This study determined the safety and recommended phase 2 dose (RP2D) of the multikinase inhibitor cabozantinib in combination with trifluridine/tipiracil (FTD/TPI) in refractory metastatic colorectal carcinoma (mCRC). Single institution investigator-initiated phase 1 study using 3+3 design. Eligible mCRC patients had received prior standard regimens. Cabozantinib was given orally (p.o.) at 20 mg (dose level [DL] 0) or 40 mg (DL 1) daily on days 1-28, and FTD/TPI p.o. at 35 mg/m on days 1-5 and 8-12 every 28 days. Prophylactic growth-factor support was allowed. Fifteen patients were enrolled. Median age 56 years (31-80), male (12/15), ECOG 0/1 = 9/6. Three patients were treated at DL 0 and another nine were treated at DL 1, none exhibiting a DLT. Most common any grade (G) treatment related adverse events (TRAE) were diarrhea (50%), nausea (42%), neutropenia (42%), fatigue (33%), and rash (25%). G3-4 TRAE were neutropenia (25%) and thrombocytopenia, hypokalemia, and weight loss (each 8%). No serious TRAE or G5 were reported. The RP2D was determined to be DL 1. Median PFS was 3.8 months (95% CI 1.9-6.8) and disease control rate was 86.7%. The combination of cabozantinib and FTD/TPI is feasible and tolerable at standard doses with the use of growth factors and showed encouraging clinical activity in refractory mCRC. NCT04868773.

中文翻译：

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卡博替尼和曲氟尿苷/替吡拉西治疗转移性结直肠腺癌的 1 期研究

本研究确定了多激酶抑制剂卡博替尼与曲氟尿苷/替匹拉西 (FTD/TPI) 联合治疗难治性转移性结直肠癌 (mCRC) 的安全性和推荐的 2 期剂量 (RP2D)。单一机构研究者发起的 1 期研究采用 3+3 设计。符合条件的转移性结直肠癌患者之前已接受过标准治疗方案。卡博替尼在第 1-28 天每天口服 20 mg（剂量水平 [DL] 0）或 40 mg (DL 1)，第 1-5 天和第 8 天以 35 mg/m 的 FTD/TPI 口服（po）。每 28 天 12 次。允许预防性生长因子支持。共招募了 15 名患者。中位年龄 56 岁 (31-80)，男性 (12/15)，ECOG 0/1 = 9/6。3 名患者在 DL 0 时接受治疗，另外 9 名患者在 DL 1 时接受治疗，没有人表现出 DLT。最常见的任何级别 (G) 治疗相关不良事件 (TRAE) 为腹泻 (50%)、恶心 (42%)、中性粒细胞减少 (42%)、疲劳 (33%) 和皮疹 (25%)。G3-4 TRAE 为中性粒细胞减少症 (25%) 和血小板减少症、低钾血症和体重减轻 (各 8%)。没有报告严重的 TRAE 或 G5。RP2D 确定为 DL 1。中位 PFS 为 3.8 个月（95% CI 1.9-6.8），疾病控制率为 86.7%。卡博替尼和 FTD/TPI 的组合在标准剂量下与生长因子的使用是可行且耐受的，并且在难治性 mCRC 中显示出令人鼓舞的临床活性。NCT04868773。