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

Mark W. Kieran, Jeffrey G. Supko, Dana Wallace, Robert Fruscio, Tina Young Poussaint, Peter Phillips, Ian Pollack, Roger Packer, James M. Boyett, Susan Blaney, Anu Banerjee, Russ Geyer, Henry Friedman, Stewart Goldman, Larry E. Kun, Tobey MacDonald

Research output: Contribution to journalArticle

31 Scopus citations

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/m2 while stratum II started at 48 mg/m2. 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/m2. The protocol was amended to determine the MTD after excluding transient AST elevation. Re-estimation of the MTD began at the 145 mg/m2 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/m2, 41.9 ± 21.4 l/m2, 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.

Original languageEnglish (US)
Pages (from-to)169-176
Number of pages8
JournalPediatric Blood and Cancer
Volume52
Issue number2
DOIs
StatePublished - Feb 2009

Keywords

  • Anti-angiogenesis
  • Brain tumor
  • SU5416
  • VEGF

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Hematology
  • Oncology

Fingerprint Dive into the research topics of 'Phase I study of SU5416, a small molecule inhibitor of the vascular endothelial growth factor receptor (VEGFR) in refractory pediatric central nervous system tumors'. Together they form a unique fingerprint.

  • Cite this

    Kieran, M. W., Supko, J. G., Wallace, D., Fruscio, R., Poussaint, T. Y., Phillips, P., Pollack, I., Packer, R., Boyett, J. M., Blaney, S., Banerjee, A., Geyer, R., Friedman, H., Goldman, S., Kun, L. E., & MacDonald, T. (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 and Cancer, 52(2), 169-176. https://doi.org/10.1002/pbc.21873