Phase I and pharmacokinetic study of the differentiating agent vesnarinonein combination with gemcitabine in patients with advanced cancer

Purpose: To evaluate the maximum-tolerated dose, dose-limiting toxicities ( DLTs), and pharmacokinetic profile of vesnarinone given once daily in combi nation with gemcitabine. Patients and Methods: Twenty-six patients were treated with oral vesnarinon e once daily on a continuous schedule at doses of 60, 90, 120, 150, and 180 mg in combination with intravenous (IV) gemcitabine at a dose of 1,000 mg/ m(2) on days 1, 8, and 15 every 4 weeks. To determine whether biologically relevant concentrations were being achieved, predose concentrations (C-min) of vesnarinone were obtained weekly. Plasma gemcitabine and 2',2'-difluoro deoxyuridine concentrations were obtained during courses 1 and 2. Results: Twenty-six patients were treated with 92 courses of vesnarinone/ge mcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pre treated new patients treated at the 90 mg/1,000 mg/m(2) dose level and one of 10 minimally pretreated new patients at the 120 mg/1.000 mg/m(2) dose le vel. None of three patients treated with 15 courses at the vesnarinone/gemc itabine dose levels of 60 mg/1,000 mg/m(2) experienced DLT. Pharmacokinetic studies of vesnarinone revealed significant interpatient variability at an y given dose level. There was evidence of a linear relationship between ves narinone dose and mean C-min at dosages of vesnarinone less than 150 mg, wi th plateauing of mean C-min values at higher dosages. There was no impact o f vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacoki netics did not change with gemcitabine between weeks 1 and 2. Two partial r esponses occurred in patients with refractory breast and non-small-cell lun g carcinoma. Conclusion: When combined with gemcitabine, the recommended dose of vesnari nane for phase II evaluations is 90 mg orally once daily with gemcitabine 1 ,000 mg/m(2) IV on days 1, 8, and 15 every 4 weeks. There is no evidence of pharmacokinetic interaction between vesnarinone and gemcitabine. Further s tudies of vesnarinone as a single agent or in combination with gemcitabine and other antineoplastic agents are warranted. (C) 2000 by American Society of Clinical Oncology.