Introduction. Gemcitabine is a nucleoside analogue with unique metabolic and mechanistic properties. Preliminary studies in dogs have shown a mild, schedule-dependent toxic profile with a broad range of gemcitabine dosages (350-800 mg/m2). We determined maximally tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary antitumor activity of intravenous gemcitabine in dogs with advanced solid tumors. Material and methods. Dogs with advanced cancer were enrolled in a prospective open-label phase 1 study of 30-min intravenous gemcitabine infusion. Gemcitabine was administered starting at 800 mg/m2 using dose escalation of 50 mg/m2 increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing a DLT after one cycle. Additional dogs were enrolled at MTD to better characterize tolerability and pharmacokinetics. Treatment continued until disease progression or unacceptable toxicity. Results. Twenty dogs were enrolled and treated at 4 dose levels, ranging from 800 mg/m2 to 950 mg/m2. Neutropenia was identified as the dose-limiting toxic event. MTD was 900 mg/m2. DLT was observed at 950 mg/m2 in 2 dogs, and consisted of grade 4 febrile neutropenia. There were no non-hematological DLTs. Eighteen dogs received multiple doses of gemcitabine, and none of them experienced severe toxicity from any of their subsequent treatments. At 900 mg/m2 dose level, 5 complete responses and 5 partial responses were observed. Conclusion. The recommended dose of gemcitabine for future phase 2 studies is weekly 900 mg/m2. In dogs with advanced solid tumor this dose level is well tolerated and merits further evaluation.

An open-label phase 1 dose-escalation clinical trial to determine the maximally tolerated dose and dose-limiting toxicities of a single intravenous gemcitabine administration in dogs with advanced solid tumors.

DACASTO, MAURO;ARESU, LUCA;
2014

Abstract

Introduction. Gemcitabine is a nucleoside analogue with unique metabolic and mechanistic properties. Preliminary studies in dogs have shown a mild, schedule-dependent toxic profile with a broad range of gemcitabine dosages (350-800 mg/m2). We determined maximally tolerated dose (MTD), dose-limiting toxicity (DLT), pharmacokinetics, and preliminary antitumor activity of intravenous gemcitabine in dogs with advanced solid tumors. Material and methods. Dogs with advanced cancer were enrolled in a prospective open-label phase 1 study of 30-min intravenous gemcitabine infusion. Gemcitabine was administered starting at 800 mg/m2 using dose escalation of 50 mg/m2 increments with 3 dogs per dose level. MTD was established based on the number of dogs experiencing a DLT after one cycle. Additional dogs were enrolled at MTD to better characterize tolerability and pharmacokinetics. Treatment continued until disease progression or unacceptable toxicity. Results. Twenty dogs were enrolled and treated at 4 dose levels, ranging from 800 mg/m2 to 950 mg/m2. Neutropenia was identified as the dose-limiting toxic event. MTD was 900 mg/m2. DLT was observed at 950 mg/m2 in 2 dogs, and consisted of grade 4 febrile neutropenia. There were no non-hematological DLTs. Eighteen dogs received multiple doses of gemcitabine, and none of them experienced severe toxicity from any of their subsequent treatments. At 900 mg/m2 dose level, 5 complete responses and 5 partial responses were observed. Conclusion. The recommended dose of gemcitabine for future phase 2 studies is weekly 900 mg/m2. In dogs with advanced solid tumor this dose level is well tolerated and merits further evaluation.
2014
Proceedings of the European Society of Veterinary Oncology Annual Congress
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11577/2828361
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