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01.02.2011 | Original Article

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

verfasst von: 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

Erschienen in: Cancer Chemotherapy and Pharmacology | Ausgabe 2/2011

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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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Titel: Phase I dose escalation study of MK-0457, a novel Aurora kinase inhibitor, in adult patients with advanced solid tumors
verfasst von: 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
Publikationsdatum: 01.02.2011
Verlag: Springer-Verlag
Erschienen in: Cancer Chemotherapy and Pharmacology / Ausgabe 2/2011
Print ISSN: 0344-5704
Elektronische ISSN: 1432-0843
DOI: https://doi.org/10.1007/s00280-010-1318-9

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