Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors
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The purpose of this study was to determine the maximum-tolerated dose (MTD), pharmacokinetics and safety profile for two different dosing regimens of barasertib, a selective inhibitor of Aurora B Kinase. In this Phase I trial, patients with advanced solid malignancies were treated with escalating doses of barasertib, administered as either a 48-h continuous infusion or as two 2-h infusions on consecutive days, both every 14 days of a 28-day cycle. Thirty-five patients were treated. The MTDs were 150 mg as a 48-h continuous infusion and 220 mg administered as two 2-h infusions (110 mg/day, days 1, 2, 15 and 16), with neutropenia the dose-limiting toxicity (DLT) of each schedule. Common Terminology Criteria of Adverse Events (CTCAE) grade ≥ 3 neutropenia (with or without fever) occurred in 34 % of patients overall. Other adverse events, many of hematologic or gastrointestinal etiology, were of mild or moderate intensity. No objective tumor responses were observed, although stable disease was observed in 23 % of patients. Systemic exposure to barasertib-hQPA, the more active moiety to which barasertib is converted, was observed by 1 and 6 h into the 2-h and continuous infusion, respectively, and exhibited linear pharmacokinetics. In summary, barasertib was generally well tolerated, with neutropenia the most frequent and dose-limiting toxicity, irrespective of schedule. Future development of barasertib will depend on better definition of its therapeutic index.
KeywordsBarasertib AZD1152 Aurora B kinase Solid tumors Phase I Pharmacokinetics
We thank Merran Macpherson of AstraZeneca UK Ltd. Clinical Pharmacology Science, for assistance with interpretation of pharmacokinetic assessments. We also thank the study teams at Memorial Sloan-Kettering Cancer Center and the Dana-Farber Cancer Institute, including Andrew Wolanski NP, Tracy Bell RN and Sarah Scofield. Editorial assistance was provided by Dr. Zoё van Helmond from Mudskipper Bioscience, funded by AstraZeneca.
Conflict of interest
P.K.S., O.A., D.W. and S.D. are employees of AstraZeneca. G.K.S. and G.I.S. have consulted for AstraZeneca. The other authors declare that they have no conflict of interest.
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