Originally published as JCO Early Release 10.1200/JCO.2008.16.1547 on October 27 2008

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Phase I Dose Escalation and Pharmacokinetic Study of BI 2536, a Novel Polo-Like Kinase 1 Inhibitor, in Patients With Advanced Solid Tumors

Klaus Mross, Annette Frost, Simone Steinbild, Susanne Hedbom, Jochen Rentschler, Rolf Kaiser, Nicolas Rouyrre, Dirk Trommeshauser, Cornelia E. Hoesl, Gerd Munzert

From the Tumor Biology Center at the Albert-Ludwigs-University Freiburg; Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany; and Boehringer Ingelheim France SAS, Cedex, France

Corresponding author: Klaus Mross, MD, PhD, Tumor Biology Center at the Albert-Ludwigs-University Freiburg, Breisacherstrasse 117, D-79106, Freiburg, Germany; e-mail:mross{at}tumorbio.uni-freiburg.de

Purpose BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression. The aim of this trial was to identify the maximum tolerated dose (MTD) of BI 2536 and to determine the safety, pharmacokinetics, and antitumor activity in patients who had advanced solid tumors.

Patients and Methods This phase I trial followed an open label, toxicity-guided, dose-titration design. Single doses of BI 2536 (25 to 250 mg) were administered as a 1-hour intravenous infusion; patients who experienced clinical benefit were eligible for additional treatment courses. Safety and pharmacokinetics were investigated. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors Group guidelines.

Results The MTD was defined at 200 mg in a total of 40 patients entered; reversible neutropenia constituted the dose-limiting toxicity (DLT) and the most frequent adverse event at the MTD (grade 3 to 4; 56%). Nausea (52%), fatigue (52%), and anorexia (44%) also were common and were mostly of mild to moderate intensity (Common Terminology Criteria of Adverse Events grade 2). One patient experienced a transient partial response. At doses equal to or greater than the MTD, 23% of patients experienced disease stabilization for 3 or more months. Dose-proportional increases in the maximum plasma concentration and total exposure were observed. BI 2536 showed a high total clearance and high distribution into tissue.

Conclusion The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed.

published online ahead of print at www.jco.org on October 27, 2008

Supported by Boehringer Ingelheim Pharma GmbH & Co KG.

Presented in part at the American Association for Cancer Research, National Cancer Institute, European Organisation for the Research and Treatment of Cancer meeting, November 14-18, 2005, Philadelphia, PA, and at the 42nd Annual Meeting of the American Society of Clinical Oncology, June 2-6, 2006, Atlanta, GA.

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

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