Dataset Information

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

ABSTRACT:

Background

Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-? 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-?, 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.

SUBMITTER: Batchelor TT

PROVIDER: S-EPMC5464374 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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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.

Batchelor Tracy T TT Gerstner Elizabeth R ER Ye Xiaobu X Desideri Serena S Duda Daniel G DG Peereboom David D Lesser Glenn J GJ Chowdhary Sajeel S Wen Patrick Y PY Grossman Stuart S Supko Jeffrey G JG

Neuro-oncology 20170401 4

<h4>Background</h4>Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-β is expressed on most endothelial cells in glioblastoma specimens.<h4>Methods</h4>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.<h4>Results</h4>In an initial feas ...[more]

PMID: 27663390

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