Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors
Phase I clinical and pharmacokinetic study of BMS-247550, a novel derivative of epothilone B, in solid tumors
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DOI：
10.1158/1078-0432.ccr-0919-03
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发表时间：
2004-02-15
影响因子：
11.5
通讯作者：
Horwitz, SB
中科院分区：
文献类型：
--
作者：
Mani, S;McDaid, H;Horwitz, SB
目的：本研究的目的是确定BMS-247550的最大耐受剂量、毒性和药代动力学，BMS-247550每3周静脉输注1小时。实验设计：对晚期实体恶性肿瘤患者进行预用药，并逐渐增加BMS-247550的剂量。取血表征BMS-247550的药效学和药代动力学。结果：25例患者接受7.4至59.2 mg/m(2) 6种剂量水平的治疗。在50 mg/m(2)时，9例患者中有4例（44.4%）出现剂量限制性毒性（中性粒细胞减少、腹痛/恶心）。在40mg /m（推荐的II期剂量）时，12例患者中有2例（16.7%）出现剂量限制性中性粒细胞减少症。总的来说，最常见的非血液学毒性是疲劳/全身无力（9.0%的患者为3-4级），其次是神经感觉缺陷，表现为周围神经病变和胃肠道不适。在40 mg/m(2)时，3级疲劳、腹痛、腹泻和神经病变的发生率为7.7%。在所有入组的患者中观察到1-2级神经病变，并以40 mg/m(2)治疗。两名紫杉醇难治性卵巢癌患者、一名紫杉醇初治乳腺癌患者和另一名多西紫杉醇难治性乳腺癌患者均有客观部分缓解（分别持续6.0、5.3、3.0和4.5个月）。在40 mg/m(2)（推荐II期剂量）剂量水平下，第一疗程中清除率、分布体积和表观终末消除半衰期的平均药代动力学参数值分别为21升/h/m(2)、826升/m(2)和35 h（不包括516 h的异常值）。课程1和课程2的数值相似。结论：BMS-247550 II期评估的推荐剂量为40 mg/m(2)，尽管需要更多的长期观察。BMS-247550在耐药方面比紫杉烷具有优势，值得进一步研究。
Purpose: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks.Experimental Design: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550.Results: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m(2). At 50 mg/m(2), 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m(2) (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m(2), the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m(2). Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naive breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively). The mean pharmacokinetic parameter values during course I for clearance, volume of distribution, and apparent terminal elimination half-life at the 40 mg/m(2) (recommended Phase II dose) dose level were 21 liters/h/m(2), 826 liters/m(2), and 35 h (excluding one outlier of 516 h), respectively. Values during course 1 and course 2 were similar.Conclusions: The recommended dose for Phase II evaluation of BMS-247550 is 40 mg/m(2), although more longterm observations are needed. BMS-247550 has advantages over taxanes in relation to drug resistance and warrants further study.