Abstract
Abstract cKIT belongs a family of transmembrane tyrosine kinase growth factor receptors and gain of function mutations result in constitutive c-KIT activation that provide an important pathogenic role in gastrointestinal stromal tumors (GIST). AZD3229 is a highly potent and selective oral best-in-class KIT inhibitor that is active against a wide spectrum of primary and secondary KIT mutations that are known to confer resistance to standard of care agents. AZD3229 demonstrates rapid, extensive and sustained inhibition of KIT signaling in preclinical xenograft models with KIT primary exon 11 del mutations and primary/secondary ATP-binding pocket mutations (GIST 430/654A and patient-derived xenograft (PDX) model of KIT V654A, HGiXF-106) and A-loop mutations (PDX model of KIT Y823D, HGiXF-105 and Ba/F3 KIT D816H). In these models, AZD3229 results in anti-tumour activity (tumour regressions ranging from -60% to -99 % TGI) when dosed orally up to 20 mg/kg BID. The objective of this PK-PD modeling work was to (1) establish the PK-PD-Efficacy relationship for AZD3229 across the four cell-lines and PDX mouse models tested; (2) to confirm the extent and duration of pKIT inhibition required for optimal efficacy, as defined by tumor regressions. Inhibition of KIT phosphorylation observed with AZD3229 shows a direct relationship to free mouse plasma concentration and an estimated in vivo EC90 was estimated for each model (Ba/F3 D816H = 20 nM; GIST 430/V654A= 43 nM; HGiX-106 = 76 nM; HGiX-105 = 4 nM). No change in the extent of inhibition of KIT phosphorylation was observed on repeat dosing. Optimal efficacy is observed when sustained inhibition of pKIT, >90% is achieved over the dosing interval. Conclusion: Exploring the in vivo activity and PK-PD relationship in multiple cell-line derived xenograft and PDX models harboring different mutations provides a benchmark from which to anchor human dose predictions that partly reflect the spectrum of responses likely to be seen in GIST patients. Citation Format: Venkatesh Pilla Reddy, Aaron Smith, Michael Grondine, Rana Anjum, Rhys D. Jones. Exploring the pharmacokinetic-pharmacodynamic relationships of AZD3229, a novel and selective inhibitor of cKIT, in a range of mouse xenograft models of gastrointestinal stromal tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1328.
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Disclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.