【ASH 2012】Quizartinib治疗复发性AML活性优异
发布时间：2012-12-19 | 来源：医脉通
关键词：
ASH 2012
quizartinib
急性髓样白血病
AML
在一项阶段II临床试验中，试验药quizartinib（安斯泰来/Ambit公司）已在治疗复发难治性急性髓样白血病（AML）患者中显示出了前所未有的活性。
安斯泰来/Ambit公司称，他们正在这些结果基础上，规划该药更大规模的阶段III临床试验。
AML患者可能出现多种基因突变，其中威胁最大的是FLT3内衔接重复（ITD），它使白血病更具攻击性，通常导致对标准化疗的抗药性。34%的AML患者会出现这种突变，并与加快复发和整体生存率下降存在相关性，美国马里兰州巴尔的摩约翰霍普金斯大学医学院悉尼金梅尔综合癌症中心肿瘤学、药理和医学副教授，研究主要作者Mark Levis博士解释说。
“Quizartinib是第一个也是唯一一种对有致命性突变、先前治疗失败的AML患者产生临床好处的单药药物，”他说，“它如此好的作用，真的让我们大吃一惊。”
Levis博士在此间的美国血液学会（ASH）第54届年会上介绍了来自该复发性或难治性AML患者的大型阶段II研究成果。经quizartinib治疗，很多患者完全有效，三分之一患者病情得到稳定，稳定期之长足以让患者进行可能的救命性造血干细胞移植（HSCT）。
“可以经过过渡接受移植的患者人数非常有意义，” Levis博士在一份声明中说。“我们打算利用这些令人鼓舞的结果来设计和实施更多的随机试验，以望quizartinib获得批准，使以前没有治愈希望的患者可以使用这种药物，”他补充道。
“我渴望在临床中使用这种药物.....我以治疗难治性患者群为主，它就是我想要在这些患者身上使用的药物，”他解释说。
ASH主席、加拿大安大略省多伦多大学血液学主任及医学教授Armand Keating博士说，“FLT3突变患者呈现一个“重大管理问题，你可以使他们的病情得到缓解，但接着就会复发……疾病进展之快，患者根本没有机会接受移植手术和治愈。”
“这项研究很重要，因为它表明，quizartinib可以使这些患者获得足够的稳定期来进行移植。它还表明，三分之一左右的患者有这种可能，”
Keating博士报告称。这是新药为难治愈患者提供新希望的又一个例子，他在会议前的新闻发布会上说。
突变就象是一个电源开关
“FTL3突变本质上是一个电源开关，白血病细胞通过这个开关进行更侵袭性传播，并帮助这些细胞在化疗后很快恢复生长， 治疗这种突变的唯一途径就是找到一种办法，关掉这一开关，――这一技术已经困扰研究人员很久了。” Levis博士解释说。
Quizartinib似乎就是这样做的。它被设计用来“关掉”FLT3突变酶，迫使不成熟癌细胞立即死亡或立即成熟然后死亡。这就消除了足够的癌症细胞，使患者有足够长的稳定期来接受另一种治疗，包括移植。
quizartinib阶段II研究就在AML复发、二线疗法无效，或HSCT后复发的患者身上进行。患者被分为两组：＞60岁组133例，18-60岁组137例。
Levis博士提交了较年轻组的队列资料。在137例患者中，99例出现FLT3突变，38例无。
单独使用口服quizartinib，男性起始剂量135 mg/d，女性90 mg/d，连续28天为一周期。性别间剂量差异与药物不良心脏效应相关，quizartinib可以导致心电图QT间期延长，女性效应敏感度强于男性，Levis博士解释说。
突变、无突变患者均出现药物反应，但以突变者反应更佳。主要终点是复合完全缓解率（CR），包括无活动性疾病完全缓解、血小板恢复不全性完全缓解（无活动性疾病，但血小板计数不全）和血液学恢复不全性完全缓解（无活动性疾病，但红细胞和白细胞计数异常)。
有FLT3突变的99例患者，复合CR为44%（CR 4%，血小板恢复不全0%，血液学恢复不全40%）。有效期中位数11.3周，总生存期中位数23.1周。
无突变的38例患者，复合CR为34%（CR 3%，血小板恢复不全3%，血液学恢复不全29%)。有效期中位数5.0周，总生存期中位数25.6周。
在137例18-60岁患者组中，47例（34%）在quizartinib显效后行HSCT。其中一些患者已经存活2年以上，未有任何疾病复发，Levis博士说。
不良事件包括恶心（患者报告率38%）、贫血（29%）、QT延长（26%）、呕吐（26%）、发热性中性粒细胞减少症（25%）、腹泻（20%）和疲劳（20%）。10%患者因不良事件导致治疗中止。
Quizartinib“耐受性极佳，”Levis博士强调。主要的不良事件是QT延长和骨髓抑制，但都“可控”，他说。
“我们仍在尝试不同的剂量，”他解释说。未来试验将研究一下该药的小剂量情况，计划作一个30 mg与60 mg的随机对比试验。
复发性和难治性AML患者quizartinib阶段II试验成果“特别令人鼓舞，”美国德克萨斯大学休斯顿安德森癌症中心白血病系副主任Jorge Cortes博士在一份声明中表示，“在有FLT3-ITD突变的患者中，quizartinib是我们在这类挑战性患者群所用试验药中观察到的最有活性单药，”他补充道。
该研究由quizartinib研制者安斯泰来/Ambit公司提供经费。Levis博士报告，他是Ambit生物科学公司业务顾问，多名合著者为公司雇员。Keating博士报告，服务于Clavis、诺华公司和辉瑞公司的临床试验数据安全监测委员会。
文章来源：美国血液学会（ASH）第54届年会：摘要第673号。提交日期：2012年12月10日。
更多阅读
文献摘要 673 Final Results of a Phase 2 Open-Label, Monotherapy Efficacy and Safety Study of Quizartinib (AC220) in Patients with FLT3-ITD Positive or Negative Relapsed/Refractory Acute Myeloid Leukemia After Second-Line Chemotherapy or Hematopoietic Stem Cell Transplantation
FMS-like tyrosine kinase 3 internal tandem duplications (FLT3-ITD) in acute myeloid leukemia (AML) are associated with early relapse after standard chemotherapy and poor survival. Quizartinib (AC220) is an oral FLT3 receptor tyrosine kinase inhibitor that is active against both ITD mutant and wild type FLT3, and has shown promising activity in a Phase 1 study of patients (pts) with AML. This Phase 2 study was conducted to assess the efficacy and safety of quizartinib monotherapy in FLT3-ITD positive (+) and FLT3-ITD negative (-) pts with a total of 333 pts included in two cohorts. Cohort 2 included pts aged ≥ 18 yrs with AML relapsed or refractory to 2nd-line, salvage chemotherapy or relapsed after hematopoietic stem cell transplantation (HSCT). A total of 137 pts were included in this cohort and constitute the basis for this analysis.
Data through 31 January 2012 from 137 pts in this cohort were analyzed. These pts included 99 (72%) who were FLT3-ITD(+) and 38 (28%) who were FLT3-ITD(-). A total of 50% of the 99 FLT3 ITD(+) pts and 61% of the 38 FLT3-ITD(-) pts were male. The FLT3-ITD(+) pts had a median age of 50 yrs (range 19 to 77 yrs), and the FLT3-ITD(-) pts had a median age of 55 yrs (range 30 to 73 yrs). Pts received quizartinib at a starting dose of 90 mg/day (females) or 135 mg/day (males), and were treated continuously during 28-day cycles.
The composite complete remission (CRc) rate included complete remission (CR), complete remission with incomplete platelet recovery (CRp), and complete remission with incomplete hematologic recovery (CRi). For FLT3-ITD(+) pts the CRc rate was 44% (4% CR, 0 CRp, and 40% CRi), with a median duration of response of 11.3 weeks and median overall survival of 23.1 weeks. Of those refractory to their last AML therapy, 47% achieved a CRc with quizartinib. For FLT3-ITD(-) pts the CRc rate was 34% (3% CR, 3% CRp, and 29% CRi), with a median duration of response of 5.0 weeks and median overall survival of 25.6 weeks. Of those refractory to their last AML therapy, 31% achieved a CRc with quizartinib.
Efficacy Results in AML Pts Relapsed/Refractory to 2nd-line Therapy or HSCT
CRc = composite complete remission; HSCT = hematopoietic stem cell transplantation; NR = not reached; PR = partial remission.
The most common (≥20%) treatment-related adverse events (AEs) were nausea (38%), anemia (29%), QT interval prolongation (26%), vomiting (26%), febrile neutropenia (25%), diarrhea (20%), and fatigue (20%). The most common (≥10%) Grade 3 or 4 treatment-related AEs were anemia (26%), febrile neutropenia (25%), thrombocytopenia (15%), neutropenia (12%), and QT interval prolongation (10%). An AE of QT interval prolongation occurred in 36/137 pts (26%) and was Grade 3 in 13 pts (10%). No Grade 4 QT interval prolongation occurred. A total of 14 pts (10%) experienced a treatment-related AE resulting in discontinuation of quizartinib.
The final data from this Phase 2 study confirm the high degree of activity of quizartinib monotherapy in FLT3 ITD(+) and FLT3-ITD(-) AML pts relapsed/refractory to 2nd-line treatment or HSCT.These data represent the highest level of single agent activity observed to date for FLT3-targeted therapy in FLT3-ITD(+) relapsed/refractory AML. Of clinical significance in this heavily pretreated population, approximately 1/3 of pts were successfully bridged to potentially curative HSCT, and many pts who were refractory to prior therapy responded to quizartinib. Safety findings were manageable, and were primarily myelosuppression and QT prolongation that was mitigated with dose modifications. Further Phase 1 and 2 studies with lower doses of quizartinib as monotherapy and in combination with other agents in FLT3-ITD(+) and FLT3-ITD(-) AML are being planned/ongoing.
Disclosures: Levis: Ambit Biosciences: Consultancy. Perl: Ambit Biosciences: Consultancy. Dombret:Celgene: Consultancy. Döhner: Celgene, Amgen, Lilly, Genzyme: Consultancy. Steffen: Novartis:Travel/accommodations/meeting expenses Other. Rousselot: Ambit Biosciences: Consultancy. Martinelli:BMS, Novartis; Pfizer, Roche: Consultancy. Estey: Ambit Biosciences: Consultancy. Burnett: Ambit Biosciences:Consultancy. Gammon: Ambit Biosciences: Employment. Trone: Ambit Biosciences: Employment. Leo: Ambit Biosciences: Employment. Cortes: Novartis: Consultancy.
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