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- W4361942609 abstract "<div>Abstract<p><b>Purpose:</b> Enzastaurin is a selective inhibitor of protein kinase C β. 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.</p><p><b>Experimental Design:</b> 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 β was analyzed as a potential biomarker of enzastaurin activity.</p><p><b>Results:</b> 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).</p><p><b>Conclusions:</b> Higher and more frequent dosing of enzastaurin resulted in improved drug exposure but with unacceptable toxicity at the doses tested. Phosphorylated glycogen synthase 3 β 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.</p></div>" @default.
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- W4361942609 date "2023-03-31" @default.
- W4361942609 modified "2023-10-16" @default.
- W4361942609 title "Data from A Phase I Trial of Enzastaurin in Patients with Recurrent Gliomas" @default.
- W4361942609 doi "https://doi.org/10.1158/1078-0432.c.6516834" @default.
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