A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy
A phase I study of danusertib (PHA-739358) in adult patients with accelerated or blastic phase chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia resistant or intolerant to imatinib and/or other second generation c-ABL therapy
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DOI：
10.3324/haematol.2014.115279
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发表时间：
2015-06-01
期刊：
影响因子：
10.1
通讯作者：
Cortes, Jorge E.
中科院分区：
文献类型：
--
作者：
Borthakur, Gautam;Dombret, Herve;Cortes, Jorge E.
Danusertib是一种泛极光激酶抑制剂，对Abl激酶（包括看门人T315 I突变体）具有强效活性。在加速期或急变期慢性髓性白血病或费城染色体阳性急性淋巴细胞白血病患者中进行了一项Danusertib剂量递增的I期研究。研究了两种给药方案：方案A，在14天周期中，每日3小时静脉输注DanusertiB，连续7天（第1-7天）;方案B，在21天周期中，每日3小时静脉输注DanusertiB，连续14天（第1-14天）。共有37例患者接受治疗，29例采用方案A，8例采用方案B。方案A的推荐II期剂量为180 mg/m（2）。由于输注频率的后勤问题，提前停止了方案B的入组。发热性中性粒细胞减少症和粘膜炎是A方案的剂量限制性毒性。4例T315 I ABL激酶突变患者均接受A方案治疗，均产生应答。Danusertib具有可接受的毒性特征，在Bcr-Abl相关晚期恶性血液病患者中具有活性。本研究在欧洲临床试验数据库（EudraCT编号2007-004070-18）中注册。
Danusertib is a pan-aurora kinase inhibitor with potent activity against Abl kinase including the gatekeeper T315I mutant. A phase 1 dose escalation study of danusertib was conducted in patients with accelerated or blastic phase chronic myeloid leukemia or Philadelphia chromosome-positive acute lymphoblastic leukemia. Two dosing schedules were studied: schedule A, in which danusertib was given by 3-hour intravenous infusion daily for 7 consecutive days (days 1-7) in a 14-day cycle, and schedule B, in which the danusertib was given by 3-hour intravenous infusion daily for 14 consecutive days (days 1-14) in a 21-day cycle. A total of 37 patients were treated, 29 with schedule A and eight with schedule B. The recommended phase 2 dose for schedule A was 180 mg/m(2). Enrollment to schedule B was stopped early because of logistical problems with the frequency of infusions. Febrile neutropenia and mucositis were dose-limiting toxicities in schedule A. Four patients with T315I ABL kinase mutation, all treated with schedule A, responded. Danusertib has an acceptable toxicity profile and is active in patients with Bcr-Abl-associated advanced hematologic malignancies. This study was registered with the European Clinical Trails Data Base (EudraCT number 2007-004070-18).