Prolonged infusion gemcitabine: a clinical phase I study at low- (300 mg/m2) and high-dose (875 mg/m2) levels

摘要: Gemcitabine (GEM) is a novel nucleoside analogue with unique mechanism of action. Preliminary studies have shown mild, schedule-dependent toxic profile broad range MTDs and promising antitumor activity in various solid tumors. This phase I study describes the infusion length-effect relationships low(300 mg/m2) high-dose (875 GEM, administered on days 1, 8 15 at 4-week intervals step-wise escalation duration (> 33%) starting level 60 minutes. At least 3 patients entered each infusion-level step more cases were treated presence significant toxicity. Conservative criteria for toxicity employed, including treatment delay until recovery de-escalation subsequent course. Forty seven (29 low- 18 GEM levels) tumors, 9 (taken as reference) who had received same dose-levels over 30 min. study. All but (with pancreatic cancer) been previously chemotherapy all extensive visceral disease. A striking infusional-effect relationship was observed both dose levels. Four steps required to define maximum tolerated time (MTIT) 6 hours 300 mg/m2 leucopenia being dose-limiting. 875 mg/m2, although no limiting (in spite increased severity leucopenia), attempted following 1 hour infusion, due rate (58% 12 patients) requiring shorter infusions. Toxicity usually mild (no grade 4 event recorded) showing usual profile, there trend towards non-hematologic (i.e. LFT abnormalities) compared MTD defined using 30-min. schedule (1,370 mg/m2). Eight achieved PR: NSCLC, gastric 2 bladder cancer (1 3- 6-hour infusion) pancreatic, cervical another (all one 1-hour infusion). These data clearly suggest that an important independent factor influences clinical effects GEM. The present not only profiles MTITs selected demonstrated retained doses small when given prolonged infusion. Further should clarify underlying mechanism(s) responsible erratic dose-effect establish optimal dose-infusion