NTT Medical Center Tokyo, Tokyo, Japan.
Saiseikai Maebashi Hospital, Gunma, Japan.
Cancer Sci. 2018 Oct;109(10):3235-3244. doi: 10.1111/cas.13749.
Gilteritinib, a novel, highly specific, potent fms-like tyrosine kinase 3/AXL inhibitor, demonstrated antileukemic activity in patients with relapsed/refractory (R/R) acute myeloid leukemia (AML). In this open-label phase 1 study (NCT02181660), Japanese patients (aged ≥18 years) with R/R AML received once-daily gilteritinib, escalating from 20 to 300 mg/d. Primary endpoints were safety/tolerability, including the maximum tolerated dose (MTD) and the recommended dose (RD); secondary endpoints were antileukemic activity and pharmacokinetics (PK). Twenty-four Japanese patients with R/R AML received once-daily oral gilteritinib in 1 of 6 dose-escalation cohorts (20, 40, 80, 120, 200, and 300 mg/d). Gilteritinib was well tolerated. The MTD was 200 mg/d; dose-limiting toxicities were grade 3 tumor lysis syndrome (120 mg/d; n = 1); and grade 3 elevated blood lactate dehydrogenase, amylase, blood creatine phosphokinase levels, and syncope (all n = 2; 300 mg/d). The RD was 120 mg/d. The most common drug-related grade ≥3 adverse events were thrombocytopenia (n = 4 [16.7%]) and increased blood creatine phosphokinase (n = 3 [12.5%]). Gilteritinib had a dose-proportional PK profile. Among patients with mutated fms-like tyrosine kinase 3, the overall response rate (ORR) was 80% (n = 4 of 5; complete remission [CR] with incomplete platelet recovery, 1 [20%]; CR with incomplete hematologic recovery, 2 [40%]; partial remission (PR), 1 [20%]). Among patients with wild-type fms-like tyrosine kinase 3, ORR was 36.4%; (n = 4 of 11; CR, 1 [9.1%]; CR with incomplete platelet recovery, 2 [18.2%]; PR, 1 [9.1%]). In conclusion, gilteritinib was well tolerated and demonstrated antileukemic activity in a Japanese R/R AML population.
吉特替尼是一种新型、高度特异、强效的 Fms 样酪氨酸激酶 3/AXL 抑制剂，在复发性/难治性（R/R）急性髓系白血病（AML）患者中显示出抗白血病活性。在这项开放标签的 1 期研究（NCT02181660）中，日本 R/R AML 患者接受每日一次吉特替尼治疗，剂量从 20 毫克逐渐增加至 300 毫克/天。主要终点为安全性/耐受性，包括最大耐受剂量（MTD）和推荐剂量（RD）；次要终点为抗白血病活性和药代动力学（PK）。24 名日本 R/R AML 患者在 6 个剂量递增队列之一中接受每日一次口服吉特替尼治疗（20、40、80、120、200 和 300 毫克/天）。吉特替尼具有良好的耐受性。MTD 为 200 毫克/天；剂量限制性毒性为 3 级肿瘤溶解综合征（120 毫克/天；n=1）；3 级血乳酸脱氢酶、淀粉酶、血肌酸磷酸激酶水平升高和晕厥（均 n=2；300 毫克/天）。RD 为 120 毫克/天。最常见的药物相关 3 级以上不良事件为血小板减少症（n=4 [16.7%]）和血肌酸磷酸激酶升高（n=3 [12.5%]）。吉特替尼具有剂量比例的 PK 特征。在突变型 Fms 样酪氨酸激酶 3 的患者中，总缓解率（ORR）为 80%（n=5；完全缓解[CR]伴不完全血小板恢复 1 [20%]；CR 伴不完全血液学恢复 2 [40%]；部分缓解[PR] 1 [20%]）。在野生型 Fms 样酪氨酸激酶 3 的患者中，ORR 为 36.4%（n=11；CR 1 [9.1%]；CR 伴不完全血小板恢复 2 [18.2%]；PR 1 [9.1%]）。总之，吉特替尼在日本 R/R AML 人群中具有良好的耐受性和抗白血病活性。
