Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients
Phase I study of nanoliposomal irinotecan (PEP02) in advanced solid tumor patients
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DOI：
10.1007/s00280-014-2671-x
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发表时间：
2015-03-01
影响因子：
3
通讯作者：
Chen, L. T.
中科院分区：
文献类型：
--
作者：
Chang, T. C.;Shiah, H. S.;Chen, L. T.
为了确定PEP 02（一种新型脂质体包封的伊立替康）在晚期难治性实体瘤患者中的剂量限制性毒性（DLT）、最大耐受剂量（MTD）和药代动力学（PK），在一项I期试验中，患者入组1 - 3人队列，接受递增剂量的PEP 02。PEP 02的剂量范围为60 - 180 mg/m（2），每3周一次，静脉输注90分钟。共11例患者入组3个剂量水平：60（1例患者）、120（6例患者）和180 mg/m（2）（4例患者）。在3名患者中观察到DLT，1名在120 mg/m2（3级导管相关感染），2名在180 mg/m2（1名4级中性粒细胞减少持续> 3天，另1名4级血液学毒性和4级腹泻）。MTD确定为120 mg/m2。与文献中游离伊立替康给药后的结果相比，PEP 02给药后SN-38（活性代谢产物）的剂量标准化PK特征为C（max）较低、终末半衰期延长和AUC较高，但具有显著的个体间变异。在180 mg/m2剂量下，1例死于治疗相关毒性的患者的SN-38 C（max）和AUC水平显著高于其他3例患者（2）。事后药物遗传学研究显示，该患者具有UGT 1A 1 *6/*28的联合杂合性基因型。2例患者出现客观肿瘤缓解。PEP 02通过脂质体包封明显改变了伊立替康和SN-38的PK参数。间隔3周的PEP 02单药治疗的MTD为120 mg/m（2），这将是未来研究的推荐剂量。
To define the dose-limiting toxicity (DLT), maximum tolerated dose (MTD) and pharmacokinetics (PK) of PEP02, a novel liposome-encapsulated irinotecan, in patients with advanced refractory solid tumors.Patients were enrolled in cohorts of one to three to receive escalating dose of PEP02 in a phase I trial. PEP02, from 60 to 180 mg/m(2), was given as a 90-min intravenous infusion, every 3 weeks.A total of 11 patients were enrolled into three dose levels: 60 (one patient), 120 (six patients) and 180 mg/m(2) (four patients). DLT was observed in three patients, one at 120 mg/m(2) (grade 3 catheter-related infection) and two at 180 mg/m(2) (grade 4 neutropenia lasting for > 3 days in one, grade 4 hematological toxicities and grade 4 diarrhea in the other). MTD was determined as 120 mg/m(2). Comparing with those after free-form irinotecan in the literature, the dose-normalized PK of SN-38 (the active metabolite) after PEP02 was characterized by lower C (max), prolonged terminal half-life and higher AUC but with significant inter-individual variation. One patient who died of treatment-related toxicity had significantly higher C (max) and AUC levels of SN-38 than those of the other three patients at 180 mg/m(2). Post hoc pharmacogenetic study showed that the patient had a combined heterozygosity genotype of UGT1A1*6/*28. Two patients had objective tumor response.PEP02 apparently modified the PK parameters of irinotecan and SN-38 by liposome encapsulation. The MTD of PEP02 monotherapy at 3-week interval is 120 mg/m(2), which will be the recommended dose for future studies.