PURPOSE This two-part phase Ib trial determined the maximum tolerated dose (MTD) of the combination of trifluridine/tipiracil (FTD/TPI) and irinotecan in patients with advanced gastrointestinal tumors, and evaluated the safety, pharmacokinetics, and antitumor activity of the FTD/TPI, irinotecan, and bevacizumab triplet combination in previously treated metastatic colorectal cancer (mCRC). PATIENTS AND METHODS Dose escalation (3+3 design) in advanced gastrointestinal tumors was followed by expansion in mCRC. During dose escalation, patients received FTD/TPI (20-35 mg/m2 twice daily; days 1-5 of a 14-day cycle) and irinotecan (120-180 mg/m2; day 1). During expansion, the MTD of FTD/TPI and irinotecan plus bevacizumab (5 mg/kg; day 1) was administered. RESULTS Fifty patients (26 across six dose-escalation cohorts and 24 in the expansion phase) were enrolled. Two dose-limiting toxicities (fatigue and neutropenia) were observed in the dose-escalation phase, and MTD was defined as FTD/TPI 25 mg/m2 twice daily plus irinotecan 180 mg/m2. In the expansion phase, 83% (20/24) experienced any-cause grade ≥3 adverse events (AEs) with the triplet combination, most frequently neutropenia (42%), leukopenia (25%), and diarrhea (12%). AEs of any-cause led to dosing interruptions, modifications, and discontinuations in 29%, 17%, and 4% of patients, respectively. No treatment-related deaths occurred. Three patients (12%) experienced partial responses and 16 (67%) patients had stable disease lasting >4 months. The median progression-free survival was 7.9 months (95% confidence interval, 5.1-13.4 months). CONCLUSIONS Tolerability and activity observed in this phase I trial support further investigation of the FTD/TPI-irinotecan-bevacizumab combination in previously treated mCRC.

中文翻译：

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Trifluridine/Tipiracil 加伊立替康和贝伐单抗治疗晚期胃肠道肿瘤的 I 期研究。

目的 这项由两部分组成的 Ib 期试验确定了曲氟尿苷/替吡嘧啶 (FTD/TPI) 和伊立替康联合治疗晚期胃肠道肿瘤患者的最大耐受剂量 (MTD)，并评估了 FTD 的安全性、药代动力学和抗肿瘤活性/TPI、伊立替康和贝伐单抗三联疗法治疗既往治疗的转移性结直肠癌 (mCRC)。患者和方法 晚期胃肠道肿瘤的剂量递增（3+3 设计）随后是 mCRC 的扩展。在剂量递增期间，患者接受 FTD/TPI（20-35 mg/m2 每天两次；14 天周期的第 1-5 天）和伊立替康（120-180 mg/m2；第 1 天）。在扩增期间，给予 FTD/TPI 和伊立替康加贝伐单抗（5 mg/kg；第 1 天）的 MTD。结果 入组了 50 名患者（6 个剂量递增队列中的 26 名患者和扩展阶段中的 24 名患者）。在剂量递增阶段观察到两种剂量限制性毒性（疲劳和中性粒细胞减少），MTD 定义为 FTD/TPI 25 mg/m2 每天两次加伊立替康 180 mg/m2。在扩展阶段，83% (20/24) 的三联疗法出现了任何原因的≥3 级不良事件 (AE)，最常见的是中性粒细胞减少症 (42%)、白细胞减少症 (25%) 和腹泻 (12%)。任何原因的 AE 分别导致 29%、17% 和 4% 的患者给药中断、修改和停药。没有发生与治疗相关的死亡。3 名患者 (12%) 出现部分缓解，16 名 (67%) 患者病情稳定持续 > 4 个月。中位无进展生存期为 7.9 个月（95% 置信区间，5.1-13.4 个月）。