Abstract：
OBJECTIVE: This phase I trial is to determine the recommended dose of the TAS-102, irinotecan plus bevacizumab regimen and assess its safety and efficacy in patients with metastatic colorectal cancer refractory to fluoropyrimidine and oxaliplatin treatment.
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.
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.
摘要：
目的：本I期试验旨在确定TAS-102、伊立替康联合贝伐单抗方案的推荐剂量，并评估其在氟嘧啶和奥沙利铂治疗难治性转移性结直肠癌患者中的安全性和有效性。
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。
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。
