title: Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients.
abstract: OBJECTIVE
  Vascular endothelial growth factor receptor (VEGFR) and epidermal growth factor receptor (EGFR) play a significant role in glioblastoma angiogenesis and proliferation, making tyrosine kinase (TK) receptors logical targets for treatment. We evaluated AEE788, a reversible TK inhibitor that inhibits EGFR and VEGFR, in recurrent glioblastoma patients.
  
  
  METHODS
  In this dose-escalation, phase I study, patients with recurrent glioblastoma received AEE788 once daily in 28-day cycles in stratified subgroups: those receiving (1) non-enzyme-inducing anticonvulsants drugs or no anticonvulsants (Group A) and (2) enzyme-inducing anticonvulsant drugs (Group B). A dose-expansion phase stratified patients by surgical eligibility. Primary objectives were to determine dose-limiting toxicity (DLT) and maximum tolerated dose; secondary objectives included evaluating (1) safety/tolerability, (2) pharmacokinetics, and (3) preliminary antitumor activity.
  
  
  RESULTS
  Sixty-four glioblastoma patients were enrolled. Two Group A patients experienced DLTs (proteinuria and stomatitis) at 550 mg; 550 mg was, therefore, the highest dose evaluated and dose limiting. One Group B patient receiving 800 mg experienced a DLT (diarrhea). The initially recommended dose for dose-expansion phase for Group A was 400 mg; additional patients received 250 mg to assess the hepatotoxicity. Most frequently reported adverse events (AEs) included diarrhea and rash. Serious AEs, most commonly grade 3/4 liver function test elevations, were responsible for treatment discontinuation in 17% of patients. AEE788 concentrations were reduced by EIACD. The best overall response was stable disease (17%).
  
  
  CONCLUSIONS
  Continuous, once-daily AEE788 was associated with unacceptable toxicity and minimal activity for the treatment of recurrent glioblastoma. The study was, therefore, discontinued prematurely.
authors.affiliation: Center for Neuro-Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, SW-460F, Boston, MA 02215, USA. David_Reardon@DFCI.harvard.edu
authors.forename: David A
authors.initials: DA
authors.lastname: Reardon
authors.forename: Charles A
authors.initials: CA
authors.lastname: Conrad
authors.forename: Timothy
authors.initials: T
authors.lastname: Cloughesy
authors.forename: Michael D
authors.initials: MD
authors.lastname: Prados
authors.forename: Henry S
authors.initials: HS
authors.lastname: Friedman
authors.forename: Kenneth D
authors.initials: KD
authors.lastname: Aldape
authors.forename: Paul
authors.initials: P
authors.lastname: Mischel
authors.forename: Jane
authors.initials: J
authors.lastname: Xia
authors.forename: Clifford
authors.initials: C
authors.lastname: DiLea
authors.forename: Jerry
authors.initials: J
authors.lastname: Huang
authors.forename: William
authors.initials: W
authors.lastname: Mietlowski
authors.forename: Margaret
authors.initials: M
authors.lastname: Dugan
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: W K Alfred
authors.initials: WK
authors.lastname: Yung
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000032:analysis; D001932:Brain Neoplasms / Q000188:drug therapy*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011687:Purines / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*
chemical_list: D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; D011687:Purines; D066246:ErbB Receptors; D040262:Receptors, Vascular Endothelial Growth Factor; C489254:AEE 788