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

Cancer Chemother Pharmacol. 2011 Feb;67(2):305-14. doi: 10.1007/s00280-010-1318-9. Epub 2010 Apr 13.


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/m(2)/h.

Results: Twenty-seven patients received a total of 86 infusions of MK-0457. Dose-limiting toxicity at 96 mg/m(2)/h included grade 4 neutropenia and grade 3 herpes zoster. The MTD was identified as 64 mg/m(2)/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.

Trial registration: NCT00104351.

Publication types

  • Clinical Trial, Phase I
  • Multicenter Study

MeSH terms

  • Administration, Oral
  • Adult
  • Aged
  • Aged, 80 and over
  • Area Under Curve
  • Aurora Kinases
  • Biological Availability
  • Female
  • Hematologic Diseases / chemically induced
  • Humans
  • Infusions, Intravenous
  • Male
  • Maximum Tolerated Dose
  • Middle Aged
  • Neoplasms / drug therapy*
  • Piperazines / pharmacology*
  • Piperazines / therapeutic use*
  • Piperazines / toxicity*
  • Protein Serine-Threonine Kinases / antagonists & inhibitors*
  • Treatment Outcome
  • Young Adult


  • Piperazines
  • tozasertib
  • Aurora Kinases
  • Protein Serine-Threonine Kinases

Associated data