Phase II study of sunitinib malate in patients with recurrent high-grade glioma.
Receptor tyrosine kinase signaling causes profound neo-angiogenesis in high-grade gliomas (HGG). The KIT, PDGFR-α, and VEGFR2 genes are frequently amplified and expressed in HGG and are molecular targets for therapeutic inhibition by the small-molecule kinase inhibitor sunitinib malate. Twenty-one patients with progressive HGG after prior radiotherapy and chemotherapy received a daily dose of 37.5 mg sunitinib until progression or unacceptable toxicity. Magnetic resonance imaging (MRI) and dynamic susceptibility contrast (DSC)-enhanced perfusion measurements were performed before and during therapy. Cerebral blood volume (CBV) and cerebral blood flow (CBF) lesion-to-normal-white matter ratios were measured to evaluate the antiangiogenic effects of sunitinib. The most frequent grade ≥3 adverse events were skin toxicity, neutropenia, thrombocytopenia, and lymphocytopenia. None of the patients achieved an objective response, whereas a decrease in CBV and CBF within the lesion compared with the normal brain was documented in four out of 14 (29%) patients evaluable for DSC-enhanced perfusion measurements. All patients experienced progression of their disease before or after eight weeks of therapy. Median time-to-progression and overall survival were 1.6 (95%CI 0.8-2.5) and 3.8 (95% CI 2.2-5.3) months, respectively. No correlation could be established between VEGFR2, PDGFR-α, and KIT gene copy numbers or protein expression and the effects of sunitinib. Single-agent sunitinib at 37.5 mg/day had insufficient activity to warrant further investigation of this monotherapy regimen in recurrent HGG.
Neyns
B
B
Department of Medical Oncology, UZ Brussel, Laarbeeklaan 101, 1090 Brussels, Belgium. Bart.Neyns@uzbrussel.be
Sadones
J
J
Chaskis
C
C
Dujardin
M
M
Everaert
H
H
Lv
S
S
Duerinck
J
J
Tynninen
O
O
Nupponen
N
N
Michotte
A
A
De Greve
J
J
D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D016543:Central Nervous System Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D002560:Cerebrovascular Circulation; D018450:Disease Progression; D005260:Female; D005910:Glioma / Q000175:diagnosis / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D007211:Indoles / Q000627:therapeutic use*; D008279:Magnetic Resonance Imaging / Q000379:methods; D008297:Male; D008875:Middle Aged; D049268:Positron-Emission Tomography; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D011758:Pyrroles / Q000627:therapeutic use*; D011760:Pyrrolidinones; D017479:Receptors, Platelet-Derived Growth Factor / Q000378:metabolism; D012008:Recurrence; D012039:Regional Blood Flow / Q000187:drug effects; D000077210:Sunitinib; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism
C554672:5-((3-fluoromethoxy)phenyl)-3-(1-phenylethylamino)-1-(4-trifluoromethylphenyl)pyrrolidin-2-one; D000970:Antineoplastic Agents; D007211:Indoles; D011758:Pyrroles; D011760:Pyrrolidinones; D019009:Proto-Oncogene Proteins c-kit; D017479:Receptors, Platelet-Derived Growth Factor; D040301:Vascular Endothelial Growth Factor Receptor-2; D000077210:Sunitinib