A phase I trial of enzastaurin in patients with recurrent gliomas.

Abstract

PURPOSE:

Enzastaurin is a selective inhibitor of protein kinase C beta. Prior phase I studies did not show increased drug exposures with escalating once daily administration. Limits from gastrointestinal absorption may be overcome by twice daily dosing, potentially improving antitumor effects.

EXPERIMENTAL DESIGN:

We conducted a phase I dose escalation study in 26 patients with recurrent malignant glioma, stratified by use of enzyme-inducing antiepileptic drugs, to investigate whether divided twice daily dosing results in higher exposures compared with once daily dosing. Phosphorylated glycogen synthase 3 beta was analyzed as a potential biomarker of enzastaurin activity.

RESULTS:

Enzastaurin was poorly tolerated at all dose levels evaluated (500, 800, and 1,000 mg total daily), with thrombocytopenia and prolonged QTc as dose-limiting toxicities. The average drug concentration of enzastaurin under steady-state conditions was doubled by twice daily dosing compared with daily dosing [1.990; 90% confidence interval (CI), 1.450-2.730]. Additionally, geometric mean ratios doubled with 800 versus 500 mg dosing for both daily (2.687; 90% CI, 1.232-5.860) and twice daily regimens (1.852; 90% CI, 0.799-4.292). Two patients achieved long-term benefit (over 150 weeks progression free).

CONCLUSIONS:

Higher and more frequent dosing of enzastaurin resulted in improved drug exposure but with unacceptable toxicity at the doses tested. Phosphorylated glycogen synthase 3 beta may be a useful biomarker of the biological activity of enzastaurin. Enzastaurin has activity in a subset of malignant glioma patients and warrants continued study in combination with other agents using a maximal once daily dose of 500 mg.

• Authors: Teri N Kreisl, Lyndon Kim, Kraig Moore, Paul Duic, Svetlana Kotliarova, Jennifer Walling, Luna Musib, Donald Thornton, Paul S Albert, Howard A Fine
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 15 Issue 10 Pg. 3617-23 (May 15 2009) ISSN: 1078-0432 [Print] United States
• PMID: 19417015 (Publication Type: Clinical Trial, Phase I, Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indoles
• Phosphoproteins
• Glycogen Synthase Kinase 3 beta
• Protein Kinase C
• Protein Kinase C beta
• Glycogen Synthase Kinase 3
• enzastaurin

Topics

• Adult
• Area Under Curve
• Cross-Over Studies
• Dose-Response Relationship, Drug
• Glioma (drug therapy, metabolism, pathology)
• Glycogen Synthase Kinase 3 (blood)
• Glycogen Synthase Kinase 3 beta
• Humans
• Indoles (adverse effects, pharmacokinetics, therapeutic use)
• Long QT Syndrome (chemically induced)
• Metabolic Clearance Rate
• Neoplasm Recurrence, Local
• Phosphoproteins (blood)
• Protein Kinase C (antagonists & inhibitors)
• Protein Kinase C beta
• Survival Analysis
• Thrombocytopenia (chemically induced)