Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-β tyrosine kinase inhibitor, in patients with recurrent glioblastoma

Tracy T. Batchelor, Elizabeth R. Gerstner, Xiaobu Ye, Serena Desideri, Daniel G. Duda, David Peereboom, Glenn J. Lesser, Sajeel Chowdhary, Patrick Y. Wen, Stuart Grossman, Jeffrey G. Supko

Research output: Contribution to journalArticlepeer-review

Abstract

Background. Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-β is expressed on most endothelial cells in glioblastoma specimens. Methods. We report the results of feasibility, phase I, and phase II studies of tandutinib (MLN518), an orally bioavailable inhibitor of type III receptor tyrosine kinases including PDGF receptor-β, Fms-like tyrosine kinase 3, and c-Kit in patients with recurrent glioblastoma. Results. In an initial feasibility study, 6 patients underwent resection for recurrent glioblastoma after receiving tandutinib 500mg twice daily for 7 days. The mean ratio of tandutinib concentration in brain tumor-to-plasma was 13.1 ± 8.9 in 4 of the 6 patients. In the phase I study, 19 patients were treated at 500, 600, and 700mg twice daily dose levels. The maximum tolerated dose was found to be 600mg twice daily, and 30 patients were treated with this dose in the phase II study. The trial was closed after interim analysis, as the prespecified goal of patients alive and progression-free survival at 6 months was not achieved. Biomarker studies suggested that tandutinib treatment could lead to vascular disruption rather than normalization, which was associated with rapid progression. Conclusions. Tandutinib readily distributed into the brain following oral administration and achieved concentrations within the tumor that exceed the corresponding concentration in plasma. The phase II study was closed at interim analysis due to lack of efficacy, although this study was not enriched for glioblastomas with alterations of the PDGF pathway.

Original languageEnglish (US)
Pages (from-to)567-575
Number of pages9
JournalNeuro-oncology
Volume19
Issue number4
DOIs
StatePublished - Apr 1 2017

Keywords

  • Glioblastoma
  • Overall survival
  • Platelet-derived growth factor receptor
  • Progression-free survival
  • Tandutinib

ASJC Scopus subject areas

  • Oncology
  • Clinical Neurology
  • Cancer Research

Fingerprint

Dive into the research topics of 'Feasibility, phase I, and phase II studies of tandutinib, an oral platelet-derived growth factor receptor-β tyrosine kinase inhibitor, in patients with recurrent glioblastoma'. Together they form a unique fingerprint.

Cite this