Abstract LB-317: Pediatric Preclinical Testing Program (PPTP) evaluation of volasertib (BI 6727), a Polo-like kinase (PLK) inhibitor
Authors: Smith Malcolm , Keir Stephen , Maris John , Kolb Anders , Reynolds Patrick , Kang Min , Carol Hernan , Lock Richard , Gorlick Richard , Kurmasheva Raushan , Billups Catherine , Houghton Peter 
Published: August 2012

Abstract
Background: Volasertib is a first in class, selective and potent cell cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting PLK. Genomic screens have identified PLK1 as a potential therapeutic target for several pediatric cancers, including rhabdomyosarcoma and neuroblastoma. Methods: Volasertib (provided by Boehringer Ingelheim) was tested in vitro at concentrations from 0.1 nM to 1.0 µM. Volasertib was tested against the PPTP solid tumor xenografts using a dose of 30 mg/kg administered intravenously weekly x 3. For the ALL panel (using NOD-SCID mice), the MTD was 15 mg/kg, and this dose was used for efficacy testing. The total planned treatment period was 3 weeks with an additional 3 weeks observation. Two measures of antitumor activity were primarily used: 1) an objective response measure modeled after the clinical setting; and 2) a time to event (4-fold increase in tumor volume) measure based on the median event-free survival (EFS) of treated (T) and control (C) animals for each xenograft. Intermediate activity requires EFS T/C &gt; 2, with high activity additionally requiring regression at the end of the observation period. Results: The median relative IC50 (rIC50) value for the PPTP cell lines was 14.1 nM, with a range from 6.0 nM to 135 nM. The median rIC50 values were lowest for the ALL cell line panel compared to the remaining cell lines (11.9 versus 16.0 nM, respectively), but this difference was not significant, and overall there were no differences in rIC50 by histotype. Against the PPTP in vivo panels volasertib induced significant differences in EFS distribution compared to control in 19 of 32 (59%) evaluable solid tumor xenografts and in 2 of 4 (50%) evaluable ALL xenografts. Volasertib induced tumor growth inhibition meeting criteria for intermediate EFS T/C activity in 11 of 30 (37%) evaluable solid tumor xenografts. Intermediate activity for the EFS T/C metric was most consistently observed in the neuroblastoma (4 of 6) and glioblastoma (2 of 3) panels. For the ALL panel, 2 of 4 (50%) xenografts met criteria for intermediate activity. Objective responses were observed for 4 of 32 solid tumor and 1 of 4 ALL xenografts. Two of 6 neuroblastoma xenografts demonstrated CRs, as did 1 of 3 glioblastoma and 1 of 5 rhabdomyosarcoma xenografts evaluable for this response measure. Conclusions: Volasertib showed low nanomolar in vitro potency against the PPTP cell lines with no histotype selectivity. Volasertib induced regressions in 5 of 36 evaluable PPTP xenografts with the neuroblastoma panel showing the most consistent pattern of responsiveness to volasertib. Given available pharmacokinetic data showing that mice tolerate higher systemic exposure to volasertib than humans, it is unlikely that the PPTP in vivo results are under-estimating the potential clinical activity of volasertib against the childhood cancer types evaluated here. (Supported by NCI NO1CM42216)
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-317. doi:1538-7445.AM2012-LB-317