Phase I study of oral gemcitabine prodrug (LY2334737) in Japanese patients with advanced solid tumors.
Cancer Chemother Pharmacol
; 71(6): 1645-55, 2013 Jun.
Article
em En
| MEDLINE
| ID: mdl-23616084
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.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Pró-Fármacos
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Desoxicitidina
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Desoxiuridina
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Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Adult
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Aged
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Revista:
Cancer Chemother Pharmacol
Ano de publicação:
2013
Tipo de documento:
Article