Abstract 311: Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers

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Abstract A nanoparticle formulation of AZD2811, a selective aurora kinase B inhibitor, is currently under clinical development for the treatment of both haematological and solid tumour disease. AZD2811 is the active derivative of the prodrug Barasertib (AZD1152) which gave promising clinical activity in elderly AML patients delivered as a 7-day infusion (Kantarjian et al, Cancer, 119, 2611-2619, 2013). To address the limitations associated with the clinical utility of Barasertib and other cell cycle inhibitors in the clinic, AZD2811 has been incorporated into an AccurinTM nanoparticle using a pamoic acid ion pairing approach to optimise drug release rate (Song et al, Journal of Controlled Release, 229, 106-119, 2016), improve the drug exposure to tumour and reduce the duration of administration. A proof of principle formulation of AZD2811 as an AccurinTM nanoparticle established the principle that anti-tumour activity and improved therapeutic index could be achieved (Ashton et al, Science Translational Medicine, 325, 1-10, 2016). The clinical nanoparticle formulation of AZD2811 has been optimised for drug loading and release rate. In pre-clinical models, the clinical formulation can be used flexibly to optimise drug delivery for use in both haematological disease such as AML, or in solid tumour settings. Anti-tumour activity in solid tumours can be achieved at doses where bone marrow toxicity is reduced compared to Barasertib. In sensitive xenograft and PDX solid tumour models greater than 90% tumour regression is observed after a total dose of 50mg/kg with no tumour progression for greater than 40 days. In contrast, for AML, increasing the dose intensity by 2-4 fold leads to neutropenia and to complete tumour regression in a range of AML xenograft models for greater than 60 days. These data establish the concept that drug delivery using nanoparticles is able to resolve therapeutic index challenges, and is able to do so across different disease types. AZD2811 is currently in Phase 1 clinical trial (D6130C0000). The current pre-clinical and clinical data with this novel approach to inhibition of the cell cycle will be discussed. Citation Format: Susan Ashton, Nicholas Floch, Paula Taylor, Colin Howes, Doug Ferguson, Matthew Ling, Maureen Hattersley, Shenghua Wen, Kim Maratea, Adina Hughes, Sean Redmond, Wolfram Brugger, Simon Smith, Alexander MacDonald, Keith Parry, Howard Burris, Young-Ho Song, Jim Nolan, Elizabeth Pease, Simon T. Barry. Development of AZD2811, an aurora kinase B inhibitor, incorporated into an AccurinTM nanoparticle for use in haematological and solid cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 311. doi:10.1158/1538-7445.AM2017-311

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