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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Reardon, DA; Conrad, CA; Cloughesy, T; Prados, MD; Friedman, HS; Aldape, KD; Mischel, P; Xia, J; DiLea, C; Huang, J; Mietlowski, W; Dugan, M; Chen, W; Yung, WKA

Published Date

  • June 2012

Published In

Volume / Issue

  • 69 / 6

Start / End Page

  • 1507 - 1518

PubMed ID

  • 22392572

Pubmed Central ID

  • 22392572

Electronic International Standard Serial Number (EISSN)

  • 1432-0843

Digital Object Identifier (DOI)

  • 10.1007/s00280-012-1854-6

Language

  • eng

Conference Location

  • Germany