Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas
Phase II Study of Alisertib, a Selective Aurora A Kinase Inhibitor, in Relapsed and Refractory Aggressive B- and T-Cell Non-Hodgkin Lymphomas
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DOI：
10.1200/jco.2012.46.8793
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发表时间：
2014-01-01
影响因子：
45.3
通讯作者：
Bernstein, Steven H.
中科院分区：
文献类型：
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作者：
Friedberg, Jonathan W.;Mahadevan, Daruka;Bernstein, Steven H.
Aurora A激酶（AAK）在侵袭性淋巴瘤中过度表达，并可能与组织学上更具侵袭性的疾病形式相关。因此，我们设计了一项针对复发和难治性侵袭性非霍奇金淋巴瘤患者的选择性AAK抑制剂alisertib的II期研究。患者和方法年龄18岁的复发或难治性弥漫性大b细胞淋巴瘤（DLBCL）、mantle-cell淋巴瘤（MCL）、转化滤泡性淋巴瘤、Burkitt淋巴瘤或非皮肤t细胞淋巴瘤纳入研究。Alisertib口服50mg，每日两次，共7天，21天为一个周期。结果共入组48例患者。组织学包括DLBCL （n = 21）、MCL （n = 13）、外周t细胞淋巴瘤（n = 8）、转化滤泡性淋巴瘤（n = 5）和Burkitt淋巴瘤（n = 1）。最常见的3 - 4级不良事件是中性粒细胞减少（63%）、白细胞减少（54%）、贫血（35%）、血小板减少（33%）、口炎（15%）、发热性中性粒细胞减少（13%）和疲劳（6%）。研究期间的4例死亡归因于进行性非霍奇金淋巴瘤（n = 2）、治疗相关败血症（n = 1）和未知原因（n = 1）。总有效率为27%，包括21例DLBCL患者中的3例，13例MCL患者中的3例，1例Burkitt淋巴瘤患者中的1例，5例转化滤泡性淋巴瘤患者中的2例，8例非皮肤t细胞淋巴瘤患者中的4例。alisertib稳态谷浓度（n = 25）显示了预期的药代动力学变异性，在较高的谷浓度下，不良事件相关剂量减少的发生率较高。AAK基因扩增和AAK总蛋白分析显示两组组织学无差异，与临床反应无相关性。结论新型AAK抑制剂alisertib对B细胞和t细胞侵袭性淋巴瘤均有临床活性。在这些结果的基础上，已经开始了确证性的单药和联合研究。
Purpose Aurora A kinase (AAK) is overexpressed in aggressive lymphomas and can correlate with more histologically aggressive forms of disease. We therefore designed a phase II study of alisertib, a selective AAK inhibitor, in patients with relapsed and refractory aggressive non-Hodgkin lymphomas.Patients and Methods Patients age 18 years were eligible if they had relapsed or refractory diffuse large B-cell lymphoma (DLBCL), mantle-cell lymphoma (MCL), transformed follicular lymphoma, Burkitt's lymphoma, or noncutaneous T-cell lymphoma. Alisertib was administered orally at 50 mg twice daily for 7 days in 21-day cycles.Results We enrolled 48 patients. Histologies included DLBCL (n = 21), MCL (n = 13), peripheral T-cell lymphoma (n = 8), transformed follicular lymphoma (n = 5), and Burkitt's (n = 1). Most common grade 3 to 4 adverse events were neutropenia (63%), leukopenia (54%), anemia (35%), thrombocytopenia (33%), stomatitis (15%), febrile neutropenia (13%), and fatigue (6%). Four deaths during the study were attributed to progressive non-Hodgkin lymphoma (n = 2), treatment-related sepsis (n = 1), and unknown cause (n = 1). The overall response rate was 27%, including responses in three of 21 patients with DLBCL, three of 13 with MCL, one of one with Burkitt's lymphoma, two of five with transformed follicular lymphoma, and four of eight with noncutaneous T-cell lymphoma. The alisertib steady-state trough concentration (n = 25) revealed the expected pharmacokinetic variability, with a trend for higher incidence of adverse event-related dose reductions at higher trough concentrations. Analysis for AAK gene amplification and total AAK protein revealed no differences between histologies or correlation with clinical response.Conclusion The novel AAK inhibitor alisertib seems clinically active in both B- and T-cell aggressive lymphomas. On the basis of these results, confirmatory single-agent and combination studies have been initiated.