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A phase I trial of MK-0731, a Kinesin Spindle Protein (KSP) inhibitor, in patients with solid tumors

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Summary

Purpose The kinesin spindle protein (KSP) is essential for separation of spindle poles during mitosis. Its inhibition results in mitotic arrest. This phase I trial examined safety, tolerability, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), pharmacokinetic parameters, and anti-tumor activity of MK-0731, a potent inhibitor of KSP. Experimental design In part 1, patients with advanced solid tumors received MK-0731 intravenously over 24 h every 21 days starting at 6 mg/m2, escalating until MTD was reached. In part 2, patients with taxane-resistant tumors received the MTD. Plasma samples were collected to analyze the pharmacokinetics of MK-0731. Tumor response was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) v1.0. Results In part 1, 21 patients (median age 63 years) were treated with MK-0731 at doses ranging from 6 to 48 mg/m2/24 h for median four cycles. The dose-limiting toxicity was neutropenia and the MTD was 17 mg/m2/24 h. At the MTD, AUC (±SD) was 10.5 (±7.3) μM × hour, clearance (±SD) was 153 mL/min (±84), and t1/2 was 5.9 h. In part 2, 22 patients received the MTD and there were no DLTs. Although there were no objective tumor responses, four patients (with cervical, non-small cell lung, and ovarian cancers) had prolonged stable disease. Conclusions MK-0731 at the MTD of 17 mg/m2/day every 21 days in patients with solid tumors had few grade 3 and 4 toxicities with the major DLTs at higher doses being myelosuppression. Anti-tumor efficacy was suggested by the length of stable disease in selected patients with taxane-resistant tumors.

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Acknowledgements

The authors want to thank Robert D. Crane and Jennifer Pawlowski for their assistance in the preparation of this manuscript.

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Authors and Affiliations

  1. University of Wisconsin Carbone Cancer Center, 600 Highland Ave., Madison, WI, 53792–5666, USA

    Kyle Holen, Glenn Liu & George Wilding

  2. Cancer Institute of New Jersey, New Brunswick, NJ, USA

    Robert DiPaola, Antoinette R. Tan & Mark Stein

  3. Merck, Whitehouse Station, NJ, USA

    Karl Hsu, Nancy Agrawal, Cong Chen, Lingling Xue & Elizabeth Rosenberg

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  1. Kyle Holen
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  2. Robert DiPaola
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  3. Glenn Liu
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  4. Antoinette R. Tan
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  8. Cong Chen
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  9. Lingling Xue
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  10. Elizabeth Rosenberg
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Correspondence to Kyle Holen.

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Holen, K., DiPaola, R., Liu, G. et al. A phase I trial of MK-0731, a Kinesin Spindle Protein (KSP) inhibitor, in patients with solid tumors. Invest New Drugs 30, 1088–1095 (2012). https://doi.org/10.1007/s10637-011-9653-1

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  • DOI: https://doi.org/10.1007/s10637-011-9653-1

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