Abstract 3102: AZD1152HQPA Accurin™ nanoparticles inhibit growth of diffuse large B-cell lymphomas and small cell lung cancer

Abstract

Abstract Inhibitors of the Aurora Kinases have been developed to treat both liquid and solid tumours. The prodrug AZD1152 is an inhibitor of Aurora kinase B that is clinically active in acute myeloid leukaemia. Despite this clinical proof-of-concept, the broader clinical utility of AZD1152 is limited by the requirement for continuous IV infusion, and the mechanism-related dose-limiting toxicities seen with this class of inhibitors, in particular bone marrow toxicity. To address these challenges and maximise the clinical utility, an Accurin nanoparticle containing AZD1152HQPA, the active metabolite of AZD1152, has been developed. In preclinical models, the AZD1152HQPA Accurin shows increased efficacy without the bone marrow toxicity seen with the prodrug formulation. In preclinical studies, models of Diffuse Large B Cell Lymphoma (DLBCL) and Small Cell Lung Cancer (SCLC) show sensitivity to monotherapy Aurora B kinase inhibitors. Consistent with this, AZD1152 inhibits the growth of subsets of DLBCL and SCLC cells lines in vitro, while in vivo, AZD1152HQPA Accurin consistently reduces the growth of DLBCL and SCLC models. When given at 25mg/kg on days 1 and 3, AZD1152HQPA Accurin gave either equivalent or superior activity to AZD1152 delivered at 25mg/kg on days 1, 2, 3 and 4. When the dose-schedule was explored, increasing the dose intensity increases the anti-tumour effect, while modifying the timing and dose intensity of each dose cycle also influenced the anti-tumour activity. In a DLBCL model, low dose AZD1152HQPA Accurin (25mg/kg delivered as a fractionated dose on day 1 and 3) gave tumour stasis or partial regression, while a higher dose (50mg/kg delivered weekly) gave increased tumour response, which was durable on repeated dosing. The timing of AZD1152HQPA Accurin doses had significant impact on the shape of the tumour response, indicating that optimal scheduling is important to maximize the benefits of sustained release and enhanced tumour accumulation of Accurin nanoparticles. Collectively the preclinical data indicate that the AZD1152HQPA Accurin has the potential for activity in SCLC and DLBCL; is able to be used flexibly; and has an improved therapeutic index. Citation Format: Susan Ashton, Paula Taylor, Nicola Curtis, James Pilling, Thierry Dorval, Jeff Hrkach, Philip J. Jewsbury, Simon T. Barry. AZD1152HQPA Accurin™ nanoparticles inhibit growth of diffuse large B-cell lymphomas and small cell lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3102. doi:10.1158/1538-7445.AM2015-3102