Cancer Chemotherapy and Pharmacology

, Volume 67, Issue 2, pp 305–314 | Cite as

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

  • Anne M. Traynor
  • Maureen Hewitt
  • Glenn Liu
  • Keith T. Flaherty
  • Jason Clark
  • Steven J. Freedman
  • Boyd B. Scott
  • Ann Marie Leighton
  • Patricia A. Watson
  • Baiteng Zhao
  • Peter J. O’Dwyer
  • George Wilding
Original Article

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.

Keywords

Phase I Aurora kinase Serine/threonine protein kinases BCR-ABL mutations 

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Copyright information

© Springer-Verlag 2010

Authors and Affiliations

  • Anne M. Traynor
    • 1
  • Maureen Hewitt
    • 2
  • Glenn Liu
    • 1
  • Keith T. Flaherty
    • 2
  • Jason Clark
    • 3
  • Steven J. Freedman
    • 3
    • 4
  • Boyd B. Scott
    • 3
  • Ann Marie Leighton
    • 3
  • Patricia A. Watson
    • 3
  • Baiteng Zhao
    • 3
  • Peter J. O’Dwyer
    • 2
  • George Wilding
    • 1
  1. 1.University of Wisconsin Carbone Cancer Center, University of Wisconsin School of Medicine and Public HealthMadisonUSA
  2. 2.University of PennsylvaniaPhiladelphiaUSA
  3. 3.Merck Research LaboratoriesNorth WalesUSA
  4. 4.GlaxoSmithKlineKing of PrussiaUSA

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