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Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors
Author(s) -
Kieran Mark W.,
Supko Jeffrey G.,
Wallace Dana,
Fruscio Robert,
Poussaint Tina Young,
Phillips Peter,
Pollack Ian,
Packer Roger,
Boyett James M.,
Blaney Susan,
Banerjee Anu,
Geyer Russ,
Friedman Henry,
Goldman Stewart,
Kun Larry E.,
MacDonald Tobey
Publication year - 2009
Publication title -
pediatric blood and cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.116
H-Index - 105
eISSN - 1545-5017
pISSN - 1545-5009
DOI - 10.1002/pbc.21873
Subject(s) - medicine , refractory (planetary science) , pharmacokinetics , choroid plexus , tyrosine kinase inhibitor , pharmacology , gastroenterology , central nervous system , biology , cancer , astrobiology
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. Pediatr Blood Cancer 2009;52:169–176. © 2008 Wiley‐Liss, Inc.