Phase I trial of weekly gemcitabine at 3-h infusion in refractory, heavilypretreated advanced solid tumors

Gemcitabine (2',2'-difluorodeoxycytidine) is a nucleoside analog with antit umor activity against a variety of malignancies. The critical enzyme cytidi ne kinase is saturated at plasma concentrations achieved after a 30-min inf usion at conventional doses. Prolonged infusion time may yield higher intra cellular dFdCTP concentrations. A phase I study was designed to determine t he maximum tolerated dose (MTD) of gemcitabine, given by infusion for 3 h, in heavily pretreated patients. Twenty-seven patients (13 head and neck can cer, seven sarcoma, three esophageal cancer, three non-small-cell lung canc er and one ovarian cancer) were enrolled. Twenty patients were defined as r efractory at first- or second-line chemotherapy. Four different entry dose levels (300, 400, 450 and 500 mg/m(2)) were evaluated for gemcitabine admin istered on days 1, 8 and 15 of a 28-day cycle. The MTD was defined as 450 m g/m(2), with granulocytopenia, thrombocytopenia and asthenia being dose lim iting. The maximum grade III/IV patient toxicities for hemoglobin, leukocyt es, neutrophils and platelets for all doses were 7, 19, 19 and 11%, respect ively. Nonhematological toxicities included asthenia, nausea/vomiting and d iarrhea. Thus, gemcitabine administered at a fixed 3-h infusion was well to lerated up to 450 mg/m(2) in heavily pretreated patients. Myelosupression a nd asthenia were dose-limiting toxicities. [(C) 2001 Lippincott Williams & Wilkins.].