Initial testing (stage 1) of sunitinib by the pediatric preclinical testing program

Abstract

BACKGROUND: Sunitinib is an orally bioavailable, multi-targeted tyrosine kinase inhibitor with selectivity for PDGF receptors, VEGF receptors, FLT3, and KIT. PROCEDURES: Sunitinib was tested at concentrations ranging from 0.1 nM to 1.0 microM against 23 cell lines from the PPTP in vitro panel. We also compared sunitinib (53.5 mg/kg) or vehicle administered for 28 days by oral gavage in 46 murine xenograft models representing 9 distinct pediatric cancer histologies. RESULTS: The leukemia cell line, Kasumi-1 (gain-of-function KIT(Asn822Lys) mutation) was the only line with an in vitro response to sunitinib (IC(50) 75.7 nM). Sunitinib significantly prolonged EFS in 19 of 35 (54%) of the solid tumor, and in 3 of 8 (38%) of the ALL xenografts analyzed. Using the PPTP time to event measure of efficacy, sunitinib had intermediate (13) and high (1) levels of activity against 14 of 34 evaluable solid tumor xenografts, including 4 of 6 rhabdomyosarcoma, 4 of 5 Ewing tumor, and 2 of 3 rhabdoid tumor xenografts. Following cessation of treatment for the 14 solid tumor xenografts without tumor events by day 28, tumor growth rate increased in most. The only regression noted to sunitinib in the solid tumor panels was a complete response in a rhabdoid tumor xenograft. CONCLUSIONS: Sunitinib demonstrated significant tumor growth inhibition against most of the PPTP's solid tumor panels, but little activity against the neuroblastoma and ALL panel. Antitumor activity was manifested primarily as tumor growth delay, consistent with an anti-angiogenic effect for sunitinib against many of the pediatric preclinical models evaluated. Pediatr Blood Cancer 2008;51:42-48. (c) 2008 Wiley-Liss, Inc.