A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors.
A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors.
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DOI：
10.1186/s12885-016-2933-6
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发表时间：
2016-11-21
期刊：
影响因子：
3.8
通讯作者：
Chen LT
中科院分区：
文献类型：
--
作者：
Chiang NJ;Chao TY;Hsieh RK;Wang CH;Wang YW;Yeh CG;Chen LT
PEP02(也称为MM-398，Nal-IRI)是一种新型的伊立替康脂质体纳米制剂。本研究的目的是研究PEP02联合5-FU和LV治疗晚期难治性实体瘤的剂量限制毒性(DLT)、最大耐受量(MTD)和药代动力学(PK)。患者在第1天接受PEP02 60~120 mg/m2(剂量以盐酸伊立替康三水盐表示)90min静脉滴注，然后在第1天和第8天24小时静脉滴注5-FU 2000 mg/m2和LV 200 mg/m2，每3周一次。共有16名患者被分配到四个剂量水平，60(3名患者)，80(6名患者)，100(5名患者)和120 mg/m2(2名患者)。在4名患者中观察到DLT，其中2名患者在100 mg/m2剂量水平(1名患者出现III级感染伴低血压和III级出血；另一名患者出现III级腹泻和IV级中性粒细胞减少症)，2名患者在120 mg/m2剂量水平(1名患者出现III级腹泻和IV级中性粒细胞减少症；另一名患者出现III级腹泻)。测得PEP02的最大抑菌浓度为80 mg/m2。与治疗相关的最常见的不良反应是恶心(81%)、腹泻(75%)和呕吐(69%)。在接受MTD治疗的6名患者中，1名患者部分缓解，4名患者病情稳定，1名患者病情进展。药代动力学数据显示，与伊立替康相比，PEP02具有较低的血药浓度、较长的半衰期和较大的血药浓度-时间曲线下面积。PEP02第1天联合5-FU和LV 24 h静脉滴注第1、8天，每3周1次的MTD为80 mg/m2，可作为今后研究的推荐剂量。该试验追溯登记(NCT02884128)，登记日期：2016年8月12日。本文的在线版本(doi：10.1186/s12885-0162933-6)包含补充材料，授权用户可以使用。
PEP02 (also known as MM-398, nal-IRI) is a novel nanoparticle formulation of irinotecan encapsulated in liposomes. The aims of this study were to investigate the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02 in combination with 5-FU and LV, in patients with advanced refractory solid tumors. Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m2 (dose expressed as the irinotecan hydrochloride trihydrate salt) as a 90-min intravenous infusion on day 1, followed by 24 h infusion of 5-FU 2,000 mg/m2 and LV 200 mg/m2 on days 1 and 8, every 3 weeks. A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m2 (two patients). DLT was observed in four patients, two at the 100 mg/m2 dose level (one had grade III infection with hypotension and grade III hemorrhage; the other had grade III diarrhea and grade IV neutropenia), and two at the 120 mg/m2 dose level (one had grade III diarrhea and grade IV neutropenia; the other had grade III diarrhea). The MTD of PEP02 was determined as 80 mg/m2. The most common treatment-related adverse events were nausea (81%), diarrhea (75%) and vomiting (69%). Among the six patients who received the MTD, one patient exhibited partial response, four patients had stable disease and one showed progressive disease. Pharmacokinetic data showed that PEP02 had a lower peak plasma concentration, longer half-life, and increased area under the plasma concentration-time curve from zero to time t of SN-38 than irinotecan at similar dose level. The MTD of PEP02 on day 1 in combination with 24-h infusion of 5-FU and LV on days 1 and 8, every 3 weeks was 80 mg/m2, which will be the recommended dose for future studies. The trial was retrospectively registered (NCT02884128) with date of registration: August 12, 2016. The online version of this article (doi:10.1186/s12885-016-2933-6) contains supplementary material, which is available to authorized users.
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