Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.
Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial.
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DOI：
10.1016/s1470-2045(18)30240-7
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发表时间：
2018-07
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通讯作者：
Levis M
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作者：
Cortes J;Perl AE;Döhner H;Kantarjian H;Martinelli G;Kovacsovics T;Rousselot P;Steffen B;Dombret H;Estey E;Strickland S;Altman JK;Baldus CD;Burnett A;Krämer A;Russell N;Shah NP;Smith CC;Wang ES;Ifrah N;Gammon G;Trone D;Lazzaretto D;Levis M
老年和FMS样酪氨酸激酶3内部串联重复（FLIT 3-ITD）突变与急性髓系白血病患者早期复发和生存率低相关Quizartinib是一种口服、高效、选择性的下一代FLT 3抑制剂，对复发性或难治性急性髓性白血病具有临床抗白血病活性。我们的目的是评估quizartinib单药治疗复发性或难治性急性髓系白血病患者的疗效和安全性。我们在美国、欧洲和加拿大的76家医院和癌症中心进行了一项开放标签、多中心、单臂、2期试验。我们将有形态学记录的原发性急性髓性白血病或继发于骨髓增生异常综合征的急性髓性白血病且东部肿瘤协作组（ECOG）体力状态为0-2的患者纳入两个预定义的独立队列：一线治疗后1年内患有复发性或难治性急性髓性白血病的60岁或以上患者（队列1），以及18岁或以上的复发性或难治性疾病后挽救化疗或造血干细胞移植（队列2）。FLT 3-ITD等位基因频率超过10%的患者被认为是FLT 3-ITD阳性，而所有其他患者被认为是FLT 3-ITD阴性。患者接受quizartinib口服溶液每日一次;最初的17例患者接受200 mg每日一次，但其中一些患者的QTcF间期较基线延长60 ms以上。随后，将所有患者的剂量修改为男性每天135 mg，女性每天90 mg。协同主要终点是达到复合完全缓解（定义为完全缓解+完全缓解伴血小板不完全恢复+完全缓解伴血液学不完全恢复）的患者比例和达到完全缓解的患者比例。疗效和安全性分析包括所有接受至少一剂quizartinib的患者（即意向治疗人群）。按缓解将接受当地评估的治疗后骨髓穿刺或活检的患者纳入疗效分析;所有其他患者均被视为缓解未知。本研究已在ClinicalTrials.gov（编号NCT 00989261）和欧洲临床试验数据库（EudraCT 2009-013093-41）注册，并已完成。2009年11月19日至2011年10月31日期间，共入组333例患者（队列1中157例，队列2中176例）。在队列1中，112例FLT 3-ITD阳性患者中的63例（56%）和44例FLT 3-ITD阴性患者中的16例（36%）达到复合完全缓解，3例（3%）FLT 3-ITD阳性患者和2例（5%）FLT 3-ITD阴性患者达到完全缓解。在队列2中，136例FLT 3-ITD阳性患者中有62例（46%）达到复合完全缓解，5例（4%）达到完全缓解，而40例FLT 3-ITD阴性患者中有12例（30%）达到复合完全缓解，1例（3%）达到完全缓解。在两个队列中（即，333例患者的意向治疗人群），≥ 5%的患者发生的3级或更严重的治疗相关治疗后出现的不良事件为发热性中性粒细胞减少症（333例中的76例[23%]），贫血（75 [23%]），血小板减少症（39 [12%]），使用Fridericia公式校正的QT间期（QTcF）延长（33例[10%]）、中性粒细胞减少症（31例[9%]）、白细胞减少症（22例[7%]）、血小板计数降低（20例[6%]）和肺炎（17例[5%]）。5%或以上患者发生的严重不良事件为发热性中性粒细胞减少症（126/333 [38%]; 76例治疗相关），急性髓性白血病进展（73 [22%]），肺炎（40例[12%]; 14例治疗相关），QTcF延长（33例[10%]; 32例治疗相关）、脓毒症（25例[8%]; 8例治疗相关）和发热（18例[5%]; 9例治疗相关）。在少于5%的患者中发生的显著严重不良事件为尖端扭转型室性心动过速（1例[<1%]）和肝功能衰竭（2例[<1%]）。333例患者中共有125例（38%）在研究治疗期间（包括30天随访）死亡。18例（5%）患者死于研究者认为与治疗相关的不良事件（队列1中10例[6%]/157例患者，队列2中8例[5%]/176例患者）。单药quizartinib在复发性或难治性急性髓性白血病患者中表现出高度活性，通常耐受良好，特别是FLT 3-ITD突变患者。这些发现证实，用高效和选择性FLT 3抑制剂靶向FLT 3-ITD驱动突变是一种有前途的临床策略，有助于改善选择很少的患者的临床结局。III期研究（NCT 02039726; NCT 02668653）将在较低的起始剂量下检查quizartinib。Ambit Biosciences/Daiichi Sankyo。
Old age and FMS-like tyrosine kinase 3 internal tandem duplication (FLIT3-ITD) mutations in patients with acute myeloid leukaemia are associated with early relapse and poor survival. Quizartinib is an oral, highly potent, and selective next-generation FLT3 inhibitor with clinical antileukaemic activity in relapsed or refractory acute myeloid leukaemia. We aimed to assess the efficacy and safety of single-agent quizartinib in patients with relapsed or refractory acute myeloid leukaemia. We did an open-label, multicentre, single-arm, phase 2 trial at 76 hospitals and cancer centres in the USA, Europe, and Canada. We enrolled patients with morphologically documented primary acute myeloid leukaemia or acute myeloid leukaemia secondary to myelodysplastic syndromes and an Eastern Cooperative Oncology Group (ECOG) performance status of 0–2 into two predefined, independent cohorts: patients who were aged 60 years or older with relapsed or refractory acute myeloid leukaemia within 1 year after first-line therapy (cohort 1), and those who were 18 years or older with relapsed or refractory disease following salvage chemotherapy or haemopoietic stem cell transplantation (cohort 2). Patients with an FLT3-ITD allelic frequency of more than 10% were considered as FLT3-ITD positive, whereas all other patients were considered as FLT3-ITD negative. Patients received quizartinib once daily as an oral solution; the initial 17 patients received 200 mg per day but the QTcF interval was prolonged for more than 60 ms above baseline in some of these patients. Subsequently, doses were amended for all patients to 135 mg per day for men and 90 mg per day for women. The co-primary endpoints were the proportion of patients who achieved a composite complete remission (defined as complete remission + complete remission with incomplete platelet recovery + complete remission with incomplete haematological recovery) and the proportion of patients who achieved a complete remission. Efficacy and safety analyses included all patients who received at least one dose of quizartinib (ie, the intention-to-treat population). Patients with a locally assessed post-treatment bone marrow aspirate or biopsy were included in efficacy analyses by response; all other patients were considered to have an unknown response. This study is registered with ClinicalTrials.gov, number NCT00989261, and with the European Clinical Trials Database, EudraCT 2009-013093-41, and is completed. Between Nov 19, 2009, and Oct 31, 2011, a total of 333 patients were enrolled (157 in cohort 1 and 176 in cohort 2). In cohort 1, 63 (56%) of 112 FLT3-ITD-positive patients and 16 (36%) of 44 FLT3-ITD-negative patients achieved composite complete remission, with three (3%) FLT3-ITD-positive patients and two (5%) FLT3-ITD-negative patients achieving complete remission. In cohort 2, 62 (46%) of 136 FLT3-ITD-positive patients achieved composite complete remission with five (4%) achieving complete remission, whereas 12 (30%) of 40 FLT3-ITD-negative patients achieved composite complete remission with one (3%) achieving complete remission. Across both cohorts (ie, the intention-to-treat population of 333 patients), grade 3 or worse treatment-related treatment-emergent adverse events in 5% or more of patients were febrile neutropenia (76 [23%] of 333), anaemia (75 [23%]), thrombocytopenia (39 [12%]), QT interval corrected using Fridericia’s formula (QTcF) prolongation (33 [10%]), neutropenia (31 [9%]), leucopenia (22 [7%]), decreased platelet count (20 [6%]), and pneumonia (17 [5%]). Serious adverse events occurring in 5% or more of patients were febrile neutropenia (126 [38%] of 333; 76 treatment related), acute myeloid leukaemia progression (73 [22%]), pneumonia (40 [12%]; 14 treatment related), QTcF prolongation (33 [10%]; 32 treatment related), sepsis (25 [8%]; eight treatment related), and pyrexia (18 [5%]; nine treatment related). Notable serious adverse events occurring in less than 5% of patients were torsades de pointes (one [<1%]) and hepatic failure (two [1%]). In total, 125 (38%) of 333 patients died within the study treatment period, including the 30-day follow-up. 18 (5%) patients died because of an adverse event considered by the investigator to be treatment related (ten [6%] of 157 patients in cohort 1 and eight [5%] of 176 in cohort 2. Single-agent quizartinib was shown to be highly active and generally well tolerated in patients with relapsed or refractory acute myeloid leukaemia, particularly those with FLT3-ITD mutations. These findings confirm that targeting the FLT3-ITD driver mutation with a highly potent and selective FLT3 inhibitor is a promising clinical strategy to help improve clinical outcomes in patients with very few options. Phase 3 studies (NCT02039726; NCT02668653) will examine quizartinib at lower starting doses. Ambit Biosciences/Daiichi Sankyo.