Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study
Trabectedin monotherapy after standard chemotherapy versus best supportive care in patients with advanced, translocation-related sarcoma: a randomised, open-label, phase 2 study
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DOI：
10.1016/s1470-2045(15)70098-7
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发表时间：
2015-04-01
期刊：
影响因子：
51.1
通讯作者：
Takahashi, Shunji
中科院分区：
文献类型：
--
作者：
Kawai, Akira;Araki, Nobuhito;Takahashi, Shunji
背景Trabectedin与DNA小沟结合并阻断DNA修复机制。临床前数据表明，trabectedin还调节易位相关肉瘤的致癌融合蛋白的转录。我们的目的是评估trabectedin作为二线治疗或晚期易位相关sarcoma.Methods患者的疗效和安全性，我们在日本进行了一项多中心随机开放标签研究。符合条件的患者有病理诊断为易位相关肉瘤，年龄在19岁或以上，对标准化疗方案无反应或不耐受，既往化疗方案不超过4种，东部肿瘤协作组体能状态为0或1，骨髓储备充足，肾和肝功能正常，并且有可测量的病变。通过最小化方法将患者随机分配（1：1）接受trabectedin（1.2 mg/m2）（在21天治疗周期的第1天通过中心静脉管线给予24 h）或最佳支持治疗，根据病理亚型进行集中调整。研究者、患者和申办者对治疗分配揭盲。通过设盲的中心放射学影像学审查评估无进展生存期和客观缓解。通过设盲的中心放射学成像审查评估疗效。主要终点是全分析集人群的无进展生存期。正在对接受研究治疗的患者进行随访。研究结果2012年7月11日至2014年1月20日期间，76例患者入组并分配接受曲贝替丁（n= 39）或最佳支持治疗（n= 37）。在中心审查确认病理亚型后，73例患者（37例在曲贝替丁组，36例在最佳支持治疗组）被纳入主要疗效分析。曲贝替丁组的中位无进展生存期为5.6个月（95%CI 4.1-7.5），最佳支持治疗组为0.9个月（0.7-1.0）。根据考克斯比例风险模型（p< 0.0001），曲贝替丁与最佳支持治疗的无进展生存率的风险比（HR）为0.07（90% CI 0.03-0.14和95% CI 0.03-0.16）。使用曲贝替定治疗的患者最常见的药物相关不良事件是恶心（32/36 [89%]），食欲减退（21例[58%]），中性粒细胞计数降低（30 [83%]），丙氨酸氨基转移酶升高（24人[67%]），以及白色血细胞数量减少（20 [56%]）.解释曲贝替定显著降低了标准化疗如阿霉素后晚期易位相关肉瘤患者的疾病进展和死亡风险并且应该被认为是该患者群体的新的治疗选择。
Background Trabectedin binds to the minor groove of DNA and blocks DNA repair machinery. Preclinical data have shown that trabectedin also modulates the transcription of the oncogenic fusion proteins of translocation-related sarcomas. We aimed to assess the efficacy and safety of trabectedin as second-line therapy or later for patients with advanced translocation-related sarcoma.Methods We did a multicentre randomised open-label study in Japan. Eligible patients had pathological diagnosis of translocation-related sarcoma, were aged 19 years or older, were unresponsive or intolerant to standard chemotherapy regimens, no more than four previous chemotherapy regimens, Eastern Cooperative Oncology Group performance status 0 or 1, adequate bone marrow reserve, renal and liver functions, and had measurable lesions. Patients were randomly assigned (1: 1) by the minimisation method to receive either trabectedin (1.2 mg/m(2) given via a central venous line over 24 h on day 1 of a 21 day treatment cycle) or best supportive care, which was adjusted centrally by pathological subtype. Investigators, patients, and the sponsor were unmasked to the treatment assignment. Progression-free survival and objective responses were assessed by a masked central radiology imaging review. Efficacy was assessed by masked central radiology imaging review. The primary endpoint was progression-free survival for the full analysis set population. Follow-up is ongoing for the patients under study treatment. The study is registered with Japan Pharmaceutical Information Center, number JapicCTI-121850.Findings Between July 11, 2012, and Jan 20, 2014, 76 patients were enrolled and allocated to receive either trabectedin (n= 39) or best supportive care (n= 37). After central review to confirm pathological subtypes, 73 patients (37 in the trabectedin group and 36 in the best supportive care group) were included in the primary efficacy analysis. Median progression-free survival of the trabectedin group was 5.6 months (95% CI 4.1-7.5) and the best supportive care group was 0.9 months (0.7-1.0). The hazard ratio (HR) for progression-free survival of trabectedin versus best supportive care was 0.07 (90% CI 0.03-0.14 and 95% CI 0.03-0.16) by a Cox proportional hazards model (p< 0.0001). The most common drug-related adverse events for patients treated with trabectedin were nausea (32 [89%] of 36), decreased appetite (21 [58%]), decreased neutrophil count (30 [83%]), increased alanine aminotransferase (24 [67%]), and decreased white blood cell count (20 [56%]).Interpretation Trabectedin significantly reduced the risk of disease progression and death in patients with advanced translocation-related sarcoma after standard chemotherapy such as doxorubicin, and should be considered as a new therapeutic treatment option for this patient population.