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


METHODS
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.
Kreisl
Teri N
TN
Neuro-Oncology Branch and Biometric Research Branch, National Cancer Institute, National Institute of Neurological Disorder and Stroke, NIH, Bethesda, MD 20892, USA.
Kim
Lyndon
L
Moore
Kraig
K
Duic
Paul
P
Kotliarova
Svetlana
S
Walling
Jennifer
J
Musib
Luna
L
Thornton
Donald
D
Albert
Paul S
PS
Fine
Howard A
HA
D000328:Adult; D019540:Area Under Curve; D018592:Cross-Over Studies; D004305:Dose-Response Relationship, Drug; D005910:Glioma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D038362:Glycogen Synthase Kinase 3 / Q000097:blood; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D007211:Indoles / Q000009:adverse effects / Q000493:pharmacokinetics* / Q000627:therapeutic use; D008133:Long QT Syndrome / Q000139:chemically induced; D008657:Metabolic Clearance Rate; D009364:Neoplasm Recurrence, Local; D010750:Phosphoproteins / Q000097:blood; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D064546:Protein Kinase C beta; D016019:Survival Analysis; D013921:Thrombocytopenia / Q000139:chemically induced
D007211:Indoles; D010750:Phosphoproteins; D000071679:Glycogen Synthase Kinase 3 beta; D011493:Protein Kinase C; D064546:Protein Kinase C beta; D038362:Glycogen Synthase Kinase 3; C504878:enzastaurin