Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.
Selective inhibition of FLT3 by gilteritinib in relapsed or refractory acute myeloid leukaemia: a multicentre, first-in-human, open-label, phase 1-2 study.
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Gilteritinib对复发或难治性急性髓样白血病对FLT3的选择性抑制：一种多中心，人类，开放标签，第1-2期研究。
DOI：
10.1016/s1470-2045(17)30416-3
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发表时间：
2017-08
期刊：
影响因子：
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通讯作者：
Levis M
中科院分区：
文献类型：
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作者：
Perl AE;Altman JK;Cortes J;Smith C;Litzow M;Baer MR;Claxton D;Erba HP;Gill S;Goldberg S;Jurcic JG;Larson RA;Liu C;Ritchie E;Schiller G;Spira AI;Strickland SA;Tibes R;Ustun C;Wang ES;Stuart R;Röllig C;Neubauer A;Martinelli G;Bahceci E;Levis M
FMS样酪氨酸激酶3-内部串联重复（FLT 3-ITD）突变在急性髓细胞白血病（AML）中很常见，并与快速复发和短生存期相关。在复发性/难治性（R/R）AML中，FLT 3抑制剂的临床获益受到快速产生耐药突变（尤其是FLT 3-D835）的限制。Gilteritinib是一种强效、高选择性的口服FLT 3/AXL抑制剂，对FLT 3-ITD和FLT 3-D835突变具有临床前活性。这项I/II期研究的目的是评估gilteritinib在FLT 3突变阳性（FLT 3 mut+）R/R AML中的安全性、耐受性和药代动力学（PK）效应。这项正在进行的药效学驱动的I/II期试验（NCT 02014558）于2013年10月至2015年8月入组了年龄≥18岁且诱导治疗难治性或既往治疗达到缓解后复发的受试者。受试者入组7个剂量递增或剂量扩展队列之一，分配接受每日一次口服gilteritinib（20、40、80、120、200、300或450 mg）。队列扩展基于安全性/耐受性、相关试验中的FLT 3抑制和抗白血病活性; 120和200 mg剂量队列进一步扩展至仅包括FLT 3 mut+患者。安全性和耐受性以及PK效应是主要终点;抗白血病应答是主要次要终点。通过监测安全性分析集中的剂量限制性毒性和治疗后出现的不良事件以及安全性评估（例如，临床实验室评价、心电图），评估安全性和耐受性。共有252名R/R AML成年人，包括58名野生型FLT 3和194名FLT 3突变（FLT 3-ITD，n=162; FLT 3-D835，n=16; FLT 3-ITD和-D835，n=13;其他，n=3），在7个剂量递增（n=23）或剂量扩展（n=229）队列之一中接受口服gilteritinib（20-450 mg）每日一次。Gilteritinib在这一接受过大量预治疗的人群中耐受良好; 3级腹泻和肝转氨酶升高限制剂量高于300 mg/d。最常见的3/4级不良事件为发热性中性粒细胞减少（39%; n=97/252）、贫血（24%; n=61/252）、血小板减少（13%; n=33/252）、脓毒症（11%; n=28/252）和肺炎（11%; n=27/252）。≥5%患者的严重不良事件为发热性中性粒细胞减少症（31%; n=78/252），疾病进展（17%; n=43/252），脓毒症（14%; n=36/252），肺炎（11%; n=27/252）、急性肾衰竭（10%; n=25/252）、发热（8%; n=21/252）、菌血症（6%; n=14/252）和呼吸衰竭（6%; n=14/252）。在相关试验中，Gilteritinib在≥80 mg/d剂量下表现出对FLT 3磷酸化的一致、强效抑制作用。尽管在所有剂量水平下均观察到缓解（无论FLT 3突变状态如何）（总缓解率[ORR]=40%），但剂量≥80 mg/d时FLT 3 mut+患者的缓解率提高（ORR=52%）。在FLT 3-ITD患者中，FLT 3-D835的额外存在不会改变应答率;仅FLT 3-D835的患者应答频率较低。Gilteritinib具有良好的安全性特征，并产生强效FLT 3抑制，导致FLT 3 mut + R/R AML患者的抗白血病应答率较高。这些发现证实FLT 3是R/R AML中的高价值靶标，并且通过对FLT 3-ITD突变和FLT 3酪氨酸激酶结构域突变具有强效、选择性和持续活性的药物优化了AML中治疗性FLT 3抑制的长期成功。本研究由Astellas Pharma，Inc.资助，由国家癌症研究所白血病专业卓越研究计划（CA 100632）授予Mark Levis和Jorge科尔特斯博士，并由意大利Ricerca sul Cancro协会授予Giovanni Martinelli教授。
Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutations are common in acute myeloid leukemia (AML) and are associated with rapid relapse and short survival. In relapsed/refractory (R/R) AML, the clinical benefit of FLT3 inhibitors has been limited by rapid generation of resistance mutations, especially FLT3-D835. Gilteritinib is a potent, highly selective oral FLT3/AXL inhibitor with preclinical activity against FLT3-ITD and FLT3-D835 mutations. The aim of this Phase 1/2 study was to assess the safety, tolerability, and pharmacokinetic (PK) effects of gilteritinib in FLT3 mutation-positive (FLT3mut+) R/R AML. This ongoing pharmacodynamic-driven Phase 1/2 trial (NCT02014558) enrolled subjects from October 2013 to August 2015 who were aged ≥18 years and were either refractory to induction therapy or had relapsed after achieving remission with prior therapy. Subjects were enrolled in one of seven dose-escalation or dose-expansion cohorts that were assigned to receive once-daily doses of oral gilteritinib (20, 40, 80, 120, 200, 300, or 450 mg). Cohort expansion was based on safety/tolerability, FLT3 inhibition in correlative assays, and antileukemic activity; the 120 and 200 mg dose cohorts were further expanded to include FLT3mut+ patients only. Safety and tolerability, and PK effects were the primary endpoints; antileukemic response was the main secondary endpoint. Safety and tolerability were assessed by monitoring dose-limiting toxicities and treatment-emergent adverse events, and safety assessments (eg, clinical laboratory evaluations, electrocardiograms) in the Safety Analysis Set. A total of 252 adults with R/R AML, including 58 with wild-type FLT3 and 194 with FLT3 mutations (FLT3-ITD, n=162; FLT3-D835, n=16; FLT3-ITD and -D835, n=13; other, n=3), received oral gilteritinib (20–450 mg) once daily in one of seven dose-escalation (n=23) or dose-expansion (n=229) cohorts. Gilteritinib was well tolerated in this heavily pretreated population; Grade 3 diarrhea and hepatic transaminase elevation limited dosing above 300 mg/d. The most common Grade 3/4 adverse events were febrile neutropenia (39%; n=97/252), anemia (24%; n=61/252), thromobocytopenia (13%; n=33/252), sepsis (11%; n=28/252), and pneumonia (11%; n=27/252). Serious adverse events in ≥5% of patients were febrile neutropenia (31%; n=78/252), progressive disease (17%; n=43/252), sepsis (14%; n=36/252), pneumonia (11%; n=27/252), and acute renal failure (10%; n=25/252), pyrexia (8%; n=21/252), bacteremia (6%; n=14/252), and respiratory failure (6%; n=14/252). Gilteritinib demonstrated consistent, potent inhibition of FLT3 phosphorylation at doses ≥80 mg/d in correlative assays. While responses were observed across all dose levels regardless of FLT3 mutation status (overall response rate [ORR]=40%), response rate was improved in FLT3mut+ patients at doses ≥80 mg/d (ORR=52%). Among patients with FLT3-ITD, the additional presence of FLT3-D835 did not alter response rate; patients with only FLT3-D835 responded less frequently. Gilteritinib had a favorable safety profile and generated potent FLT3 inhibition leading to high rates of antileukemic responses in patients with FLT3mut+ R/R AML. These findings confirm that FLT3 is a high-value target in R/R AML and that long-term success of therapeutic FLT3 inhibition in AML is optimized by agents with potent, selective, and sustained activity against FLT3-ITD mutations and FLT3 tyrosine kinase domain mutations. This study was funded by Astellas Pharma, Inc., by a National Cancer Institute Leukemia Specialized Program of Research Excellence grant (CA100632) awarded to Drs Mark Levis and Jorge Cortes, and by Associazione Italiana Ricerca sul Cancro awarded to Professor Giovanni Martinelli.