文章：

一项在骨髓纤维化患者中开展的JAK2选择性抑制剂fedratinib（SAR302503）的2期随机剂量范围研究

A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis

原文发布日期：2015-08-07

DOI: 10.1038/bcj.2015.63

类型: Original Article

开放获取: 是

英文摘要：

In this phase 2 open-label randomized study, 31 patients with intermediate-2 or high-risk myelofibrosis received fedratinib 300, 400 or 500 mg once daily in consecutive 4-week cycles. Mean spleen volume reductions at 12 weeks (primary end point) were 30.3% (300 mg), 33.1% (400 mg) and 43.3% (500 mg). Spleen response rates (patients achieving ⩾35% spleen reduction) at 12/24 weeks were 30%/30% (300 mg), 50%/60% (400 mg) and 64%/55% (500 mg), respectively. By 4 weeks, improvements in myelofibrosis (MF)-associated symptoms were observed. At 48 weeks, 68% of patients remained on fedratinib and 16% had discontinued because of adverse events (AEs). Common grade 3/4 AEs were anemia (58%), fatigue (13%), diarrhea (13%), vomiting (10%) and nausea (6%). Serious AEs included one case of reversible hepatic failure and one case of Wernicke’s encephalopathy (after analysis cutoff). Fedratinib treatment led to reduced STAT3 phosphorylation but no meaningful change in JAK2V617F allele burden. Significant modulation (P<0.05, adjusted for multiple comparisons) of 28 cytokines was observed, many of which correlated with spleen reduction. These data confirm the clinical activity of fedratinib in MF. After the analysis cutoff date, additional reports of Wernicke's encephalopathy in other fedratinib trials led to discontinuation of the sponsored clinical development program.

摘要翻译： 

在这项2期开放性随机研究中，31例中危-2或高危骨髓纤维化患者连续接受非德拉尼300、400或500毫克每日一次治疗（每4周为一个周期）。12周时（主要终点）平均脾脏体积缩小率分别为30.3%（300毫克组）、33.1%（400毫克组）和43.3%（500毫克组）。12/24周时脾脏应答率（脾脏缩小≥35%的患者比例）分别为300毫克组30%/30%、400毫克组50%/60%、500毫克组64%/55%。至第4周时即可观察到骨髓纤维化相关症状的改善。第48周时，68%的患者仍持续接受非德拉尼治疗，16%因不良事件终止治疗。常见3/4级不良事件包括贫血（58%）、疲劳（13%）、腹泻（13%）、呕吐（10%）和恶心（6%）。严重不良事件包含1例可逆性肝衰竭和1例韦尼克脑病（发生在数据分析截止后）。非德拉尼治疗可降低STAT3磷酸化水平，但未引起JAK2V617F等位基因负荷的显著改变。研究观察到28种细胞因子的显著调节（经多重比较校正后P<0.05），其中多数与脾脏缩小相关。这些数据证实了非德拉尼在骨髓纤维化中的临床活性。数据分析截止后，其他非德拉尼试验中陆续报告的韦尼克脑病病例导致该药物赞助临床开发项目终止。

原文链接：

A phase 2 randomized dose-ranging study of the JAK2-selective inhibitor fedratinib (SAR302503) in patients with myelofibrosis