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506592 
Journal Article 
A phase I study of the angiogenesis inhibitor SU5416 (semaxanib) in solid tumours, incorporating dynamic contrast MR pharmacodynamic end points 
O'Donnell, A; Padhani, A; Hayes, C; Kakkar, AJ; Leach, M; Trigo, JM; Scurr, M; Raynaud, F; Phillips, S; Aherne, W; Hardcastle, A; Workman, P; Hannah, A; Judson, I 
2005 
Yes 
British Journal of Cancer
ISSN: 0007-0920
EISSN: 1532-1827 
93 
8 
876-883 
English 
SU5416 (Z-3-[(2,4-dimethylpyrrol-5-yl) methylidenyl]-2-indolinone; semaxanib) is a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR2). A Phase I dose escalation study was performed. Dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) was used as a pharmacodynamic assessment tool. In all, 27 patients were recruited. SU5416 was administered twice weekly by fixed rate intravenous infusion. Patients were treated in sequential cohorts of three patients at 48, 65, 85 110 and 145 mg m(-2). A further dose level of 190 mg m(-2) after a 2-week lead in period at a lower dose was completed; thereafter, the cohort at 145 mg m(-2) was expanded. SU5416 showed linear pharmacokinetics to 145 mg m(-2) with a large volume of distribution and rapid clearance. A significant degree of interpatient variability was seen. SU5416 was well tolerated, by definition a maximum-tolerated dose was not defined. No reproducible changes were seen in DCE-MRI end points. Serial assessments of VEGF in a cohort of patients treated at 145 mg m(-2) did not show a statistically significant treatment-related change. Parallel assessments of the impact of SU5416 on coagulation profiles in six patients showed a transient effect within the fibrinolytic pathway. Clinical experience showed that patients who had breaks of therapy longer than a week could not have treatment reinitiated at a dose of 190 mg m(-2) without unacceptable toxicity. The 145 mg m(-2) dose level is thus the recommended dose for future study. 
antiangiogenic therapy; phase I clinical trial; pharmacokinetics; pharmacodynamics; endothelial growth-factor; antiangiogenic agent su5416; hippel-lindau-syndrome; tyrosine kinase; cancer-patients; carcinoma; therapy; patient; vegf