A phase I study of AT9283, an aurora kinase inhibitor, in patients with refractory solid tumors

2566 Background: AT9283, a multitargeted kinase inhibitor, inhibits several closely related tyrosine and serine/threonine kinases with an IC50 of <10 nM including Aurora A and B, JAK and ABL. Exposure of solid tumour cell lines to AT9283 in vitro induces an “aurora inhibitory” phenotype. Cell survival decreases with increased duration of exposure. Methods: A phase I dose escalation study was performed using a 72 hour continuous intravenous (iv) infusion schedule repeated three weekly according to a stand ard “3+3” design. Results: Thirty-three patients have been treated with a median age of 61 (range 33 to 76 years). The maximum tolerated dose (MTD) was 9 mg/m2/day. Treatment was well tolerated with febrile neutropenia the only dose limiting toxicity. Other adverse events considered possibly related to AT9283 were reversible and included gastrointestinal disturbance and fatigue. Biological evidence of aurora B inhibition manifest as a reduction in histone H3 phosphorylation in skin biopsies during the inf...