tezacitabine and Neoplasms

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.. 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.. 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.. 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.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Deoxycytidine; Dose-Response Relationship, Drug; Female; Fluorouracil; Humans; Male; Maximum Tolerated Dose; Middle Aged; Neoplasms; Treatment Outcome

The authors performed a dose escalation study of cisplatin and the novel deoxycytidine analog, tezacitabine, to determine the maximum tolerated dose of the combination.. Twenty-three patients with advanced cancer and good performance status were accrued to 3 dose levels of tezacitabine (150-270 mg/m(2)) and cisplatin (50 mg/m(2)). Using a 28-day treatment cycle, both drugs were administered on Days 1 and 15.. Hematologic toxicity was the most frequently observed side effect and was dose limiting. Grade 3 or 4 neutropenia and thrombocytopenia complicated 75% and 31% of all cycles, respectively. Nonhematologic toxicities were mild. Among 18 evaluable patients, 2 with upper gastrointestinal tract tumors achieved partial responses and 4 had stable disease.. Based on dose-limiting neutropenia and thrombocytopenia at the highest dose level, the recommended Phase II doses are 200 mg/m(2) of tezacitabine and 50 mg/m(2) of cisplatin.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Deoxycytidine; Dose-Response Relationship, Drug; Female; Humans; Male; Middle Aged; Neoplasms; Treatment Outcome

To evaluate safety, tolerability, and pharmacokinetics of a new nucleoside analogue, tezacitabine [(E)-2'-deoxy-2'-(fluoromethylene)cytidine (FMdC)] in patients with refractory solid tumors.. Seventy patients were enrolled in four separate Phase I trials. Patients had metastatic or relapsed cancer of the colon, breast, pancreas, gastrointestinal tract, lung, and other sites. FMdC was administered by i.v. infusion over 30 min in one of four dose schedules--from once every 3 weeks to twice a week for 3 weeks, with dose escalation in each. Maximum doses ranged from 630 to 16 mg/m(2).. Myelotoxicity, especially neutropenia, was the dominant toxicity and was generally dose-related. Grade 3 or 4 neutropenia occurred in 53% of patients but was of relatively short duration (1-8 days) in all of the patients. One patient experienced grade 3 thrombocytopenia and one patient grade 4 (duration 15 and 11 days, respectively). Transient febrile episodes were reported in 82% of patients with drug administration but were easily controlled. Drug-related gastrointestinal events were mild and appeared unrelated to dose. Pharmacokinetics were linear with dose, not appreciably affected by schedules, and not different after single or multiple doses. Terminal half-life was 3-4 h, and 23% of the administered drug was recovered in the urine as unchanged drug. The uridine analogue (FMdU), the deaminated metabolite of FMdC, was the primary metabolite. Objective antitumor activity was observed in eight patients: one exhibited a partial response and seven exhibited stable disease.. In general, FMdC was well tolerated. On the basis of the time to recovery from neutropenia, the recommended schedule for Phase II studies is one treatment every 2 weeks, at a minimum dose of 270 mg/m(2).

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Resistance, Neoplasm; Female; Half-Life; Humans; Infections; Infusions, Intravenous; Male; Middle Aged; Molecular Structure; Neoplasm Metastasis; Neoplasm Recurrence, Local; Neoplasms; Neutropenia; Thrombocytopenia