医脉通编译整理，转载请务必注明出处

凋亡蛋白抑制剂（IAPs）编码一组结构相关的蛋白，该家族成员不仅可以抑制细胞凋亡，而且参与多种似无关联的生物学功能，如调节细胞周期和细胞分裂等。SMAC是存在于线粒体并调节细胞凋亡的蛋白质，其促凋亡作用是通过逆转IAPs的作用实现的。Birinapant是一种有效的SMAC类似物。一项Ib期研究表明了该药治疗骨髓增生异常综合征（MDS）可接受的安全性以及早期的临床活性。

【方法】

这是一项多中心、双盲、安慰剂对照、随机试验，旨在探讨5-AZA联合或不联合birinapant治疗未接受过低甲基化药物（HMA）治疗的MDS和CMML患者的疗效。符合条件的患者最初包括IPSS INT-2/高危MDS或INT-1 风险并骨髓原始细胞> / = 5%。随后经过修订，符合条件的患者包括继发性MDS、低原始细胞计数但高危细胞遗传学异常的患者以及低原始细胞比例（20-30%）的AML患者。主要目标是比较两组的响应率（RR = CR + PR）。次要目标是不良反应。第1-7 或1-5、8、9天（28天为1疗程），患者接受了5-AZA 75 mg/m²/d，IV；Birinapant 13 mg/m²/d或安慰剂，IV，每周2次，持续3-4周（第1、4、8、11、15和18天）。

【结果】

试验中止于预先计划的期中分析。结果显示，两组的响应率无差异。就可评估患者的最佳响应率而言，安慰剂组为31.8%，birinapant组为29.4%（p = 0.96）。严重的治疗相关的急性不良反应（AEs）在birinapant组中更常见（61.4% vs. 40.8%），另外也发生了致命性AEs（8.8% vs. 0%）。Brinapant组中，增加的特殊3级以上AEs包括发热性中性粒细胞减少症（34.4% vs. 10.3%）、感染（28.1% vs. 13.8%）和血小板减少症（25% vs. 20.7%）。

【结论】

该2期研究表明，birinapant + 5-AZA所产生的响应率并不优于5-AZA单一治疗。另外，该联合方案也带了更高的不良反应发生率。

摘要原文:

A phase 2 study of azacitidine (5-AZA) with or without birinapant in subjects with higher risk myelodysplastic syndrome (MDS) or chronic myelomonocytic leukemia (CMML).Abstract No:7060

Background: Inhibitor of Apoptosis Proteins (IAPs) are a family of molecules that are dysregulated in myeloid stem cell disorders and prevent programmed cell death. SMAC (second mitochondrial activator of caspase) is an endogenous antagonist of IAPs that counteracts their anti-apoptotic effect. Birinapant is a potent SMAC mimetic and in a phase Ib study of patients with MDS it demonstrated an acceptable safety profile and early signs of clinical activity.

Methods: This was a multicenter, randomized, double-blind, placebo-controlled study of 5-AZA with or without birinapant in subjects with hypomethylating agent (HMA) naïve MDS and CMML. Eligible patients initially included de novo IPSS INT-2/high risk MDS or INT-1 risk with > / = 5% bone marrow blasts. The protocol was later amended to include secondary MDS, patients with low blast counts but high risk cytogenetics and patients with AML with low blast counts (20-30%). The primary objective was to compare response rate (RR = CR + PR) between the two arms.

Adverse event profiling was a secondary objective. Patients were treated with 5-AZA 75 mg/m2/d IV on d 1-7 or 1-5, 8, 9 in 28 d cycles. Birinapant 13 mg/m2/d or placebo was administered IV twice weekly for 3 of 4 weeks (d 1, 4, 8, 11, 15, and 18).

Results: The study was terminated early when a pre-planned interim analysis showed no difference in the response rate between the two arms. For evaluable patients the best overall response was 31.8% for placebo and 29.4% for birinapant (p = 0.96). Serious treatment-emergent adverse events (AEs) were higher in the birinapant arm than placebo arm (61.4% vs. 40.8%). Additionally, more patients had a treatment-emergent fatal AE in the birinapant arm (8.8% vs. 0%). Specific grade 3 or higher AEs that were increased in the birinapant arm included febrile neutropenia (34.4% vs. 10.3%), infections (28.1% vs. 13.8%), and thrombocytopenia (25% vs. 20.7%).

Conclusions: In this phase 2, randomized, double-blind, placebo-controlled trial, the RR of birinapant plus 5-AZA was not superior to 5-AZA alone. Additionally, the AE and SAE rate was higher in the birinapant arm as compared to the placebo arm.

会议专题》》》2016年ASCO年会专题报道