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J Thorac Oncol. 2010 Jul;5(7):1068-74. doi: 10.1097/JTO.0b013e3181da3899.

A phase I study of enzastaurin combined with pemetrexed in advanced non-small cell lung cancer.

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National Cancer Center Hospital, Tokyo, Japan.



Enzastaurin is an oral serine/threonine kinase inhibitor, which suppress signaling through protein kinase C-beta and the phosphatidylinositol 3-kinase/AKT pathway. Preclinical studies suggested synergic antitumor activity of enzastaurin and pemetrexed. We conducted this phase I study to evaluate the safety, pharmacokinetics, and clinical activity of this combination in patients with previously treated advanced non-small cell lung cancer.


An oral daily dose of 500 mg enzastaurin was administered once daily (QD) or twice daily (BID) in combination with 500 mg/m pemetrexed on day 1 in repeated 21-day cycles. Cycle 1 started with a 7-day enzastaurin lead-in treatment that preceded pemetrexed administration: a loading dose of 1125 mg enzastaurin on day 1 followed by a 500 mg total daily dose on days 2-7.


Twelve patients were treated QD (n = 6) or BID (n = 6). One dose-limiting toxicity (grade 3 QTc prolongation) was reported in the QD cohort. Grade 3/4 hematological toxicities were slightly increased in the BID cohort compared with the QD cohort. After beginning the combination therapy, enzastaurin exposures decreased slightly but remained above the target plasma concentration of 1400 nmol/L. Compared with QD, there was a higher exposure with BID. The enzastaurin dosing regimen (QD or BID) had no effect on pemetrexed pharmacokinetics. Two patients had partial responses as defined by RECIST. Five patients received more than 10 cycles of treatment without disease progression.


Both schedules of enzastaurin in combination with pemetrexed were well tolerated and clinically active in patients with advanced non-small cell lung cancer.

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