Abstract

Background: Aurora kinases are critically involved in several stages of mitosis and are a potential target for anticancer therapy in solid tumours and haematological malignancies. The aurora kinase B inhibitor AZD1152 (barasertib) has shown promising efficacy in elderly patients with untreated acute myeloid leukaemia (AML) with a 35.4% objective complete remission rate (CR+CRi) compared to low-dose AraC (11.5%) when given as a seven day continuous infusion. Responses were seen in all cytogenetic risk groups and tended to occur in the 1st or 2nd cycle of treatment. (Kantarjian HG et al., Cancer 2013). Methods and Results: AZD2811 nanoparticle is a novel, encapsulated slow release inhibitor of aurora kinase B which offers several advantages compared to AZD1152 (Ashton S et al., Sci Transl Med 2016). It can be administered as a short intravenous infusion and is currently in an ongoing clinical phase 1 study in solid tumours (NCT02579226). We have investigated the preclinical activity of AZD2811 nanoparticle in several subcutaneous xenografts and a disseminated AML disease model, both as a single agent and in combination with Ara-C (Floc'h N et al., Mol Cancer Ther 2017). The xenograft data indicate that AZD2811 nanoparticle reduces AML tumour growth in a dose-dependant manner. The AZD2811 nanoparticle, dosed at 98.7mg/kg administered on day 1, causes a durable >90% tumour regression for approximately 40 days in the HL-60 subcutaneous xenograft model and in the MOLM-13 disseminated tumour model increases median overall survival of the mice from 10 to 23.5 days (placebo vs treated mice) and reduces the human tumour burden within the mouse peripheral blood and bone marrow. In order to measure target engagement of AZD2811 nanoparticle, pharmacodynamic (PD) assays to quantify phospho-histone H3 levels and endoreduplication in tumour samples and peripheral tissues have been developed. Conclusion: Based on the promising clinical proof of principle data with AZD1152 and the preclinical evidence for AZD2811 nanoparticle, a clinical phase 1/2 study in elderly patients with newly diagnosed AML who are unfit for standard induction chemotherapy or in previously treated AML patients with relapsed disease has been initiated (NCT03217838). The study is currently enrolling patients in the dose escalation phase.

Disclosures

Brugger: AstraZeneca: Employment, Equity Ownership. Ashton: AstraZeneca: Employment, Equity Ownership. Taylor: AstraZeneca: Employment, Equity Ownership. Hattersley: AstraZeneca: Employment, Equity Ownership. Wen: AstraZeneca: Employment, Equity Ownership. Maratea: Astrazeneca: Employment, Equity Ownership. Overend: AstraZeneca: Employment, Equity Ownership; GSK: Equity Ownership. Barry: AstraZeneca: Employment, Equity Ownership. MacDonald: AstraZeneca: Employment, Equity Ownership; GSK: Equity Ownership; Hoffman La Roche: Equity Ownership; Novartis: Equity Ownership. Pease: Astrazeneca: Employment, Equity Ownership.

Author notes

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Asterisk with author names denotes non-ASH members.