Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors.

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Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors.

Cancer Chemother Pharmacol. 2013 Apr 25;

Authors: Yamamoto N, Nokihara H, Yamada Y, Uenaka K, Sekiguchi R, Makiuchi T, Slapak CA, Benhadji KA, Tamura T

Abstract
PURPOSE: LY2334737 is an oral gemcitabine prodrug. This Phase I study assessed the safety and tolerability of LY2334737 in Japanese patients with solid tumors and evaluated pharmacokinetics (PK), pharmacodynamics, and antitumor activity. METHODS: Patients with advanced/metastatic solid tumors received escalating doses of LY2334737 once daily for 14�days, followed by a 7-day drug-free period. Cycles were repeated until discontinuation criteria were met. RESULTS: Of 13 patients treated, 3 received 20�mg/day, 6 received 30�mg/day, 4 received 40�mg/day. On the 40�mg dose, 3 patients experienced dose-limiting toxicities (DLTs): hepatic toxicities (e.g., Grade [G]3/4 transaminase and G1-3 bilirubin elevation) and G4 thrombocytopenia; all 3 showed features of disseminated intravascular coagulation. One additional DLT occurred on the 30�mg dose (G3 transaminase elevation). Exploratory pharmacogenetic analyses identified a genetic variation in the CES2 gene potentially associated with these DLTs. PK data showed no clear relationship between the AUC of gemcitabine and its incorporation into leukocyte DNA; 2 of the 3 DLT patients had high incorporation. Two patients (30�mg/day) achieved stable disease with progression-free survival lasting 135 and 155�days. CONCLUSIONS: LY2334737 was tolerated by Japanese patients up to 30�mg/day. The toxicities observed at the 40�mg dose may require the development of alternative dosing schedules.

PMID: 23616084 [PubMed - as supplied by publisher]

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