Phase I studies with the novel nucleoside analog gemcitabine.
Extensive data generated from early phase I trials have demonstrated important schedule-dependent differences in gemcitabine's toxicity profile and activity. Frequent drug administration produced a high incidence of toxicities: in the daily schedule, flu-like symptoms (fever, malaise, and headache) were experienced and in some patients idiosyncratic episodes of severe hypotension; in the twice-a-week schedule the dose-limiting toxicity was thrombocytopenia. Less frequent drug administration was better tolerated (dose-limiting toxicity was myelosuppression), but little efficacy was observed. These three schedules were not followed up in phase II studies. Instead, a weekly schedule was selected in which gemcitabine was given as a 30-minute infusion once a week for 3 weeks followed by a week of rest. In this schedule, gemcitabine provided a combination of activity and acceptable tolerability, with dose-limiting toxicity being thrombocytopenia at doses of 790 to 1,500 mg/m2. An understanding of the clinical pharmacology of this novel agent has resulted in a second generation of phase I trials that attempt to increase dose intensity, maintain an acceptable toxicity profile, and improve the efficacy in minimally pre-treated or untreated patients. Most of the studies used the weekly schedule of drug administration. Strategies include escalating dose and increasing infusion duration. At present, the gemcitabine dose with the best balance of activity and tolerability is weekly doses of 1,000 mg/m2 administered over 30 minutes. However, additional studies will be needed to explore completely the newer strategies for dose intensification described in this overview.
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