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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.

Original publication

DOI

10.1007/s10637-012-9825-7

Type

Journal article

Journal

Invest New Drugs

Publication Date

04/2013

Volume

31

Pages

370 - 380

Keywords

Adult, Aged, Aged, 80 and over, Aurora Kinase B, Aurora Kinases, Cohort Studies, Dose-Response Relationship, Drug, Female, Follow-Up Studies, Humans, Immunoenzyme Techniques, Infusions, Intravenous, Male, Maximum Tolerated Dose, Middle Aged, Neoplasms, Organophosphates, Prognosis, Protein-Serine-Threonine Kinases, Quinazolines, Tissue Distribution