Initial Testing (Stage 1) of the Polo-Like Kinase Inhibitor Volasertib (BI 6727), by the Pediatric Preclinical Testing Program

BackgroundVolasertib (BI 6727) is a potent inhibitor of Polo-like kinase 1 (Plk1), that is overexpressed in several childhood cancers and cell lines. Because of its novel mechanism of action, volasertib was evaluated through the PPTP. ProceduresVolasertib was tested against the PPTP in vitro cell line panel at concentrations from 0.1nM to 1.0M and against the PPTP in vivo xenograft panels administered IV at a dose of 30mg/kg (solid tumors) or 15mg/kg (ALL models) using a q7dx3 schedule. ResultsIn vitro volasertib demonstrated cytotoxic activity, with a median relative IC50 value of 14.1nM, (range 6.0-135nM). Volasertib induced significant differences in EFS in 19 of 32 (59%) of the evaluable solid tumor xenografts and in 2 of 4 (50%) of the evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C (>2) activity in 11 of 30 (37%) evaluable solid tumor xenografts, including neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels, and 2 of 4 ALL models. Objective responses (CR's) were observed for 4 of 32 solid tumor (two neuroblastoma, one glioblastoma, and one rhabdomyosarcoma) and one of four ALL xenografts. ConclusionsVolasertib shows potent in vitro activity against the PPTP cell lines with no histotype selectivity. In vivo, volasertib induced regressions in several xenograft models. However, pharmacokinetic data suggest that mice tolerate higher systemic exposure to volasertib than humans, suggesting that the current results may over-estimate potential clinical efficacy against the childhood cancers studied. Pediatr Blood Cancer 2014;61:158-164. (c) 2013 Wiley Periodicals, Inc.