Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Status
Phase I Study of Quizartinib Administered Daily to Patients With Relapsed or Refractory Acute Myeloid Leukemia Irrespective of FMS-Like Tyrosine Kinase 3-Internal Tandem Duplication Status
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DOI：
10.1200/jco.2013.48.8783
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发表时间：
2013-10-10
影响因子：
45.3
通讯作者：
Levis, Mark
中科院分区：
文献类型：
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作者：
Cortes, Jorge E.;Kantarjian, Hagop;Levis, Mark
目的
在急性髓系白血病（AML）中，FMS样酪氨酸激酶3 - 内部串联重复（FLT3 - ITD）突变与早期复发和不良生存相关。奎扎替尼在临床前AML模型中强效且选择性地抑制FLT3激酶活性。
患者与方法
在一项针对复发或难治性AML的I期首次人体研究中，76名患者（中位年龄60岁；范围23 - 86岁；既往中位接受过3种治疗[范围0 - 12种治疗]）接受奎扎替尼口服给药，剂量从12到450 mg/天逐步递增，无论FLT3 - ITD突变状态如何。
结果
76名患者中有23名（30%）出现缓解，包括10名（13%）任何类型的完全缓解（CR）（2例CR，3例血小板不完全恢复的CR（CRp），5例血液学不完全恢复的CR（CRi））以及13名（17%）部分缓解（PR）。在17名FLT3 - ITD阳性患者中，9名有缓解（53%；1例CR，1例CRp，2例CRi，5例PR）；在37名FLT3 - ITD阴性患者中，5名有缓解（14%；2例CRp，3例PR）；在22名FLT3 - ITD不确定/未检测状态的患者中，9名有缓解（41%；1例CR，3例CRi，5例PR）。缓解持续时间中位数为13.3周；中位生存期为14.0周。最常见的药物相关不良事件（发生率>10%）为恶心（16%）、QT间期延长（12%）、呕吐（11%）和味觉障碍（11%）；大多数为……
PurposeFMS-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations in acute myeloid leukemia (AML) are associated with early relapse and poor survival. Quizartinib potently and selectively inhibits FLT3 kinase activity in preclinical AML models.Patients and MethodsQuizartinib was administered orally at escalating doses of 12 to 450 mg/day to 76 patients (median age, 60 years; range, 23 to 86 years; with a median of three prior therapies [range, 0 to 12 therapies]), enrolled irrespective of FLT3-ITD mutation status in a phase I, first-in-human study in relapsed or refractory AML.ResultsResponses occurred in 23 (30%) of 76 patients, including 10 (13%) complete remissions (CR) of any type (two CRs, three CRs with incomplete platelet recovery [CRp], five CRs with incomplete hematologic recovery [CRi]) and 13 (17%) with partial remissions (PRs). Of 17 FLT3-ITD-positive patients, nine responded (53%; one CR, one CRp, two CRis, five PRs); of 37 FLT3-ITD-negative patients, five responded (14%; two CRps, three PRs); of 22 with FLT3-ITD-indeterminate/not tested status, nine responded (41%; one CR, three CRis, five PRs). Median duration of response was 13.3 weeks; median survival was 14.0 weeks. The most common drug-related adverse events (> 10% incidence) were nausea (16%), prolonged QT interval (12%), vomiting (11%), and dysgeusia (11%); most were