Abstract LB-B13: Pediatric Preclinical Testing Consortium evaluation of the CHK1 inhibitor prexasertib
Authors: Cole Kristina A. , Houghton Peter J. , Kurmasheva Raushan T. , Gorlick Richard , Kolb E. Anders , Kang Min , Reynolds C. Patrick , Li Xiao-Nan , Lindsay Holly , Erickson Stephen W. , Guo Yuelong , Teicher Beverly A. , Smith Malcolm A. , Maris John M. 
Published: August 2018

Abstract
Introduction: Prexasertib is a CHK1 inhibitor that has entered clinical evaluation in adults and children with cancer. CHK1 plays a central role in pausing cell cycle progression in response to DNA damage, and an RNAi screen identified CHK1 as a therapeutic target for neuroblastoma (Cole KA, PNAS 2011; 108: 3336-41). Methods: Prexasertib was tested in vitro against a 23 cell line panel at concentrations from 0.1 nM to 1 µM. In vivo treatment groups included: prexasertib at 7.5 and 10 mg/kg given BID on days 1-3 x 3 weeks (Regimen [Reg] F & B, respectively); prexasertib at 4 mg/kg given BID days 1, 3, 5 (Reg C); irinotecan (IR) at 2.5 mg/kg days 1-5 (Reg D); and the combination of the agents (Reg E) with prexasertib as per Reg C and IR as per Reg D. For solid tumor testing, events are defined as 4X increase in tumor volume from day 0 and for CNS tumor testing as animals becoming moribund or developing severe neurologic deficit. The Kaplan-Meier method was used to compare EFS between treated and control groups. The objective response categories are progressive disease (PD, which is subdivided into progressive disease without and with growth delay, PD1 and PD2 respectively), stable disease (SD), partial response (PR), complete response (CR) and maintained complete response (MCR) (Houghton PJ, et al. Pediatr Blood Cancer 2007;49:928-40). Prexasertib was provided for testing by Lilly. Results: The prexasertib median IC50 for the pediatric cell lines was 3.2 nM, with a range from 0.9 nM to 22 nM and with no evidence for histotype specificity. Prexasertib as a single agent at 7.5 mg/kg consistently slowed tumor growth but failed to induce regressions in the 9 xenograft lines tested. Prexasertib at 10 mg/kg induced PR or CR in 6 of 6 neuroblastoma, 1 of 2 rhabdomyosarcoma, 0 of 1 Ewing sarcoma, and 0 of 2 osteosarcoma xenografts tested, and it induced a MCR in a rhabdoid tumor xenograft. Prexasertib single agent activity was comparable to that observed for single agent IR. The combination of IR and prexasertib (4 mg/kg) was significantly better than prexasertib (10 mg/kg) at prolonging EFS for only 1 of 6 NB, and the combination was significantly better than single agent IR for only 1 of 6 NB. For the remaining 7 xenograft lines, the combination was significantly superior to single agent IR for 3 lines (2 OS and 1 rhabdoid tumor), but the combination was significantly inferior to prexasertib (10 mg/kg) for the rhabdoid tumor line. Prexasertib had no effect as a single agent or in combination with XRT for two orthotopic medulloblastoma xenografts. Conclusions: Prexasertib at 10 mg/kg shows consistent tumor regressing activity as a single agent for neuroblastoma xenografts, confirming recently published data (Lowery, et al. CCR 23: 4354-63, 2017), and it shows tumor regressing activity for other histotypes. The limited activity of prexasertib at 7.5 mg/kg suggests a dose-response effect and that clinical trial design should seek the highest tolerated dose in children. For most xenografts, the combination of IR with prexasertib (at a reduced dose as required for tolerability) was no better than either single agent prexasertib at an optimized dose/schedule or single agent IR. An important area for future research is identifying agents that can be effectively combined with prexasertib for neuroblastoma and other childhood cancers. (Supported by NCI Grants/Contracts: CA199222, CA199221; CA199297; CA199288; CA199287; NO1-CM-42216)
Citation Format: Kristina A. Cole, Peter J. Houghton, Raushan T. Kurmasheva, Richard Gorlick, E. Anders Kolb, Min Kang, C. Patrick Reynolds, Xiao-Nan Li, Holly Lindsay, Stephen W. Erickson, Yuelong Guo, Beverly A. Teicher, Malcolm A. Smith, John M. Maris. Pediatric Preclinical Testing Consortium evaluation of the CHK1 inhibitor prexasertib [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2017 Oct 26-30; Philadelphia, PA. Philadelphia (PA): AACR; Mol Cancer Ther 2018;17(1 Suppl):Abstract nr LB-B13.