Investigational New Drugs

, Volume 30, Issue 3, pp 1088–1095

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

  • Kyle Holen
  • Robert DiPaola
  • Glenn Liu
  • Antoinette R. Tan
  • George Wilding
  • Karl Hsu
  • Nancy Agrawal
  • Cong Chen
  • Lingling Xue
  • Elizabeth Rosenberg
  • Mark Stein
PHASE I STUDIES

DOI: 10.1007/s10637-011-9653-1

Cite this article as:
Holen, K., DiPaola, R., Liu, G. et al. Invest New Drugs (2012) 30: 1088. doi:10.1007/s10637-011-9653-1

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.

Keywords

Kinesin spindle proteinOncologyNeutropenia

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Kyle Holen
    • 1
  • Robert DiPaola
    • 2
  • Glenn Liu
    • 1
  • Antoinette R. Tan
    • 2
  • George Wilding
    • 1
  • Karl Hsu
    • 3
  • Nancy Agrawal
    • 3
  • Cong Chen
    • 3
  • Lingling Xue
    • 3
  • Elizabeth Rosenberg
    • 3
  • Mark Stein
    • 2
  1. 1.University of Wisconsin Carbone Cancer CenterMadisonUSA
  2. 2.Cancer Institute of New JerseyNew BrunswickUSA
  3. 3.MerckWhitehouse StationUSA