Abstract LB-B15: Pediatric Preclinical Testing Consortium evaluation of the AZD1775 as a single agent and in combination with irinotecan
Authors: Houghton Peter J. , Kurmasheva Raushan T. , Gorlick Richard , Kolb E. Anders , Mosse Yael P. , Erickson Stephen W. , Guo Yuelong , Teicher Beverly A. , Smith Malcolm A. , Maris John M. 
Published: August 2018

Abstract
Introduction: The identification of agents that can selectively potentiate the cytotoxic effects of standard of care agents is an important childhood cancer area of research. WEE1 is a serine kinase that plays a central role in the G2 checkpoint, and its inhibition can lead to cell cycle progression despite unrepaired DNA damage leading to cell death. AZD1775 is a potent WEE1 inhibitor that is in clinical development for children and adults with cancer, with clinical trials evaluating the agent in combination with taxanes, carboplatin/cisplatin, irinotecan, and other agents. Methods: AZD1775 was tested using a dose of 120 mg/kg administered orally days 1-5. Irinotecan was administered intraperitoneally at a dose of 2.5 mg/kg days 1-5 (one hour after AZD1775 when used in combination). The following treatment Groups were studied: (A) Control; (B) AZD1775; (C) Irinotecan; (D) AZD1775 + irinotecan. Events were defined as a 4-fold increase in tumor volume from day 0. The Kaplan-Meier method was used to compare event-free survival (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]. AZD1775 was provided for testing by AstraZeneca. Results: AZD1775 alone and in combination was tested against neuroblastoma (n=3), osteosarcoma (n=4), and Wilms tumor (n=1) xenografts. All treatment regimens were well-tolerated, with no toxic mortality observed. AZD1775 as a single agent showed little activity, with all treated groups showing PD1 tumor growth delay. Irinotecan induced objective responses in two neuroblastoma lines (PRs), and the combination of AZD1775 + irinotecan induced objective responses in 2 neuroblastoma lines (PR and CR) and a Wilms tumor line (PR). The objective response measure improved for 1 neuroblastoma (PR to CR), 2 osteosarcoma (PD1 to PD2), and 1 Wilms tumor (PD2 to PR) xenograft lines. The EFS was significantly longer for the combination compared to single agent irinotecan in all models tested. The magnitude of the increase was greater for the osteosarcoma and Wilms tumor xenografts than for the neuroblastoma xenografts. The combination also induced significantly smaller minimum relative tumor volumes (minRTVs) for all xenografts lines studied when compared to the minRTVs induced by single agent irinotecan. Conclusions: AZD1775 potentiates the effects of irinotecan across all of the xenograft lines tested. The magnitude of the potentiation effect appeared greater for the osteosarcoma and Wilms tumor xenograft lines compared to the neuroblastoma lines. Additional sarcoma and Wilms tumor lines are currently being tested to further understand the range of potentiation. When considered with recently reported AZD1775 combination testing results for rhabdomyosarcoma (Stewart, et al. ASCO 2017: Abstr 10535), these results support clinical evaluations of AZD1775 in combination with irinotecan for multiple types of childhood cancers, as is ongoing in NCT02095132. (Supported by NCI Grants: CA199222, CA199221, CA199297, and CA199287)
Citation Format: Peter J. Houghton, Raushan T. Kurmasheva, Richard Gorlick, E. Anders Kolb, Yael P. Mosse, Stephen W. Erickson, Yuelong Guo, Beverly A. Teicher, Malcolm A. Smith, John M. Maris. Pediatric Preclinical Testing Consortium evaluation of the AZD1775 as a single agent and in combination with irinotecan [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-B15.