An open-label, phase I study of the polo-like kinase-1 inhibitor, BI 2536, in patients with advanced solid tumors.

Abstract

PURPOSE:

This phase I, open-label, dose-escalation study investigated the maximum tolerated dose (MTD) of BI 2536, a small-molecule polo-like kinase (Plk)-1 inhibitor, in two treatment schedules in patients with advanced solid tumors. Secondary objectives included evaluation of safety, efficacy, and pharmacokinetics.

EXPERIMENTAL DESIGN:

Patients received a single i.v. dose of BI 2536 as a 1-hour infusion on days 1 and 8 or a single 24-hour infusion on day 1 of each 21-day treatment course. MTD determination was based on dose-limiting toxicities.

RESULTS:

Forty-four and 26 patients received each treatment schedule, respectively. The MTD of BI 2536 in the day 1 and 8 schedule was 100 mg per administration (200 mg per course). The MTD for the second dosing schedule was not determined; a 225-mg dose was well tolerated. The most frequently reported treatment-related nonhematologic adverse events were gastrointestinal events and fatigue. Hematotoxicity as the most relevant side effect was similar in both schedules; neutropenia grades 3 and 4 were observed in 16 patients (36.4%) of the day 1 and 8 schedule and 13 patients (50%) of the 24-hour infusion. Fourteen patients (32%) treated in the day 1 and 8 dosing schedule had a best overall response of stable disease. Plasma concentrations of BI 2536 increased dose proportionally, with no relevant accumulation of exposure in the day 1 and 8 dosing schedule. The average terminal half-life was 50 hours.

CONCLUSIONS:

BI 2536 administered in either treatment schedule has adequate safety in patients with advanced solid tumors, warranting further clinical investigation of polo-like kinase-1 inhibitors.

• Authors: Ralf-Dieter Hofheinz, Salah-Eddin Al-Batran, Andreas Hochhaus, Elke Jäger, Volker L Reichardt, Holger Fritsch, Dirk Trommeshauser, Gerd Munzert
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 18 Pg. 4666-74 (Sep 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20682708 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: ©2010 AACR.

Chemical References

• Antineoplastic Agents
• BI 2536
• Cell Cycle Proteins
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• Pteridines
• Protein Serine-Threonine Kinases
• polo-like kinase 1

Topics

• Adult
• Aged
• Aged, 80 and over
• Antineoplastic Agents (adverse effects, pharmacokinetics, therapeutic use)
• Cell Cycle Proteins (antagonists & inhibitors)
• Disease Progression
• Dose-Response Relationship, Drug
• Drug Administration Schedule
• Female
• Humans
• Male
• Middle Aged
• Neoplasms (drug therapy, pathology)
• Protein Kinase Inhibitors (adverse effects, pharmacokinetics, therapeutic use)
• Protein Serine-Threonine Kinases (antagonists & inhibitors)
• Proto-Oncogene Proteins (antagonists & inhibitors)
• Pteridines (adverse effects, pharmacokinetics, therapeutic use)
• Treatment Outcome