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Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors

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Abstract

Purpose

To assess the maximum-tolerated dose (MTD), dose-limiting toxicity (DLT), safety, and tolerability of the 24-h continuous intravenous (CIV) infusion of MK-0457, a novel pan-Aurora kinase inhibitor, in patients with advanced solid tumors and to determine the bioavailability of an oral dose of 100 mg MK-0457.

Study design

MK-0457 was administered as a 24-h CIV infusion every 21 days. Dose escalation proceeded per toxicity criteria. A 100-mg oral dose was administered to seven patients 48 h prior to the CIV infusion dose of 64 mg/m2/h.

Results

Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m2/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m2/h. The most common adverse events were nausea, vomiting, diarrhea, and fatigue. Pharmacokinetic analyses revealed that CIV infusion MK-0457 had an estimated mean terminal half-life of approximately 6.6–10.2 h and that end-of-infusion concentrations and mean AUCs were approximately dose proportional. The estimated mean oral bioavailability of MK-0457 was 7.9%. One patient with advanced ovarian cancer attained prolonged stable disease for 11 months.

Conclusions

MK-0457 was well tolerated in this schedule. Almost half the patients attained stable disease. Further development of this class of agents will likely occur in combination with other anti-cancer treatments.

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Acknowledgments

The authors thank our patients, their families, and our clinic and research staffs for the completion of this clinical trial. We also thank Robert Crane and Elizabeth Reilly for their programming work on the MK-0457 program and acknowledge Lingling Xue, Alan Xiao, and Cynthia Chavez-eng for their analytical support. Melinda Baker and Jennifer Pawlowski provided logistical support for this manuscript.

Author information

Author notes

  1. Steven J. Freedman

    Present address: GlaxoSmithKline, 709 Swedeland Road, King of Prussia, PA, 19406, USA

Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public Health, 3103 WIMR, 1111 Highland Avenue, Madison, WI, 53705, USA

    Anne M. Traynor, Glenn Liu & George Wilding

  2. University of Pennsylvania, Philadelphia, PA, USA

    Maureen Hewitt, Keith T. Flaherty & Peter J. O’Dwyer

  3. Merck Research Laboratories, North Wales, PA, USA

    Jason Clark, Steven J. Freedman, Boyd B. Scott, Ann Marie Leighton, Patricia A. Watson & Baiteng Zhao

Authors
  1. Anne M. Traynor
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  2. Maureen Hewitt
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  3. Glenn Liu
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  4. Keith T. Flaherty
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  5. Jason Clark
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  6. Steven J. Freedman
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  7. Boyd B. Scott
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  8. Ann Marie Leighton
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  9. Patricia A. Watson
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  10. Baiteng Zhao
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  11. Peter J. O’Dwyer
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  12. George Wilding
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Corresponding author

Correspondence to Anne M. Traynor.

Additional information

This trial was registered with ClinicalTrials.gov NCT00104351.

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Traynor, A.M., Hewitt, M., Liu, G. et al. Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors. Cancer Chemother Pharmacol 67, 305–314 (2011). https://doi.org/10.1007/s00280-010-1318-9

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  • DOI: https://doi.org/10.1007/s00280-010-1318-9

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