Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes.
Phase 2, randomized, double-blind study of pracinostat in combination with azacitidine in patients with untreated, higher-risk myelodysplastic syndromes.
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DOI：
10.1002/cncr.30533
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发表时间：
2017-05-15
期刊：
影响因子：
6.2
通讯作者：
Roboz GJ
中科院分区：
文献类型：
--
作者：
Garcia-Manero G;Montalban-Bravo G;Berdeja JG;Abaza Y;Jabbour E;Essell J;Lyons RM;Ravandi F;Maris M;Heller B;DeZern AE;Babu S;Wright D;Anz B;Boccia R;Komrokji RS;Kuriakose P;Reeves J;Sekeres MA;Kantarjian HM;Ghalie R;Roboz GJ
尽管有可用的治疗方法，高危骨髓增生异常综合征（MDS）患者的预后仍然很差。组蛋白脱乙酰酶抑制剂已显示出治疗 MDS 的活性以及与阿扎胞苷的体外协同作用。我们对国际预后评分系统中 2 级或高危 MDS 患者进行了阿扎胞苷和普拉司他的 II 期随机、安慰剂对照临床试验。主要终点是治疗第 6 周期的完全缓解 (CR) 率。 102 名随机患者中，51 名接受普拉诺他组治疗，51 名接受安慰剂组治疗。中位年龄为 69 岁。 pracinostat 组和安慰剂组第 6 周期的 CR 率分别为 18% 和 33% (p=0.07)。各组之间的总生存期 (OS)（中位 16 个月与 19 个月，HR = 1.21，95% CI 0.66-2.23）或无进展生存期（PFS）（11 个月与 9 个月，HR = 0.82，95% CI 0.546-1.46）没有显着差异。普拉司他组中 3 级及以上不良事件发生的频率更高（98% 对 74%），导致更多的治疗中断（20% 对 10%）。阿扎胞苷与普拉司他的组合并没有改善高危MDS患者的预后。较高的治疗中断率可能部分解释了这些结果，表明可能需要替代剂量和时间表来提高耐受性，以确定联合用药的潜力。
The prognosis of patients with higher-risk myelodysplastic syndromes (MDS) remains poor despite available therapies. Histone deacetylase inhibitors have shown activity in MDS and in vitro synergy with azacitidine. We conducted a phase II randomized, placebo controlled clinical trial of azacitidine and pracinostat in patients with International Prognostic Scoring System intermediate-2 or high risk MDS. Primary endpoint was complete response (CR) rate by cycle 6 of therapy. Of 102 patients randomized, 51 were treated in the pracinostat group and 51 in the placebo group. Median age was 69 years. CR rate by cycle 6 of therapy was 18% and 33% (p=0.07) in the pracinostat and placebo groups, respectively. No significant differences in overall survival (OS) (median 16 vs. 19 months, HR = 1.21, 95% CI 0.66–2.23) or progression-free survival (PFS) (11 vs. 9 months, HR = 0.82, 95% CI 0.546–1.46) were observed between groups. Grade ≥3 adverse events occurred more frequently in the pracinostat group (98% vs. 74%) leading to more treatment discontinuations (20% vs. 10%). The combination of azacitidine with pracinostat did not improve outcomes of patients with higher-risk MDS. Higher rates of treatment discontinuation may partially explain these results suggesting alternative dosing and schedules to improve tolerability may be required to determine the potential of the combination.