Originally published as JCO Early Release 10.1200/JCO.2008.21.6655 on September 21 2009

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Phase I Pharmacokinetic and Pharmacodynamic Study of the Aurora Kinase Inhibitor Danusertib in Patients With Advanced or Metastatic Solid Tumors

From the Department of Clinical Oncology, Leiden University Medical Center, Leiden; and Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, the Netherlands; and Nerviano Medical Sciences S.r.l., Nerviano, Italy.

Corresponding author: Hans Gelderblom, MD, PhD, Department of Clinical Oncology, K1-P, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, the Netherlands; e-mail: a.j.gelderblom{at}lumc.nl.

Purpose Danusertib (PHA-739358) is a small-molecule pan-aurora kinase inhibitor. This phase I dose escalation study was conducted to evaluate safety and tolerability of danusertib with additional pharmacokinetic, biomarker, and efficacy assessments.

Patients and Methods Patients with solid tumors refractory to standard therapies or with no standard therapy available were enrolled. Danusertib was administered intravenously on days 1, 8, and 15 every 28 days in 6-hour or 3-hour infusion schedules (ie, 6-hour IVS or 3-hour IVS). Dose levels from 45 mg/m² in the 6-hour IVS, and from 250 mg/m² in the 3-hour IVS, were studied.

Results Fifty patients were treated. For the 6-hour IVS, the most frequently reported adverse effects were neutropenia (55%), nausea (25%), anorexia (23%), fatigue (20%), and diarrhea (18%). In the 3-hour IVS, fatigue (70%), neutropenia (60%), diarrhea (50%), and nausea (30%) were seen. Nonhematologic toxicity was mild to moderate. Neutropenia was dose limiting. The maximum-tolerated dose was 330 mg/m² for the 6-hour IVS and was not identified for the 3-hour IVS. The systemic exposure to danusertib increased linearly with dose. The infusion rate did not appear to remarkably influence the pharmacokinetics of danusertib. Biomarker analysis showed inhibition of histone H3 phosphorylation, indicative of aurora B inhibition, at doses of 190 mg/m² or greater. Stable disease was observed in 23.7% of evaluable patients, and disease stabilization occurred in 6 or more months in five patients.

Conclusion Dose-limiting toxicity of danusertib is neutropenia, which was short lasting and generally uncomplicated; danusertib administration had limited nonhematologic toxicity. The recommended dose of danusertib for phase II studies is 330 mg/m² infused over 6 hours on days 1, 8, and 15 every 28 days.

Funded by Nerviano Medical Sciences S.r.l., Nerviano, Italy.

Presented in part at the 18th Annual Meeting of the American Association for Cancer Research, National Cancer Institute, European Organisation for the Research and Treatment of Cancer, November 7-10, 2006, Prague, Czech Republic, and the 44th Annual Meeting of the American Society of Clinical Oncology, May 30-June 3, 2008, Chicago, IL.

M.M., R.S., P.C., and B.L. are affiliated with Nerviano Medical Sciences.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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