Phase I study of AEE788, a novel multitarget inhibitor of ErbB- and VEGF-receptor-family tyrosine kinases, in recurrent glioblastoma patients

Cancer Chemother Pharmacol. 2012 Jun;69(6):1507-18. doi: 10.1007/s00280-012-1854-6. Epub 2012 Mar 7.


Purpose: 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.

Publication types

  • Clinical Trial, Phase I

MeSH terms

  • Adult
  • Aged
  • Biomarkers, Tumor / analysis
  • Brain Neoplasms / drug therapy*
  • ErbB Receptors / antagonists & inhibitors*
  • Female
  • Glioblastoma / drug therapy*
  • Humans
  • Male
  • Middle Aged
  • Neoplasm Recurrence, Local / drug therapy*
  • Protein Kinase Inhibitors / therapeutic use*
  • Purines / adverse effects
  • Purines / pharmacokinetics
  • Purines / therapeutic use*
  • Receptors, Vascular Endothelial Growth Factor / antagonists & inhibitors*


  • Biomarkers, Tumor
  • Protein Kinase Inhibitors
  • Purines
  • ErbB Receptors
  • Receptors, Vascular Endothelial Growth Factor
  • AEE 788