PROLONGED INFUSION GEMCITABINE - A CLINICAL-PHASE-I STUDY AT LOW (300MG M(2)) AND HIGH-DOSE (875 MG/M(2)) LEVELS/

Gemcitabine (GEM) is a novel nucleoside analogue with a unique mechani sm of action. Preliminary studies have shown a mild, schedule-dependen t toxic profile with a broad range of MTDs and promising antitumor act ivity in various solid tumors. This phase I study describes the infusi on length-effect relationships of low- (300 mg/m(2)) and high-dose (87 5 mg/m(2)) GEM, administered on days 1, 8 and 15 at 4-week intervals i n a step-wise escalation of duration (greater than or equal to 33%) at a starting level of 60 minutes. At least 3 patients entered each infu sion-level step and 3 more cases were treated in the presence of signi ficant toxicity. Conservative criteria for toxicity were employed, inc luding treatment delay until recovery with infusion de-escalation in t he subsequent course. Forty-seven patients (29 at low- and 18 at high- dose GEM levels) with various solid tumors, including 9 (taken as a re ference) who had received the same dose levels over 30 min. entered th e study. All but 9 patients (with pancreatic cancer) had been previous ly treated with chemotherapy and all had extensive visceral disease. A striking infusional-effect relationship was observed at both GEM dose levels. Four escalation steps were required to define the maximum tol erated infusion time (MTIT) at 6 hours for 300 mg/m(2) GEM, with leuco penia being dose-limiting. At 875 mg/m(2), although no limiting toxici ty was observed (in spite of increased severity of leucopenia), no esc alation was attempted following the 1-hour infusion, due to the limiti ng rate (58% of 12 patients) of toxic delay requiring shorter infusion s. Toxicity was usually mild (no grade 4 event was recorded) showing t he usual profile, although there was a trend towards increased non-hem atologic toxicity (i.e. LFT abnormalities) as compared with the MTD pr eviously defined using a 30-min. infusion schedule (1,370 mg/m(2)). Ei ght patients achieved a PR: 1 with NSCLC, 1 with gastric and 2 with bl adder cancer at 300 mg/m(2) (1 with a 3- and 3 with a 6-hour infusion) and 2 with pancreatic, 1 with cervical and another with bladder cance r at 875 mg/m(2) (all but one with a 1-hour infusion). These data clea rly suggest that the infusion duration is an important independent fac tor that influences the clinical effects of GEM. The present study not only defined the toxic profiles and the MTITs of the selected dose le vels but demonstrated that GEM retained the antitumor activity at dose s as small as 300 mg/m(2) when given as a prolonged infusion. Further studies should clarify the underlying mechanism(s) responsible for the erratic dose-effect relationships of GEM and establish the optimal do se-infusion level in the treatment of solid tumors.