A phase I and pharmacokinetic study of novel taxane BMS-188797 and cisplatin in patients with advanced solid tumours

摘要

This phase I study investigated the maximum tolerated dose and pharmacokinetics of a 3-weekly administration of BMS-188797, a paclitaxel derivate, at three dose levels (DLs) (80, 110 and 150?mg?m?2 DL), combined with cisplatin (standard dose 75?mg?m?2). In 16 patients with advanced malignancies treated, one patient experienced dose-limiting febrile neutropenia, sepsis and severe colitis at the 150?mg?m?2 DL; at the 110?mg?m?2 DL one episode of dose-limiting grade 3 diarrhoeaausea occurred. Grade 3/4 haematological toxicities were leucopeniaeutropenia; grade 3 nonhaematological toxicities were neuropathy, nausea, diarrhoea and stomatits. Objective response was seen in four patients, with three complete remissions in ovarian and cervical cancer patients. Pharmacokinetics of BMS-188797 appeared linear through the 110?mg?m?2, but not through the 150?mg?m?2 DL. The mean±SD values for clearance, distribution volume at steady state and terminal half-life during cycle 1 were 317±60?ml?min?1?m?2, 258±96?l?m?2 and 30.8±7.7?h, respectively. The maximum tolerated and recommended phase II dose for BMS-188797 was 110?mg?m?2 (1-h infusion, every 3 weeks) combined with cisplatin 75?mg?m?2.