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Soria
authors.forename: José
authors.initials: J
authors.lastname: Baselga
authors.forename: Nasser
authors.initials: N
authors.lastname: Hanna
authors.forename: Scott A
authors.initials: SA
authors.lastname: Laurie
authors.forename: Rastislav
authors.initials: R
authors.lastname: Bahleda
authors.forename: Enriqueta
authors.initials: E
authors.lastname: Felip
authors.forename: Emiliano
authors.initials: E
authors.lastname: Calvo
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Armand
authors.forename: Frances A
authors.initials: FA
authors.lastname: Shepherd
authors.forename: Christopher T
authors.initials: CT
authors.lastname: Harbison
authors.forename: David
authors.initials: D
authors.lastname: Berman
authors.forename: Jong-Soon
authors.initials: JS
authors.lastname: Park
authors.forename: Steven
authors.initials: S
authors.lastname: Zhang
authors.forename: Blisse
authors.initials: B
authors.lastname: Vakkalagadda
authors.forename: John F
authors.initials: JF
authors.lastname: Kurland
authors.forename: Ashutosh K
authors.initials: AK
authors.lastname: Pathak
authors.forename: Roy S
authors.initials: RS
authors.lastname: Herbst
mesh_terms: D000284:Administration, Oral; D000328:Adult; D000368:Aged; D019540:Area Under Curve; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D003967:Diarrhea / Q000139:chemically induced; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005076:Exanthema / Q000139:chemically induced; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D008297:Male; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010880:Piperidines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D047428:Protein Kinase Inhibitors / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011758:Pyrroles / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D011799:Quinazolines / Q000627:therapeutic use; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors; D016896:Treatment Outcome; D014227:Triazines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000037:antagonists & inhibitors; D040321:Vascular Endothelial Growth Factor Receptor-3 / Q000037:antagonists & inhibitors
chemical_list: D066246:ErbB Receptors; D000069347:Erlotinib Hydrochloride; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014227:Triazines; D040281:Vascular Endothelial Growth Factor Receptor-1; D040321:Vascular Endothelial Growth Factor Receptor-3; C552150:BMS-690514