du Bois A, Jung B, Loehr A, Schaller-Kranz T, Cohen M, Frickhofen N
Department of Gynaecology and Gynaecologic Oncology, HSK, Dr Horst Schmidt Klinik, Ludwig-Erhard-Str. 100, Wiesbaden D-65199, Germany.
Br J Cancer. 2006 Jan 16;94(1):79-84. doi: 10.1038/sj.bjc.6602886.
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 diarrhoea/nausea occurred. Grade 3/4 haematological toxicities were leucopenia/neutropenia; 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).
本I期研究调查了每3周给药一次的紫杉醇衍生物BMS-188797在三个剂量水平（80、110和150mg/m²）联合顺铂（标准剂量75mg/m²）时的最大耐受剂量和药代动力学。在16例晚期恶性肿瘤患者中，1例在150mg/m²剂量水平出现剂量限制性发热性中性粒细胞减少、败血症和严重结肠炎；在110mg/m²剂量水平发生1次剂量限制性3级腹泻/恶心。3/4级血液学毒性为白细胞减少/中性粒细胞减少；3级非血液学毒性为神经病变、恶心、腹泻和口腔炎。4例患者出现客观缓解，其中卵巢癌和宫颈癌患者有3例完全缓解。BMS-188797的药代动力学在110mg/m²剂量水平呈线性，但在150mg/m²剂量水平则不然。第1周期的清除率、稳态分布容积和末端半衰期的平均值±标准差分别为317±60ml/min/m²、258±96l/m²和30.8±7.7小时。BMS-188797的最大耐受剂量和推荐的II期剂量为110mg/m²（静脉输注1小时，每3周一次）联合顺铂75mg/m²。
