Jia Jun, Yu Jing, Sun Zhiwei, Yang Ying, Liu Chuanling, Xiao Yanjie, Zhang Xiaodong
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), the VIP-II Gastrointestinal Cancer Division of the Medical Department, Peking University Cancer Hospital & Institute, Beijing, China.
Transl Cancer Res. 2021 Feb;10(2):627-636. doi: 10.21037/tcr-20-2492.
Apatinib, an inhibitor of vascular endothelial growth factor receptor (VEGFR), has been used to treat esophagogastric adenocarcinoma. However, the dosage of apatinib varies greatly in clinical practice, and its safety in esophageal squamous cell carcinoma (ESCC) patients is unclear. Therefore, we initiated a phase 1 dose-escalation trial to identify the maximum tolerated dose (MTD) of apatinib when combined with irinotecan in ESCC.
The trial had a standard 3+3 design. The dosage of irinotecan was fixed at 150 mg/m repeated every 2 weeks, while the daily dosage of apatinib was escalated from 250 mg, to 500 mg, to 750 mg. Dose-limiting toxicity (DLT) was defined as grade 4 hematological or grade 3-4 non-hematological adverse events (AEs).
Twelve patients were enrolled. Three DLTs occurred, comprising a grade 3 perianal abscess and a grade 3 case of kaliopenia in the level 3 cohort, and a grade 4 leukopenia in the level 2 cohort. Based on these DLTs, the MTD of apatinib was 500 mg daily. The most common AEs were leukopenia (91.7%), fatigue (91.7%), anemia (66.7%), and diarrhea (58.3%). One case of grade 2 hematochezia and one case of grade 2 subclavian vein thrombosis were observed. In the nine evaluable cases, the disease control rate (DCR) was 66.7% (6/9). The median progression-free and overall survival (OS) times were 3.6±1.2 and 6.6±3.4 months, respectively.
This phase 1 dose-escalation trial showed that, when combined with irinotecan, a daily dose of 500 mg apatinib was the optimum dose to treat ESCC.
阿帕替尼是一种血管内皮生长因子受体（VEGFR）抑制剂，已被用于治疗食管胃腺癌。然而，阿帕替尼在临床实践中的剂量差异很大，其在食管鳞状细胞癌（ESCC）患者中的安全性尚不清楚。因此，我们开展了一项1期剂量递增试验，以确定阿帕替尼与伊立替康联合用于ESCC时的最大耐受剂量（MTD）。
该试验采用标准的3+3设计。伊立替康的剂量固定为每2周重复150mg/m，而阿帕替尼的每日剂量从250mg逐步递增至500mg、750mg。剂量限制毒性（DLT）定义为4级血液学或3-4级非血液学不良事件（AE）。
共纳入12例患者。发生了3例DLT，包括3级肛周脓肿1例、3级队列中的1例低钾血症以及2级队列中的1例4级白细胞减少症。基于这些DLT，阿帕替尼的MTD为每日500mg。最常见的AE为白细胞减少症（91.7%）、疲劳（91.7%）、贫血（66.7%）和腹泻（58.3%）。观察到1例2级便血和1例2级锁骨下静脉血栓形成。在9例可评估病例中，疾病控制率（DCR）为66.7%（6/9）。无进展生存期和总生存期（OS）的中位数分别为3.6±1.2个月和6.6±3.4个月。
这项1期剂量递增试验表明，阿帕替尼与伊立替康联合使用时，每日500mg是治疗ESCC的最佳剂量。
