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.
Platelet-derived growth factor (PDGF) signaling is important in gliomagenesis and PDGF receptor-β is expressed on most endothelial cells in glioblastoma specimens.



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.



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.



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.
Departments of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Tracy T
TT
Batchelor
Departments of Neurology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.|Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Elizabeth R
ER
Gerstner
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Xiaobu
X
Ye
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Serena
S
Desideri
Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Daniel G
DG
Duda
Cleveland Clinic, Cleveland, Ohio, USA.
David
D
Peereboom
Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, North Carolina, USA.
Glenn J
GJ
Lesser
Moffitt Cancer Center, Tampa, Florida, USA.
Sajeel
S
Chowdhary
Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
Patrick Y
PY
Wen
Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Stuart
S
Grossman
Division of Hematology and Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA.
Jeffrey G
JG
Supko
D000284:Administration, Oral; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000097:blood; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D018572:Disease-Free Survival; D005260:Female; D005909:Glioblastoma / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006801:Humans; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D010879:Piperazines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D011799:Quinazolines / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D020797:Receptor, Platelet-Derived Growth Factor beta / Q000037:antagonists & inhibitors*; D014018:Tissue Distribution; D016896:Treatment Outcome
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D010879:Piperazines; D011799:Quinazolines; C464670:tandutinib; D020797:Receptor, Platelet-Derived Growth Factor beta
glioblastoma; overall survival; platelet-derived growth factor receptor; progression-free survival; tandutinib
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