Safety, Pharmacokinetics, and Efficacy of CPX-1 Liposome Injection in Patients with Advanced Solid Tumors
Safety, Pharmacokinetics, and Efficacy of CPX-1 Liposome Injection in Patients with Advanced Solid Tumors
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DOI：
10.1158/1078-0432.ccr-08-0515
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发表时间：
2009-01-15
影响因子：
11.5
通讯作者：
Louie, Arthur C.
中科院分区：
文献类型：
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作者：
Batist, Gerald;Gelmon, Karen A.;Louie, Arthur C.
目的：CPX-1是一种新型的伊立替康和氟尿定的脂质体包封制剂，旨在延长两种药物在体外输注后的最佳协同摩尔比。这项开放标签、单臂、剂量递增的I期研究旨在确定CPX-1在晚期实体瘤患者中的最大耐受剂量和药代动力学。实验设计：患者接受CPX-1以30、60、100、150、210或270单位/m(2)（1单位= 1mg伊立替康+ 0.36 mg氟尿定）每14天输注90分钟，28天为周期。在第1周期第1天和第15天采集药代动力学样本。结果：33例患者入组、治疗和安全性评估；对30例患者的反应进行了评估。血浆中伊立替康与氟尿定的摩尔比为1:1，维持8 ~ 12小时。3/4级毒性包括腹泻（24.2%）、中性粒细胞减少（12.1%）和低钾血症（12.1%）；1例患者（270单位/米）死于持续腹泻，导致脱水和肾功能衰竭（5级）。通过实体瘤反应评价标准评估的25例受试者中有3例（12%）出现部分反应。9例患者无进展生存期为6个月，其中6例为结直肠癌。在15例结直肠癌患者中（10例既往使用伊立替康），计算的中位无进展生存期为5.4个月；11例（72.7%）获得疾病控制，2例（13%）部分缓解。结论：门诊CPX-1耐受性良好，在晚期实体瘤患者中显示出抗肿瘤活性。未来研究的推荐剂量为210单位/米(2)。这是第一个固定药物比例剂量的临床评估，旨在保持协同的摩尔比，以增强治疗效益。
Purpose: CPX-1 is a novel, liposome-encapsulated formulation of irinotecan and floxuridine designed to prolong in vitro optimized synergistic molar ratios of both drugs postinfusion. This open-label, single-arm, dose-escalating phase I study was designed to determine the maximum tolerated dose and pharmacokinetics of CPX-1 in patients with advanced solid tumors.Experimental Design: Patients received CPX-1 at 30, 60, 100, 150, 210, or 270 units/m(2) (1 unit = 1 mg irinotecan + 0.36 mg floxuridine) infused over 90 minutes every 14 days in 28-day cycles. Pharmacokinetic samples were collected on days 1 and 15 of cycle 1.Results: Thirty-three patients were enrolled, treated, and evaluated for safety; 30 patients were evaluated for response. A 1:1 plasma irinotecan to floxuridine molar ratio was maintained for 8 to 12 hours. Grade 3/4 toxicities included diarrhea (24.2%), neutropenia (12.1%), and hypokalemia (12.1%); 1 patient (270 units/m(2)) died of persistent diarrhea, which led to dehydration and renal failure (grade 5). Partial response occurred in 3 (12%) of the 25 subjects evaluated through Response Evaluation Criteria in Solid Tumors. Progression-free survival lasting)6 months occurred in 9 patients, 6 with colorectal cancer. Among 15 colorectal cancer patients (10 with prior irinotecan), the calculated median progression-free survival was 5.4 months; 11 patients (72.7%) achieved disease control and 2 patients (13%) had partial response.Conclusions: Outpatient CPX-1 was well tolerated and antitumor activity was shown in patients with advanced solid tumors. The recommended dose for future studies is 210 units/m(2). This is the first clinical evaluation of fixed drug ratio dosing designed to maintain synergistic molar ratios for enhanced therapeutic benefit.