Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer.
Phase 1 study of oral TAS-102 in patients with refractory metastatic colorectal cancer.
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DOI：
10.1007/s00280-015-2850-4
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发表时间：
2015-11
影响因子：
3
通讯作者：
Patel MR
中科院分区：
文献类型：
--
作者：
Bendell JC;Rosen LS;Mayer RJ;Goldman JW;Infante JR;Benedetti F;Lin D;Mizuguchi H;Zergebel C;Patel MR
评价TAS-102在4周周期的第1-5天和第8-12天每日两次（bid）给药的安全性，确认日本推荐剂量（RD）35 mg/m2在标准化疗难治性转移性结直肠癌（mCRC）西方患者中的可行性，并描述初步抗肿瘤活性。这项开放标签、剂量递增的I期研究在4个美国中心进行。患者入组两个连续队列[30（队列1）或35 mg/m2/剂bid（队列2）];在剂量递增队列中，在第1周期评估了剂量限制性毒性（DLT）。在RD时，扩展队列入组了另外15例患者。难治性mCRC患者（N = 27）接受TAS-102治疗; 74%的患者接受过≥4种既往治疗方案。在队列1的3名患者中未观察到DLT，在队列2的9名患者中有1名患者观察到DLT（3级发热性中性粒细胞减少症）。因此，RD确定为35 mg/m2 bid。在RD时，疲乏（63%）、胃肠道紊乱和恶心（46%）、呕吐（46%）和腹泻（42%）很常见，但很少发生3/4级。3/4级恶心、呕吐和腹泻的发生率各为4%。3/4级毒性主要为血液学[中性粒细胞减少（71%），贫血（25%）];在2例患者中观察到发热性中性粒细胞减少。16例可评价患者（70%）实现了持续≥6周的疾病稳定;中位无进展生存期和总生存期分别为5.3和7.5个月。TAS-102在西方难治性mCRC患者中具有可接受的安全性特征和疾病稳定的初步证据。一项随机III期研究的结果显示，该人群的生存获益与疾病稳定证据。
To evaluate safety of TAS-102 administered twice daily (bid) on days 1–5 and 8–12 of a 4-week cycle, confirm feasibility of the Japanese recommended dose (RD), 35 mg/m2, in Western patients with metastatic colorectal cancer (mCRC) refractory to standard chemotherapies, and describe preliminary antitumor activity. This open-label, dose-escalation phase 1 study was conducted at four US centers. Patients were enrolled into two sequential cohorts [30 (cohort 1) or 35 mg/m2/dose bid (cohort 2)]; dose-limiting toxicities (DLT) were evaluated during cycle 1 in dose-escalation cohorts. At RD, 15 additional patients were enrolled in an expansion cohort. Patients (N = 27) with refractory mCRC received TAS-102; 74 % had received ≥4 prior regimens. DLT was not observed in three patients in cohort 1, and was in one out of nine patients in cohort 2 (grade 3 febrile neutropenia). Therefore, RD was identified as 35 mg/m2 bid. At RD, fatigue (63 %), gastrointestinal disturbances and nausea (46 %), vomiting (46 %), and diarrhea (42 %) were common but rarely grade 3/4. Grade 3/4 nausea, vomiting, and diarrhea occurred at 4 % each. Grade 3/4 toxicity was predominantly hematologic [neutropenia (71 %), anemia (25 %)]; febrile neutropenia was observed in two patients. Stable disease lasting ≥6 weeks was achieved by 16 evaluable patients (70 %); median progression-free survival and overall survival were 5.3 and 7.5 months, respectively. TAS-102 has an acceptable safety profile and preliminary evidence of disease stabilization in Western patients with refractory mCRC. Results from a randomized phase 3 study have shown survival benefit with disease stabilization evidence in this population.