A phase 1 and pharmacokinetic study of enzastaurin in pediatric patients with refractory primary central nervous system tumors: a pediatric brain tumor consortium study

Kilburn, L. B.; Kocak, M.; Decker, R. L.; Wetmore, C.; Chintagumpala, M.; Su, J.; Goldman, S.; Banerjee, A.; Gilbertson, R.; Fouladi, M.; Kun, L.; Boyett, J. M.; Blaney, S. M.

Neuro Oncol. 2014 Nov 29; 17(2):303-11

Abstract

BACKGROUND: We sought to estimate the maximum tolerated or recommended phase 2 dose and describe the pharmacokinetics and toxicities of enzastaurin, an oral inhibitor of protein kinase Cbeta, in children with recurrent central nervous system malignancies. METHODS: Enzastaurin was administered continuously once daily at 3 dose levels (260, 340, and 440 mg/m(2)) and twice daily at 440 mg/m(2)/day. Plasma pharmacokinetics were evaluated following a single dose and at steady state. Inhibition of protein kinase C and Akt cell signaling in peripheral blood mononuclear cells was evaluated. Akt pathway activity was measured in pretreatment tumor samples. RESULTS: Thirty-three patients enrolled; 1 was ineligible, and 3 were nonevaluable secondary to early progressive disease. There were no dose-limiting toxicities during the dose-finding phase. Two participants receiving 440 mg/m(2) given twice daily experienced dose-limiting toxicities of grade 3 thrombocytopenia resulting in delayed start of course 2 and grade 3 alanine transaminase elevation that did not recover within 5 days. There were no grade 4 toxicities during treatment. The concentration of enzastaurin increased with increasing dose and with continuous dosing; however, there was not a significant difference at the 440 mg/m(2) dosing level when enzastaurin was administered once daily versus twice daily. There were no objective responses; however, 11 participants had stable disease >3 cycles, 7 with glioma, 2 with ependymoma, and 2 with brainstem glioma. CONCLUSION: Enzastaurin was well tolerated in children with recurrent CNS malignancies, with chromaturia, fatigue, anemia, thrombocytopenia, and nausea being the most common toxicities. The recommended phase 2 dose is 440 mg/m(2)/day administered once daily.

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