Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial
Nanoliposomal irinotecan with fluorouracil and folinic acid in metastatic pancreatic cancer after previous gemcitabine-based therapy (NAPOLI-1): a global, randomised, open-label, phase 3 trial
复制标题
DOI：
10.1016/s0140-6736(15)00986-1
复制
发表时间：
2016-02-06
期刊：
影响因子：
168.9
通讯作者：
Chen, Li-Tzong
中科院分区：
文献类型：
--
作者：
Wang-Gillam, Andrea;Li, Chung-Pin;Chen, Li-Tzong
背景：纳米脂质体伊立替康在既往接受过吉西他滨治疗的转移性胰腺导管腺癌患者的II期研究中显示出活性。我们评估了纳米脂质体伊立替康单独或联合氟尿嘧啶和亚叶酸在3期临床试验在此population.Methods的效果，我们做了一个全球性的，3期，随机，开放标签试验在76个网站在14个国家。在中心位置使用交互式网络应答系统将既往接受过吉西他滨治疗的符合条件的转移性胰腺导管腺癌患者随机分配（1：1）接受纳米脂质体伊立替康单药治疗（120 mg/m2，每3周一次，相当于100 mg/m2伊立替康碱）或氟尿嘧啶和亚叶酸。第三组由纳米脂质体伊立替康（80 mg/m2，相当于70 mg/m2伊立替康碱）与氟尿嘧啶和亚叶酸组成，每2周一次，随后在方案修订案中加入（1：1：1）。根据基线白蛋白、Karnofsky体力状态和种族对随机化进行分层。持续治疗直至疾病进展或出现不可耐受的毒性作用。主要终点是在意向治疗人群中评估的总生存期。计划在305起事件后进行主要分析。在所有接受研究药物的患者中评估安全性。在2012年1月11日至2013年9月11日期间，417名患者被随机分配为纳米脂质体伊立替康+氟尿嘧啶和亚叶酸（n=117），纳米脂质体伊立替康单药治疗（n=151）或氟尿嘧啶和亚叶酸（n=149）。ClinicalTrials.gov在发生313起事件后，接受纳米脂质体伊立替康+氟尿嘧啶和亚叶酸治疗的患者的中位总生存期为6.1个月（95% CI 4.8-8.9），而接受氟尿嘧啶和亚叶酸治疗的患者为4.2个月（3.3-5.3）（风险比0.67，95% CI 0.49-0.92; p=0.012）。接受纳米脂质体伊立替康单药治疗的患者与接受氟尿嘧啶和亚叶酸治疗的患者之间的中位总生存期无差异（4.9个月[4.2-5.6] vs 4.2个月[3.6-4.9]; 0.99，0.77-1.28; p=0.94）。在117例接受纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸治疗的患者中，最常发生的3级或4级不良事件是中性粒细胞减少症（32 [27%]），腹泻（15 [13%]），呕吐（13 [11%]），和疲劳（16人[14%]）解释纳米脂质体伊立替康联合氟尿嘧啶和亚叶酸延长了生存期，并具有可管理的安全性。既往接受过吉西他滨治疗的转移性胰腺导管腺癌。该药物代表了该人群的新治疗选择。
Background Nanoliposomal irinotecan showed activity in a phase 2 study in patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapies. We assessed the effect of nanoliposomal irinotecan alone or combined with fluorouracil and folinic acid in a phase 3 trial in this population.Methods We did a global, phase 3, randomised, open-label trial at 76 sites in 14 countries. Eligible patients with metastatic pancreatic ductal adenocarcinoma previously treated with gemcitabine-based therapy were randomly assigned (1: 1) using an interactive web response system at a central location to receive either nanoliposomal irinotecan monotherapy (120 mg/m(2) every 3 weeks, equivalent to 100 mg/m(2) of irinotecan base) or fluorouracil and folinic acid. A third arm consisting of nanoliposomal irinotecan (80 mg/m(2), equivalent to 70 mg/m(2) of irinotecan base) with fluorouracil and folinic acid every 2 weeks was added later (1: 1: 1), in a protocol amendment. Randomisation was stratified by baseline albumin, Karnofsky performance status, and ethnic origin. Treatment was continued until disease progression or intolerable toxic effects. The primary endpoint was overall survival, assessed in the intention-to-treat population. The primary analysis was planned after 305 events. Safety was assessed in all patients who had received study drug. This trial is registered at ClinicalTrials.gov, number NCT01494506.Findings Between Jan 11, 2012, and Sept 11, 2013, 417 patients were randomly assigned either nanoliposomal irinotecan plus fluorouracil and folinic acid (n=117), nanoliposomal irinotecan monotherapy (n=151), or fluorouracil and folinic acid (n=149). After 313 events, median overall survival in patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid was 6.1 months (95% CI 4.8-8.9) vs 4.2 months (3.3-5.3) with fluorouracil and folinic acid (hazard ratio 0.67, 95% CI 0.49-0.92; p=0.012). Median overall survival did not differ between patients assigned nanoliposomal irinotecan monotherapy and those allocated fluorouracil and folinic acid (4.9 months [4.2-5.6] vs 4.2 months [3.6-4.9]; 0.99, 0.77-1.28; p=0.94). The grade 3 or 4 adverse events that occurred most frequently in the 117 patients assigned nanoliposomal irinotecan plus fluorouracil and folinic acid were neutropenia (32 [27%]), diarrhoea (15 [13%]), vomiting (13 [11%]), and fatigue (16 [14%]).Interpretation Nanoliposomal irinotecan in combination with fluorouracil and folinic acid extends survival with a manageable safety profile in patients with metastatic pancreatic ductal adenocarcinoma who previously received gemcitabine-based therapy. This agent represents a new treatment option for this population.