PEP02（伊立替康脂质体注射液）联合5-氟尿嘧啶和亚叶酸钙用于晚期实体瘤的I期剂量递增研究。
A phase I dose-escalation study of PEP02 (irinotecan liposome injection) in combination with 5-fluorouracil and leucovorin in advanced solid tumors.
作者信息
Chiang Nai-Jung, Chao Tsu-Yi, Hsieh Ruey-Kuen, Wang Cheng-Hsu, Wang Yi-Wen, Yeh C Grace, Chen Li-Tzong
机构信息
National Institute of Cancer Research, National Health Research Institutes, 2F, No. 367, Sheng-Li Road, Tainan, 704, Taiwan.
Division of Hematology/Oncology, Department of Internal Medicine, National Cheng Kung University Hospital, Tainan, Taiwan.
出版信息
BMC Cancer. 2016 Nov 21;16(1):907. doi: 10.1186/s12885-016-2933-6.
BACKGROUND
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.
METHODS
Patients were enrolled in cohorts to receive PEP02 from 60 to 120 mg/m (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/m and LV 200 mg/m on days 1 and 8, every 3 weeks.
RESULTS
A total of 16 patients were assigned to four dose levels, 60 (three patients), 80 (six patients), 100 (five patients) and 120 mg/m (two patients). DLT was observed in four patients, two at the 100 mg/m 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/m 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/m. 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.
CONCLUSIONS
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/m, which will be the recommended dose for future studies.
TRIAL REGISTRATION
The trial was retrospectively registered ( NCT02884128 ) with date of registration: August 12, 2016.
背景
PEP02（也称为MM - 398、nal - IRI）是一种新型的脂质体包裹的伊立替康纳米颗粒制剂。本研究旨在调查PEP02与5 - FU和LV联合应用于晚期难治性实体瘤患者时的剂量限制性毒性（DLT）、最大耐受剂量（MTD）和药代动力学（PK）。
方法
患者被纳入不同队列，在第1天接受90分钟静脉输注PEP02，剂量为60至120mg/m²（剂量以三水合盐酸伊立替康盐表示），随后在第1天和第8天进行24小时输注5 - FU 2000mg/m²和LV 200mg/m²，每3周重复一次。
结果
共有16名患者被分配到四个剂量水平，分别为60mg/m²（3例患者）、80mg/m²（6例患者）、100mg/m²（5例患者）和120mg/m²（2例患者）。4名患者出现DLT，2名在100mg/m²剂量水平（1例为III级感染伴低血压和III级出血；另1例为III级腹泻和IV级中性粒细胞减少），2名在120mg/m²剂量水平（1例为III级腹泻和IV级中性粒细胞减少；另1例为III级腹泻）。PEP02的MTD确定为80mg/m²。最常见的治疗相关不良事件为恶心（81%）、腹泻（75%）和呕吐（69%）。在接受MTD的6名患者中，1例患者出现部分缓解，4例患者病情稳定，1例患者病情进展。药代动力学数据显示，在相似剂量水平下，与伊立替康相比，PEP02的血浆峰浓度较低、半衰期较长，SN - 38从0至时间t的血浆浓度 - 时间曲线下面积增加。
结论
PEP02在第1天与第1天和第8天24小时输注5 - FU和LV联合应用，每3周一次时的MTD为80mg/m²，这将是未来研究的推荐剂量。
试验注册
该试验为回顾性注册（NCT02884128），注册日期：2016年8月12日。
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