Bilenker J H, Stevenson J P, Gallagher M L, Vaughn D, Cohen M B, O'Dwyer P J
Abramson Family Cancer Center, University of Pennsylvania Cancer Center, 51 N. 39th St., MAB, Philadelphia, PA 19104, USA.
Br J Cancer. 2004 Jul 19;91(2):213-8. doi: 10.1038/sj.bjc.6601885.
The aim of the study was to determine the maximum-tolerated dose and dose-limiting toxicities for BMS-184476, in combination with carboplatin, in patients with advanced solid tumours and to describe any preliminary antitumour activity associated with this regimen. Patients received combination therapy with BMS-184476 given intravenously over 1 h followed by carboplatin administered over 30 min on day 1 of a 21-day cycle. In all, 28 patients received 146 cycles of BMS-184476 and carboplatin. Patients were enrolled at four dose levels: BMS-184476 (mg m(-2))/carboplatin (mg min ml(-1)): 40/5, 50/5, 50/6 and 60/6. Dose-limiting toxicity at 60/6 was neutropenia. Among 27 evaluable patients, 11 demonstrated stable disease for a median of 8.5 cycles. In 22 patients, the pharmacokinetics of BMS-184476 appeared independent of dose of BMS-184476. The mean+/-s.e.m. values for clearance (Cl), volume of distribution at steady state and apparent terminal half-life of BMS-184476 in the four dose groups during cycle 1 were 192+/-25 ml min m(-2), 377+/-69 l m(-2) and 33.7+/-5.9 h, respectively. An increase in the dose of carboplatin from 5 to 6 mg min ml(-1) may have decreased Cl of BMS-184476. BMS-184476 in combination with carboplatin was well tolerated at a dose of 50/6 and shows evidence of antitumour activity in a pretreated population.
本研究的目的是确定BMS-184476联合卡铂用于晚期实体瘤患者时的最大耐受剂量和剂量限制性毒性，并描述与该方案相关的任何初步抗肿瘤活性。患者接受联合治疗，在21天周期的第1天，静脉输注BMS-184476 1小时，随后30分钟内输注卡铂。共有28例患者接受了146个周期的BMS-184476和卡铂治疗。患者分为四个剂量水平：BMS-184476（mg m⁻²）/卡铂（mg min ml⁻¹）：40/5、50/5、50/6和60/6。60/6剂量水平的剂量限制性毒性为中性粒细胞减少。在27例可评估患者中，11例病情稳定，中位时间为8.5个周期。在22例患者中，BMS-184476的药代动力学似乎与BMS-184476的剂量无关。第1周期四个剂量组中BMS-184476的清除率（Cl）、稳态分布容积和表观终末半衰期的均值±标准误分别为192±25 ml min m⁻²、377±69 l m⁻²和33.7±5.9小时。将卡铂剂量从5 mg min ml⁻¹增加到6 mg min ml⁻¹可能会降低BMS-184476的Cl。BMS-184476联合卡铂在50/6剂量下耐受性良好，在预处理人群中显示出抗肿瘤活性的证据。
