SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110 mg/m(2) while stratum II started at 48 mg/m(2). Thirty-three eligible patients were treated on stratum I (n = 23) and stratum II (n = 10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas, and 2 choroid plexus carcinomas. The MTD in stratum I was initially estimated to be 110 mg/m(2). The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m(2) dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia, and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in stratum I were 26.1 +/- 12.5 l/hr/m(2), 41.9 +/- 21.4 l/m(2), and 1.11 +/- 0.41 hr, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum I patients.

Kieran, M., Supko, J., Wallace, D., Fruscio, R., Poussaint, T., Phillips, P., et al. (2009). Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors. PEDIATRIC BLOOD & CANCER, 52(2), 169-176 [10.1002/pbc.21873].

Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors

FRUSCIO, ROBERT;
2009

Abstract

SU5416 is a novel small molecule tyrosine kinase inhibitor of the VEGF receptors 1 and 2. A phase I dose escalation study stratified by concurrent use (stratum II) or absence (stratum I) of enzyme-inducing anticonvulsant drugs was undertaken to estimate the maximum-tolerated dose (MTD) and to describe the toxicity profile of SU5416 in pediatric patients with refractory brain tumors. Dose escalations were conducted independently for stratum I starting at 110 mg/m(2) while stratum II started at 48 mg/m(2). Thirty-three eligible patients were treated on stratum I (n = 23) and stratum II (n = 10). Tumor types included 23 glial tumors, 4 neural tumors, 4 ependymomas, and 2 choroid plexus carcinomas. The MTD in stratum I was initially estimated to be 110 mg/m(2). The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m(2) dose level but due to development of SU5416 being stopped by the sponsor, the trial was closed before completion. The most serious drug-related toxicities were grade 3 liver enzyme abnormalities, arthralgia, and hallucinations. The plasma pharmacokinetics of SU5416 was not significantly affected by the concurrent administration of enzyme-inducing anticonvulsant drugs. Mean values of the total body clearance, apparent volume of distribution, and terminal phase half-life of SU5416 for the 19 patients in stratum I were 26.1 +/- 12.5 l/hr/m(2), 41.9 +/- 21.4 l/m(2), and 1.11 +/- 0.41 hr, respectively. The plasma pharmacokinetics of SU5416 in children was similar to previously reported findings in adult cancer patients. Prolonged disease stabilization was observed in 4 of 16 stratum I patients.
Articolo in rivista - Articolo scientifico
Treatment Outcome; Male; Adolescent; Arthralgia; Receptors, Vascular Endothelial Growth Factor; Young Adult; Female; Maximum Tolerated Dose; Protein Kinase Inhibitors; Drug Therapy, Combination; Indoles; Humans; Central Nervous System Neoplasms; Anticonvulsants; Liver; Angiogenesis Inhibitors; Child; Hallucinations; Pyrroles; Drug Interactions
English
169
176
Kieran, M., Supko, J., Wallace, D., Fruscio, R., Poussaint, T., Phillips, P., et al. (2009). Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors. PEDIATRIC BLOOD & CANCER, 52(2), 169-176 [10.1002/pbc.21873].
Kieran, M; Supko, J; Wallace, D; Fruscio, R; Poussaint, T; Phillips, P; Pollack, I; Packer, R; Boyett, J; Blaney, S; Banerjee, A; Geyer, R; Friedman, H; Goldman, S; Kun, L; Macdonald, T
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/10281/14644
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