title: Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors.
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.
authors.affiliation: Pediatric Neuro-Oncology Program, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. mark_kieran@dfci.harvard.edu
authors.forename: Mark W
authors.initials: MW
authors.lastname: Kieran
authors.forename: Jeffrey G
authors.initials: JG
authors.lastname: Supko
authors.forename: Dana
authors.initials: D
authors.lastname: Wallace
authors.forename: Robert
authors.initials: R
authors.lastname: Fruscio
authors.forename: Tina Young
authors.initials: TY
authors.lastname: Poussaint
authors.forename: Peter
authors.initials: P
authors.lastname: Phillips
authors.forename: Ian
authors.initials: I
authors.lastname: Pollack
authors.forename: Roger
authors.initials: R
authors.lastname: Packer
authors.forename: James M
authors.initials: JM
authors.lastname: Boyett
authors.forename: Susan
authors.initials: S
authors.lastname: Blaney
authors.forename: Anu
authors.initials: A
authors.lastname: Banerjee
authors.forename: Russ
authors.initials: R
authors.lastname: Geyer
authors.forename: Henry
authors.initials: H
authors.lastname: Friedman
authors.forename: Stewart
authors.initials: S
authors.lastname: Goldman
authors.forename: Larry E
authors.initials: LE
authors.lastname: Kun
authors.forename: Tobey
authors.initials: T
authors.lastname: Macdonald
mesh_terms: D000293:Adolescent; D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000927:Anticonvulsants / Q000627:therapeutic use; D018771:Arthralgia / Q000139:chemically induced; D016543:Central Nervous System Neoplasms / Q000188:drug therapy*; D002648:Child; D004347:Drug Interactions; D004359:Drug Therapy, Combination; D005260:Female; D006212:Hallucinations / Q000139:chemically induced; D006801:Humans; D007211:Indoles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D008099:Liver / Q000201:enzymology; D008297:Male; D020714:Maximum Tolerated Dose; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage* / Q000493:pharmacokinetics / Q000633:toxicity; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D020533:Angiogenesis Inhibitors; D000927:Anticonvulsants; D007211:Indoles; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; C116890:Semaxinib; D040262:Receptors, Vascular Endothelial Growth Factor