聚乙二醇化脂质体阿霉素联合环磷酰胺和长春新碱治疗复发/难治性实体瘤儿科患者：一项单臂、开放标签的I期研究。
Pegylated liposomal doxorubicin combined with cyclophosphamide and vincristine in pediatric patients with relapsed/refractory solid tumor: a single-arm, open-label, phase I study.
作者信息
Lu Suying, Wang Juan, Huang Junting, Sun Feifei, Zhu Jia, Que Yi, Li Hui, Guo Ying, Cai Ruiqing, Zhen Zijun, Sun Xiaofei, Zhang Yizhuo
机构信息
Department of Pediatric Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
Department of Radiology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou 510060, PR China.
出版信息
EClinicalMedicine. 2024 Jun 20;73:102701. doi: 10.1016/j.eclinm.2024.102701. eCollection 2024 Jul.
BACKGROUND
The combined vincristine, pegylated liposomal doxorubicin (PLD), and cyclophosphamide (VPC) regimen has never been studied in pediatric patients.
METHODS
This open-label, single-center, single-arm phase I study utilizing a "3 + 3" design enrolled children with relapsed/refractory (R/R) solid tumors. Three dose levels of PLD (Duomeisu®) were studied (30, 40, or 50 mg/m) in combination with cyclophosphamide (1500 mg/m), mesna (1500 mg/m), and vincristine (1.5 mg/m, maximum 2 mg) once every 3 weeks. The primary endpoints included safety, the maximum tolerated dose (MTD) of PLD (Duomeisu®), and the recommended phase 2 dose (RP2D) of PLD (Duomeisu®) for further phase 2 investigation. The secondary endpoints were objective response rate (ORR) and disease control rate (DCR). This study is registered with ClinicalTrials.gov, NCT04213612.
FINDINGS
Between January 7, 2020, and November 18, 2021, 34 patients were eligible and evaluable for toxicity, while 26 patients were evaluable for response. The MTD of PLD (Duomeisu®) was 30 mg/m. The most common adverse event (AE) was grade 3 or 4 neutropenia (61.8%). The most common grade 1 or 2 non-hematologic AE and cardiotoxicity effects were vomiting (35.3%) and abnormal electrocardiogram T waves (20.6%), respectively. ORR and DCR to VPC regimen after two cycles were 50.0% and 92.3%, respectively. Targeted gene panel sequencing revealed the activation of mutation may be an adverse prognostic factor.
INTERPRETATION
The VPC regimen showed a promising safety profile and had preliminary efficacy in children with R/R solid tumors. The RP2D for PLD (Duomeisu®) combined with cyclophosphamide and vincristine is 30 mg/m once every 3 weeks.
FUNDING
CSPC Ouyi Pharmaceutical Co., Ltd., Shijiazhuang, the National Key Research and Development Program of China [No. 2022YFC2705005], the National Natural Science Foundation of China [No. 82203303], and the Basic and Applied Basic Research Foundation of Guangdong Province [No. 2021A1515110234].
背景
长春新碱、聚乙二醇化脂质体阿霉素（PLD）和环磷酰胺联合方案（VPC）从未在儿科患者中进行过研究。
方法
本项采用“3+3”设计的开放标签、单中心、单臂I期研究纳入了复发/难治性（R/R）实体瘤患儿。研究了三种剂量水平的PLD（多美素®）（30、40或50mg/m²）与环磷酰胺（1500mg/m²）、美司钠（1500mg/m²）和长春新碱（1.5mg/m²，最大2mg）联合使用，每3周一次。主要终点包括安全性、PLD（多美素®）的最大耐受剂量（MTD）以及用于进一步II期研究的PLD（多美素®）的推荐II期剂量（RP2D）。次要终点为客观缓解率（ORR）和疾病控制率（DCR）。本研究已在ClinicalTrials.gov注册，注册号为NCT04213612。
研究结果
在2020年1月7日至2021年11月18日期间，34例患者符合毒性评估标准且可进行评估，26例患者可进行疗效评估。PLD（多美素®）的MTD为30mg/m²。最常见的不良事件（AE）为3级或4级中性粒细胞减少（61.8%）。最常见的1级或2级非血液学AE和心脏毒性效应分别为呕吐（35.3%）和心电图T波异常（20.6%）。两个周期后VPC方案的ORR和DCR分别为50.0%和92.3%。靶向基因panel测序显示 突变的激活可能是不良预后因素。
解读
VPC方案显示出良好的安全性，并且在R/R实体瘤患儿中具有初步疗效。PLD（多美素®）联合环磷酰胺和长春新碱的RP2D为每3周一次30mg/m²。
资助
石药集团欧意药业有限公司、中国国家重点研发计划[编号2022YFC2705005]、中国国家自然科学基金[编号82203303]以及广东省基础与应用基础研究基金[编号2021A1515110234]。
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