Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma
Nilotinib as Coadjuvant Treatment with Doxorubicin in Patients with Sarcomas: A Phase I Trial of the Spanish Group for Research on Sarcoma
复制标题
DOI：
10.1158/1078-0432.ccr-18-0851
复制
发表时间：
2018-11-01
影响因子：
11.5
通讯作者：
Martin-Broto, Javier
中科院分区：
文献类型：
--
作者：
Alemany, Regina;Moura, David S.;Martin-Broto, Javier
目的：尼洛替尼联合阿霉素对几种肉瘤细胞株的细胞凋亡有协同作用。因此，设计了一项I/II期试验，以探讨尼洛替尼通过抑制MRP-1/P-gp外排活性作为阿霉素辅助佐剂的可行性。患者和方法：尼洛替尼400 mg/12h，固定剂量，第1~6天，阿霉素，每周期第5天。阿霉素60、65和75 mg/m(2)的三个剂量递增水平被计划。每3周重复1个周期，共4个周期。结果：共入选13例患者，其中软骨肉瘤7例，脂肪肉瘤4例，平滑肌肉瘤2例。在46个周期中，每个患者最相关的3/4级不良反应是中性粒细胞减少54%，发热中性粒细胞减少15%，虚弱8%。未观察到心脏毒性。在第三剂量水平中只有一种剂量限制毒性(发热性中性粒细胞减少症)被报告。在疗效方面，1例部分缓解(1例脂肪肉瘤)，9例稳定(软骨肉瘤5例，脂肪肉瘤2例，平滑肌肉瘤1例)，3例进展性疾病(软骨肉瘤2例，平滑肌肉瘤1例)。在周期的第5天，ABCB1和ABCC1的RNA表达水平分别下降了58.47倍和1.47倍。结论：MRP-1/P-gp抑制剂尼洛替尼与阿霉素联合应用是可行的，与阿霉素单用相比似乎没有明显的毒性。药效学研究支持这一概念。阿霉素II期的推荐剂量为75 mg/m(2)。(C)2018年AACR。
Purpose: Nilotinib plus doxorubicin showed to be synergistic regarding apoptosis in several sarcoma cell lines. A phase I/II trial was thus designed to explore the feasibility of nilotinib as coadjuvant of doxorubicin by inhibiting MRP-1/P-gp efflux activity. The phase I part of the study is presented here.Patients and Methods: Nilotinib 400 mg/12 hours was administered in fixed dose from day 1 to 6, and doxorubicin on day 5 of each cycle. Three dose escalation levels for doxorubicin at 60, 65, and 75 mg/m(2) were planned. Cycles were repeated every 3 weeks for a total of 4 cycles. Eligible subtypes were retroperitoneal liposarcoma, leiomyosarcoma, and unresectable/metastatic high-grade chondrosarcoma.Results: Thirteen patients were enrolled: 7 chondrosarcoma, 4 liposarcoma, and 2 leiomyosarcoma. In 46 cycles administered, the most relevant grade 3/4 adverse effects per patient were neutropenia 54%, febrile neutropenia 15%, and asthenia 8%. No cardiac toxicity was observed. Only one doselimiting toxicity (febrile neutropenia) was reported in the third dose level. With regard to efficacy, 1 partial response (1 liposarcoma), 9 stable diseases (5 chondrosarcoma, 2 liposarcoma, 1 leiomyosarcoma), and 3 progressive diseases (2 chondrosarcoma and 1 leiomyosarcoma) were present. ABCB1 and ABCC1 RNA expression levels decreased by 58.47-fold and 1.47-fold, respectively, on day 5 of the cycle.Conclusions: Combination of MRP-1/P-gp inhibitor, nilotinib, as coadjuvant with doxorubicin is feasible; it appears not to add substantial toxicity compared with doxorubicin alone. Pharmacodynamic study supports this concept. The recommended dose for the phase II part for doxorubicin was 75 mg/m(2). (C) 2018 AACR.