A phase I and pharmacologic study of weekly gemcitabine in combination with infusional 5-fluorodeoxyuridine and oral calcium leucovorin

Purpose Since preclinical studies have shown more than additive cytotoxicity and DNA damage with the combination of gemcitabine and 5-fluoro-2′-deoxyuridine (FUDR), we studied this combination in a phase I trial. Methods Gemcitabine alone was given in cycle 1 as a 24-h, 2-h or 1-h i.v. infusion weekly for 3 of 4 weeks; if tolerated, a 24-h i.v. infusion of FUDR was added with oral leucovorin. The cycle was aborted for grade 3 thrombocytopenia, grade 4 neutropenia, and grade 2 or worse nonhematologic toxicity. Results During cycle 1, six of eight patients who received 150 or 100 mg/m 2 over 24 h had dose-limiting neutropenia, thrombocytopenia, fatigue or mucositis. Six of seven patients treated with 1000 mg/m 2 over 2 h required a gemcitabine dose reduction for cycle 2 (thrombocytopenia, neutropenia, fatigue). Of 25 assessable patients who received gemcitabine 1000 mg/m 2 over 1 h, 7 did not complete cycle 1 due to thrombocytopenia ( n =6) or diarrhea ( n =1). Of 42 patients entered, 27 received at least one course of gemcitabine/FUDR (5–19.5 mg/m 2 over 24 h) without appreciable toxicity. Due to a shortage of FUDR, the protocol was closed early. Gemcitabine plasma concentrations averaged 0.061 μ M (24 h), 16.3 μ M (2 h), and 31.9 μ M (1 h). In 21 paired bone marrow mononuclear cell samples obtained before treatment and during FUDR infusion, thymidylate synthase ternary complex was only seen during FUDR infusion. Conclusions Gemcitabine 100–150 mg/m 2 over 24 h was poorly tolerated, whereas toxicity was acceptable with 800–1000 mg/m 2 over 1 h. Inhibition of the target enzyme was demonstrated at all FUDR doses.