Phase I dose-escalation study of tezacitabine in combination with 5-fluorouracil in patients with advanced solid tumors

BACKGROUND. Tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene) cytidine; FMdC] is a novel nucleoside analog with potent antiproliferative and antitumor activity in preclinical studies. A tolerable safety profile and clinical activity have been shown in Phase I and Phase II clinical studies. The purpose of the current open-label, Phase I dose-escalation trial was to evaluate the combination of tezacitabine and 5-fluorouracil (5-FU) in the treatment of patients with advanced solid tumors. METHODS. Twenty-four patients with a variety of advanced solid tumors for which there was no curative therapy were enrolled. Bolus infusion tezacitabine was administered on Day 1 of a 14-day cycle at escalating doses of 150-350 mg/m(2), with continuous infusion 5-FU (CI 5-FU) given on Days 1-7 at a fixed dose of 200 mg/m(2) per day. Patients underwent objective tumor evaluation by radiologic methods or clinical examination at baseline and after every fourth treatment cycle. RESULTS. The maximum tolerated dose of the combination therapy was determined to be tezacitabine, 200 mg/m(2), with CI 5-FU, 200 mg/m(2) per day. The toxicities were manageable, the most notable being transient severe (National Cancer Institute Common Toxicity Criteria Grade 3 or 4) neutropenia in 23 patients (96%). Eleven (55%) of the 20 assessable patients had partial responses or stabilization of disease. The highest response rate was in patients with primary tumors of esophageal origin. CONCLUSIONS. Tezacitabine at a dose of 200 mg/m(2) in combination with CI 5-FU at a dose of 200 mg/m(2) per day was relatively well tolerated and had clinical activity in patients with advanced solid tumors, particularly in patients with esophageal and other gastrointestinal carcinomas. (c) 2005 American Cancer Society.