Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma
Phase I clinical and pharmacokinetic study of pemetrexed and carboplatin in patients with malignant pleural mesothelioma
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DOI：
10.1200/jco.2002.10.073
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发表时间：
2002-08-15
影响因子：
45.3
通讯作者：
Calvert, H
中科院分区：
文献类型：
--
作者：
Hughes, A;Calvert, P;Calvert, H
目的：确定培美曲塞和卡铂联合给药的最大耐受剂量（MTD），得出II期研究的推荐剂量，并探讨其疗效。我们评估了毒性，并探讨了药物联合治疗恶性胸膜间皮瘤（MPM）患者的活性。研究了两种药物的药代动力学。患者和方法：27例MPM患者（男性23例，女性4例）接受5个递增剂量水平的治疗。剂量范围从培美曲塞400mg /m（10分钟静脉输注），随后是卡铂在血浆浓度-时间曲线下的面积（AUC） 4mg /mL(.)min（作为30分钟静脉输注）到培美曲塞500mg /m(2)，卡铂AUC 6mg /mL.min。所有患者的世界卫生组织绩效状态均为1。总共进行了163个疗程的治疗（中位数为6个；范围为1到10个）。结果：主要毒性是血液学，特别是中性粒细胞减少症，尽管这是典型的短暂性，很少引起临床问题。MTD为培美曲塞500 mg/m(2)，卡铂AUC为6，因为在该剂量水平治疗的5名患者中有3名出现了剂量限制性毒性。在25例可评估的患者中观察到8例部分缓解，缓解率为32%。70%的患者注意到症状改善，通常（84%）仅在两个疗程后。中位进展时间为305天，中位生存时间为451天。结论：培美曲塞的MTD为500 mg/m(2)，卡铂的AUC为6 mg/mL.min。推荐的II期联合剂量为培美曲塞500mg /m(2)和卡铂AUC 5mg /mL.min。该组合在MPM中既有效又耐受性良好，值得进一步探索。(C) 2002年由美国临床肿瘤学会出版。
Purpose: To determine the maximum tolerated dose (MTD) of pemetrexed and carboplatin given in combination, to derive a recommended dose for phase II studies, and to explore its efficacy. We assessed toxicities and explored the activity of the drug combination exclusively in patients with malignant pleural mesothelioma (MPM). The pharmacokinetics of both agents was investigated.Patients and Methods: Twenty-seven patients (23 male, four female) with MPM were treated: on five escalating dose levels. Doses ranged from pemetrexed 400 mg/m(2) (as a 10-minute intravenous infusion), followed by carboplatin area under the plasma concentration-time curve (AUC) 4 mg/mL(.)min (as a 30-minute intravenous infusion) to pemetrexed 500 mg/m(2), Carboplatin AUC 6 mg/mL.min. All patients had a World Health Organization performance status of 1. A total of 163 courses of treatment were administered (median, six; range, one to 10).Results: The main toxicity was hematologic, particularly neutropenia, although this was characteristically short-lived and caused few clinical problems. The MTD was pemetrexed 500 mg/m(2), carboplatin AUC 6, because three of the five patients treated at this dose level experienced a dose-limiting toxicity. Eight partial responses (in 25 assessable patients) were observed for a response rate of 32%. Seventy percent of patients noticed an improvement in symptoms, usually (84%) after only two courses. Median time to progression was 305 days, and median survival time was 451 days.Conclusion: The MTD was pemetrexed 500 mg/m(2) and carboplatin AUC 6 mg/mL.min. The recommended phase II dose of the combination is pemetrexed 500 mg/m(2) and carboplatin AUC 5 mg/mL.min. The combination is both active and well tolerated in MPM and deserves further exploration. (C) 2002 by American Society of Clinical Oncology.