ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC)
ASCEND-8: A Randomized Phase 1 Study of Ceritinib, 450 mg or 600 mg, Taken with a Low-Fat Meal versus 750 mg in Fasted State in Patients with Anaplastic Lymphoma Kinase (ALK)-Rearranged Metastatic Non-Small Cell Lung Cancer (NSCLC)
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DOI：
10.1016/j.jtho.2017.07.005
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发表时间：
2017-09-01
影响因子：
20.4
通讯作者：
Wrona, Anna
中科院分区：
文献类型：
--
作者：
Cho, Byoung Chul;Kim, Dong-Wan;Wrona, Anna
简介：Ceritinib，750 mg，禁食，被批准用于治疗ALK受体酪氨酸激酶基因(ALK)重排(ALK阳性)的NSCLC患者，以前用过Crizotinib治疗。Ascend-8研究的第一部分确定了在维持相似暴露的情况下，在ALK阳性的非小细胞肺癌患者中，在低脂饮食中服用450 mg或600 mg的Ceritinib是否可以提高胃肠道(GI)耐受性。方法：Ascend-8是一项多中心、随机、开放的1期研究。第一部分研究了CELITINB的稳态药代动力学(PK)和安全性，在ALK阳性的晚期NSCLC患者中，450 mg或600 mg与750 mg禁食相比，450 mg或600 mg与低脂膳食一起服用，这些患者要么未接受治疗，要么接受化疗和/或克里佐替尼的预治疗。结果：截至2016年6月16日，137例患者被随机分为3组(450 mg口服[44例]、600 mg口服[47例]和750 mg禁食[46例])；135例患者接受西里替尼治疗。中位随访期为4.14个月。稳态时，与750 mg禁食相比，450 mg禁食后的最大血药浓度和24小时的血药浓度-时间曲线下面积与禁食前相当，而600 mg禁食后的PK比禁食前高约25%。与750 mg禁食相比，450 mg配合食物的患者发生胃肠道毒性的比例较低，主要是1级(腹泻[43.2%]、恶心[29.5%]和呕吐[18.2%])；没有发生3级或4级事件、研究中停药或严重的不良反应。结论：在ALK阳性的非小细胞肺癌禁食患者中，450 mg的Ceritinib与Ceritinib的暴露相似，GI安全性更好。(C)2017年国际肺癌研究协会。爱思唯尔公司出版，版权所有。
Introduction: Ceritinib, 750 mg fasted, is approved for treatment of patients with ALK receptor tyrosine kinase gene (ALK)-rearranged (ALK-positive) NSCLC previously treated with crizotinib. Part 1 of the ASCEND-8 study determined whether administering ceritinib, 450 mg or 600 mg, with a low-fat meal may enhance gastrointestinal (GI) tolerability versus 750 mg fasted in patients with ALK-positive NSCLC while maintaining similar exposure.Methods: ASCEND-8 is a multicenter, randomized, open label, phase 1 study. Part 1 investigated the steady-state pharmacokinetics (PK) and safety of ceritinib, 450 mg or 600 mg, taken with a low-fat meal versus 750 mg fasted in patients with advanced ALK-positive NSCLC who were either treatment naive or pretreated with chemotherapy and/or crizotinib. Part 2 will assess efficacy and safety of ceritinib in treatment-naive patients.Results: As of June 16, 2016, 137 patients were randomized (450 mg fed [n = 44], 600 mg fed [n = 47], and 750 mg fasted [n = 46]); 135 patients received ceritinib. Median follow-up duration was 4.14 months. At steady state, relative to 750 mg fasted, 450 mg with food demonstrated comparable PK as assessed by maximum (peak) concentration of drug in plasma and area under the plasma concentration-time curve from time zero to 24 hours, whereas 600 mg with food demonstrated approximately 25% higher PK. Relative to 750 mg fasted, 450 mg with food was associated with a lower proportion of patients with GI toxicities, mostly grade 1 (diarrhea [43.2%], nausea [29.5%], and vomiting [18.2%]); there were no grade 3 or 4 events, study drug discontinuations, or serious AEs due to GI toxicities.Conclusion: Ceritinib, 450 mg with food, had similar exposure and a more favorable GI safety profile than ceritinib, 750 mg in fasted patients with ALK-positive NSCLC. (C) 2017 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.