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Phase I and Pharmacokinetic Study of the Differentiating Agent Vesnarinone in Combination With Gemcitabine in Patients With Advanced Cancer

From the Institute for Drug Development, Cancer Therapy and Research Center, and The University of Texas Health Science Center at San Antonio, San Antonio, TX; and Otsuka America Pharmaceutical, Inc, Palo Alto, CA.

Address reprint requests to Amita Patnaik, MD, Institute for Drug Development, Cancer Therapy and Research Center, 8122 Datapoint Dr, Suite 250, San Antonio, TX, 78229; email apatnaik{at}saci.org

PURPOSE: To evaluate the maximum-tolerated dose, dose-limiting toxicities (DLTs), and pharmacokinetic profile of vesnarinone given once daily in combination with gemcitabine.

PATIENTS AND METHODS: Twenty-six patients were treated with oral vesnarinone 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/m² 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'-difluorodeoxyuridine concentrations were obtained during courses 1 and 2.

RESULTS: Twenty-six patients were treated with 92 courses of vesnarinone/gemcitabine. The principal toxicities of the regimen consisted of neutropenia and thrombocytopenia, which were dose-limiting in two of eight heavily pretreated new patients treated at the 90 mg/1,000 mg/m² dose level and one of 10 minimally pretreated new patients at the 120 mg/1,000 mg/m² dose level. None of three patients treated with 15 courses at the vesnarinone/gemcitabine dose levels of 60 mg/1,000 mg/m² experienced DLT. Pharmacokinetic studies of vesnarinone revealed significant interpatient variability at any given dose level. There was evidence of a linear relationship between vesnarinone dose and mean C_min at dosages of vesnarinone less than 150 mg, with plateauing of mean C_min values at higher dosages. There was no impact of vesnarinone on gemcitabine concentrations, and the vesnarinone pharmacokinetics did not change with gemcitabine between weeks 1 and 2. Two partial responses occurred in patients with refractory breast and non–small-cell lung carcinoma.

CONCLUSION: When combined with gemcitabine, the recommended dose of vesnarinone for phase II evaluations is 90 mg orally once daily with gemcitabine 1,000 mg/m² IV on days 1, 8, and 15 every 4 weeks. There is no evidence of pharmacokinetic interaction between vesnarinone and gemcitabine. Further studies of vesnarinone as a single agent or in combination with gemcitabine and other antineoplastic agents are warranted.

Some patients were treated at the Frederic C. Barter Clinical Research Unit of the Audie Murphy Veterans Administration Hospital, San Antonio, TX, supported in part by grant no. MO1 RR01346 from the National Institutes of Health, Bethesda, MD.

Presented in part at the Thirty-Fourth Annual Meeting of the American Society of Clinical Oncology, Los Angeles, CA, May 16-19, 1998.

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