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Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors

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Summary

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.

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Acknowledgments

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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Authors and Affiliations

  1. Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY, USA

    Gary K. Schwartz & Richard D. Carvajal

  2. Department of Oncology, University of Oxford, Oxford, United Kingdom

    Rachel Midgley

  3. Department of Pathology, Brigham and Women’s Hospital, 75 Francis Street, Boston, MA, 02115, USA

    Scott J. Rodig

  4. AstraZeneca Pharmaceuticals, Macclesfield, Cheshire, United Kingdom

    Paul K. Stockman, Ozlem Ataman, David Wilson & Shampa Das

  5. Early Drug Development Center, Department of Medical Oncology, Dana-Farber Cancer Institute, 450 Brookline Avenue, Boston, MA, 02215, USA

    Geoffrey I. Shapiro

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  1. Gary K. Schwartz
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Supplementary Figure 1

Absolute neutrophil count over time in a patient who received barasertib on both schedules with growth factor support. A 65-year old with mesothelioma, enrolled to the 225 mg dose level of Schedule A experienced dose limiting toxicity with grade 4 neutropenia lasting >3 days after the first 48-h infusion, necessitating a delay in cycle 1, day 15 dosing, and prompting a reduction to 150 mg for the second infusion. Although the nadir after the second infusion was improved, she initiated cycle 2 with a grade 1 ANC, and again suffered prolonged grade 4 neutropenia after that infusion, prompting a delay in the day 15 infusion. At that time, a chest wall mass was decreasing in size. Growth factor support was not routinely used during the study. Nonetheless, a decision was made to maintain the 150 mg dose level with pegfilgrastim, which was administered 24 h after the end of each subsequent 48-h infusion. She received her first dose of pegfilgrastim on day 58, which ameliorated the degree of neutropenia save for the nadir that occurred on day 91. She did not receive pegfilgrastim prior to the nadir that occurred on day 119. With the use of pegfilgrastim, neutropenic nadirs were routinely between ~1,200–3,200, and no further dosing delays were required. After the first infusion of the sixth cycle, a port-a-cath occlusion occurred; for this reason, as well as for convenience, she was permitted to switch to 2-h infusions, and received 75 mg over 2 h on consecutive days every other week thereafter (i.e. similar cumulative dose) beginning with day 15 of cycle 6. Pegfilgrastim was administered 24 h after the end of each second 2-h infusion. Overall, nadir neutrophil counts were substantially higher on this schedule, ranging from ~5,200–10,800. Thick gray bars represent 48-h infusions; thin gray bars represent consecutive day 2-h infusions. (TIFF 2783 kb)

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Schwartz, G.K., Carvajal, R.D., Midgley, R. et al. Phase I study of barasertib (AZD1152), a selective inhibitor of Aurora B kinase, in patients with advanced solid tumors. Invest New Drugs 31, 370–380 (2013). https://doi.org/10.1007/s10637-012-9825-7

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