A Phase I trial of weekly gemcitabine administered as a prolonged infusion in patients with pancreatic cancer and other solid tumors

Purpose: Pharmacological studies of gemcitabine (2',2'-difluorodeoxycytidine) have shown that increased levels of the active triphosphate metabolite are achieved by prolonging infusion time while holding the dose rate constant. The primary aim of this study was to determine the maximum tolerated dose (MTD) of gemcitabine administered as a fixed rate infusion (10 mg/m(2)/min) on a weekly schedule in patients with untreated non-hematologic malignancies. Patients ann methods: Twenty-seven patients (21 pancreatic adenocarcinoma, 3 hepatoma, 1 neuroendocrine tumor, and 2 adenocarcinoma of unknown primary) were enrolled in this open-label, non-randomized study. Three different entry dose levels (1200 mg/m(2), 1500 mg/m(2) and 1800 mg/m(2)) were evaluated for gemcitabine administered on days 1, 8, and 15 of a 28-day cycle. Results: The MTD was defined as 1500 mg/m(2) with granulocytopenia and thrombocytopenia being dose-limiting. There were no non-hematological dose limiting toxicities. The maximum WHO grade 3 or 4 toxicities for hemoglobin, leukocytes, neutrophils, and platelets for all doses of gemcitabine administered were 11.5%, 30.8%, 57.7%, and 26.9%, respectively. Non-hematologic toxicities included nausea, vomiting and fever. Four patients were withdrawn from the study for non-hematological toxicities: pneumonitis, ascites, disabling fatigue, and an acute myocardial infarction. Two of these events were severe (pneumonitis and myocardial infarction) but these may not be related to drug administration. Conclusion: Gemcitabine administered at a rate of 10 mg/m(2)/min was tolerated up to 1500 mg/m(2) in patients with previously untreated non-hematologic malignancies. Myelosuppression seen in this study is more severe than anticipated based on previous reports of bolus administration of similar doses of gemcitabine. This supports earlier studies suggesting that prolonged duration of infusion increases the intracellular accumulation of active metabolites of gemcitabine.