Tsimafeyeu Ilya, Statsenko Galina, Vladimirova Liubov, Besova Natalia, Artamonova Elena, Raskin Grigory, Rykov Ivan, Mochalova Anastasia, Utyashev Igor, Gorbacheva Svetlana, Kazey Vasily, Gavrilova Evgenia, Dragun Nadezhda, Moiseyenko Vladimir, Tjulandin Sergei
Bureau of Cancer Research, Moscow office, Mayakovskogo pereulok 2, Moscow, Russia, 109147, Russian Federation.
Omsk Regional Cancer Center, Omsk, Russian Federation.
Invest New Drugs. 2023 Apr;41(2):324-332. doi: 10.1007/s10637-023-01340-z. Epub 2023 Mar 13.
Alofanib is a small-molecule allosteric extracellular FGFR2 inhibitor. We report safety and preliminary efficacy from the first-in-human phase 1b study of alofanib in heavily pretreated patients with advanced gastric cancer. The standard dose-escalation design 3+3 aimed to establish the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Alofanib was administered daily intravenously 5 days on, 2 days off. There were five dose levels (50-350 mg/m2). All patients received alofanib until disease progression or unacceptable toxicity. 21 patients were enrolled. Patients were predominantly male (71%), 67% had 2 and more metastatic sites, including liver metastases (43%), 19% had ECOG PS 2, and were heavily pretreated (86% had previous 2 and more treatment lines). During dose escalation, no dose-limiting toxicities were observed, and MTD was not defined. 15 (71.4%) patients had at least one adverse event associated with the treatment (TRAE). Grade 3 or higher TRAEs were observed in 6 patients (28.6%). The most common TRAEs included reactions immediately after administration, diarrhea, thrombocytopenia, arthralgia, and headache. The median progression-free survival and overall survival was 3.63 (95% CI 1.58-5.68) and 7.0 (95% CI 3.82-10.18) months, respectively. The 6- and 12-month overall survival rates were 57.1% and 33.3%. Disease control rate was 68% with one durable partial response. The MTD has not been reached and dose of 350 mg/m2, 5 days on, 2 days off has been declared as RP2D. Alofanib showed acceptable tolerability and preliminary signs of clinical activity in the late-line treatment of metastatic gastric cancer. (ClinicalTrials.gov identifier: NCT04071184).
阿洛法尼布是一种小分子变构细胞外FGFR2抑制剂。我们报告了阿洛法尼布在晚期胃癌经大量预处理患者中的首次人体1b期研究的安全性和初步疗效。标准的3+3剂量递增设计旨在确定最大耐受剂量（MTD）或推荐的2期剂量（RP2D）。阿洛法尼布采用静脉注射，每天给药5天，休息2天。共有五个剂量水平（50-350mg/m²）。所有患者接受阿洛法尼布治疗直至疾病进展或出现不可接受的毒性。共纳入21例患者。患者以男性为主（71%），67%有2个及以上转移部位，包括肝转移（43%），19%的东部肿瘤协作组（ECOG）体能状态评分为2，且均经过大量预处理（86%曾接受过2个及以上治疗线）。在剂量递增过程中，未观察到剂量限制性毒性，未确定MTD。15例（71.4%）患者至少有1次与治疗相关的不良事件（TRAE）。6例（28.6%）患者出现3级或更高等级的TRAE。最常见的TRAE包括给药后即刻反应、腹泻、血小板减少、关节痛和头痛。中位无进展生存期和总生存期分别为3.63个月（95%CI 1.58-5.68）和7.0个月（95%CI 3.82-10.18）。6个月和12个月的总生存率分别为57.1%和33.3%。疾病控制率为68%，有1例持久部分缓解。尚未达到MTD，已宣布350mg/m²、每天给药5天、休息2天的剂量为RP2D。阿洛法尼布在转移性胃癌的晚期治疗中显示出可接受的耐受性和初步的临床活性迹象。（ClinicalTrials.gov标识符：NCT04071184）
