A phase I trial of gemcitabine administered as a 96-h continuous intravenous infusion in patients with advanced carcinoma and lymphoma

Background and objective: Preclinical data suggest gemcitabine may have schedule-dependent activity favoring prolonged infusion. We sought to determine the recommended phase II dose (RPTD) and toxicity of gemcitabine when given as a continuous intravenous (CIVI) over 96 h. Patients and methods: Gemcitabine was initially given at 1 mg/m²/d for 48, then 72, and finally 96 h. The dose was then increased to 2, 4, 6, 10, 15, 20, and 25 mg/m²/d. Dose levels of 7, 8, 9 mg/m²/d as 96-h infusion were added later after a protocol modification. After identifying the RPTD using an every 3-wk schedule, we then evaluated the feasibility of repeating the infusion every 2 wk, and then weekly for 3 of 4 wk. Results: Thirty-four patients with a variety of tumor types received a total of 126 cycles of therapy (median of 2 cycles, range 1-10 cycles). The RPTD was 8 mg/m²/d every 3 wk, and 6 mg/m²/d every 2 wk. The most common grade 2 or higher toxicities at all dose levels (≥ grade 2) included fever (n = 14), dyspnea (n = 7), mucositis (n = 6), hypotension (n = 6), nausea/vomiting (n = 6), and fatigue (n = 5). Neutropenia and/or thrombocytopenia were uncommon. Conclusion: Administration of gemcitabine as a 96-h infusion results in a markedly different toxicity profile and RPTD than when given by a conventional 30-min infusion. The RPTD was 8 mg/m ²/d (32 mg/m²/course) when given every 3 wk, or 6 mg/m²/d (24 mg/m²/course) when given every 2 wk.