Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma.
Phase I combination study of trabectedin and doxorubicin in patients with soft-tissue sarcoma.
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DOI：
10.1158/1078-0432.ccr-08-0336
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发表时间：
2008-10-15
期刊：
影响因子：
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通讯作者：
Le Cesne A
中科院分区：
文献类型：
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作者：
Blay JY;von Mehren M;Samuels BL;Fanucchi MP;Ray-Coquard I;Buckley B;Gilles L;Lebedinsky C;Elsayed YA;Le Cesne A
确定复发性或持续性软组织肉瘤（STS）患者可控制的中性粒细胞减少症和可接受的剂量限制性毒性（dlt）与trabectedin加阿霉素联合粒细胞集落刺激因子（G-CSF）支持的剂量。在这项I期、开放标签、多中心试验中，先前接受0-1次化疗方案（不包括阿霉素）、ECOG表现状态0-1、器官功能充足的患者在3周周期的第1天立即接受10 - 15分钟静脉（IV）输注阿霉素60mg /m2，随后3小时静脉输注trabectedin 0.9-1.3 mg/m2。由于前6例患者中有4例在第1周期出现了dlt定义性中性粒细胞减少症，因此所有后续患者均接受了初级预防性G-CSF治疗。最大耐受剂量（MTD）是最高剂量水平，≥6例患者中不到三分之一的患者出现严重中性粒细胞减少或DLT。第1周期采集血液进行药代动力学分析。评估不良事件（ae）、肿瘤反应和生存率。患者（N = 41）接受了中位数为6个周期的治疗（范围2-13）。MTD为1.1 mg/m2，阿霉素为60 mg/m2。常见的3/4级治疗突发ae为中性粒细胞减少症（71%）、ALT升高（46%）和血小板减少症（37%）。总体而言，5例（12%）患者获得部分缓解，34例（83%）患者保持疾病稳定。中位无进展生存期为9.2个月。阿霉素和曲比定的药代动力学在同时给药时没有明显改变。阿霉素60mg /m2联合曲比汀1.1 mg/m2每21天在STS患者中是安全有效的。
To determine the dose of trabectedin plus doxorubicin with granulocyte colony stimulating factor (G-CSF) support associated with manageable neutropenia and acceptable dose-limiting toxicities (DLTs) in patients with recurrent or persistent soft tissue sarcoma (STS). In this phase I, open-label, multicenter trial, patients previously treated with 0–1 prior chemotherapy regimens excluding doxorubicin, an ECOG performance status 0–1, and adequate organ function received a 10–15-minute intravenous (IV) infusion of doxorubicin 60 mg/m2 immediately followed by a 3-hour IV infusion of trabectedin 0.9–1.3 mg/m2 on day 1 of a 3-week cycle. Because four of the first six patients experienced DLT-defining neutropenia during cycle 1, all subsequent patients received primary prophylactic G-CSF. The maximum tolerated dose (MTD) was the highest dose level with ≥6 patients in which less than one third of the patients experienced severe neutropenia or DLT. Blood was collected during cycle 1 for pharmacokinetic analyses. Adverse events (AEs), tumor response, and survival were assessed. Patients (N = 41) received a median of six cycles of treatment (range, 2–13). The MTD was trabectedin 1.1 mg/m2 and doxorubicin 60 mg/m2. Common grade 3/4 treatment-emergent AEs were neutropenia (71%), ALT increase (46%), and thrombocytopenia (37%). Overall, five (12%) patients achieved a partial response, and 34 (83%) maintained stable disease. Median progression-free survival was 9.2 months. Doxorubicin and trabectedin pharmacokinetics were not altered substantially with concomitant administration. The combination of doxorubicin 60 mg/m2 followed by trabectedin 1.1 mg/m2 every 21 days is safe and active in patients with STS.