METHODS: A 3 + 3 designed dose escalation was performed. Patients were administered TAS-102 (30-35 mg/m2 twice daily on days 1-5) and irinotecan (150-165 mg/m2 on day 1) combined with a fixed dose of bevacizumab (5 mg/kg on day 1) every two weeks. The primary endpoint was the determination of the recommended phase II dose.
RESULTS: Eighteen patients were enrolled: 6 at the Level 1 (TAS-102 30 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), six at the Level 2 (TAS-102 35 mg/m2 twice daily, irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg), and six at the Level 3 (TAS-102 30 mg/m2 twice daily, irinotecan 165 mg/m2 plus bevacizumab 5 mg/kg). Five dose-limiting toxicities occurred: one observed at Level 1 (thrombocytopenia), two at Level 2 (neutropenia and diarrhea), and two at Level 3 (fatigue and neutropenia). The RP2D was established as TAS-102 30 mg/m2 twice daily and irinotecan 150 mg/m2 plus bevacizumab 5 mg/kg. The most frequent grade 3/4 treatment-related adverse events were neutropenia (33.3%), diarrhea (16.7%), and thrombocytopenia (11.1%). No treatment-related death occurred. Two patients (11.1%) experienced partial responses and 14 (77.8%) had stable disease.
CONCLUSIONS: The regimen of TAS-102, irinotecan, and bevacizumab is tolerable with antitumor activity for metastatic colorectal cancer patients refractory to first-line fluoropyrimidines and oxaliplatin treatment.
方法:进行A3+3设计剂量递增。每两周给患者施用TAS-102(30-35mg/m2,每天两次,在第1-5天)和伊立替康(150-165mg/m2,在第1天),以及固定剂量的贝伐单抗(在第1天5mg/kg)。主要终点是确定推荐的II期剂量。
结果:纳入18例患者:6例1级(TAS-10230mg/m2,每日两次,伊立替康150mg/m2加贝伐单抗5mg/kg),6级2级(TAS-10235mg/m2,每天两次,伊立替康150mg/m2加贝伐单抗5mg/kg),和6个在3级(TAS-10230毫克/平方米,每天两次,伊立替康165mg/m2加贝伐单抗5mg/kg)。发生了五种剂量限制性毒性:一种在1级(血小板减少症),2级(中性粒细胞减少和腹泻),和两个在3级(疲劳和中性粒细胞减少症)。RP2D确定为TAS-10230mg/m2,每日两次,伊立替康150mg/m2加贝伐单抗5mg/kg。最常见的3/4级治疗相关不良事件是中性粒细胞减少症(33.3%),腹泻(16.7%),和血小板减少(11.1%)。无治疗相关死亡发生。2例患者(11.1%)出现部分缓解,14例(77.8%)病情稳定。
结论:TAS-102、伊立替康、对于一线氟嘧啶和奥沙利铂治疗难以治疗的转移性结直肠癌患者,贝伐单抗具有抗肿瘤活性。