Garcia-Manero Guillermo, Khoury Hanna J, Jabbour Elias, Lancet Jeffrey, Winski Shannon L, Cable LouAnn, Rush Selena, Maloney Lara, Hogeland Grant, Ptaszynski Mieke, Calvo Monica Cabrero, Bohannan Zach, List Alan, Kantarjian Hagop, Komrokji Rami
Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Winship Cancer Institute of Emory University, Atlanta, Georgia.
Clin Cancer Res. 2015 Mar 1;21(5):985-94. doi: 10.1158/1078-0432.CCR-14-1765. Epub 2014 Dec 5.
Data suggest that activity of p38 MAPK and Tie2 kinases is dysregulated in myelodysplastic syndromes (MDS) and may be targets for novel therapies. A phase I study of ARRY-614, an oral dual inhibitor of p38 MAPK and Tie2, was conducted in patients with low or intermediate-1 International Prognostic Scoring System risk MDS to evaluate safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary responses by International Working Group 2006 criteria.
Forty-five patients received ARRY-614 either once daily or twice daily in dose escalation (400, 600, 900, or 1,200 mg once daily; 200 or 300 mg twice daily) or expansion cohorts.
The 300 mg twice daily schedule was not tolerated, and an MTD was not reached for once daily dosing. Treatment-related adverse events were primarily grade 1-2, with the most common being rash, diarrhea, dry skin, fatigue and anorexia. Interpatient PK variability was high, although exposure was sufficient to achieve reduction in p38 MAPK activation in bone marrow and in the levels of circulating biomarkers. Disease responses were observed in 14 of 44 (32%) evaluable patients, 13 (93%) of whom had previously been treated with a hypomethylating agent. Responses were observed in all lineages, with 5 patients experiencing bilineage responses. Three of 25 red blood cell transfusion-dependent (TD) patients achieved transfusion independence (TI) and 5 of 7 platelet TD patients achieved TI.
ARRY-614 was well tolerated and has sufficient activity to warrant further evaluation in this patient population. We recommend 1,200 mg once daily as the optimal dose for further study.
数据表明，p38丝裂原活化蛋白激酶（MAPK）和Tie2激酶的活性在骨髓增生异常综合征（MDS）中失调，可能成为新型疗法的靶点。对ARRY - 614（一种p38 MAPK和Tie2的口服双重抑制剂）进行了一项I期研究，纳入国际预后评分系统低危或中危 - 1的MDS患者，以评估安全性、药代动力学（PK）、药效动力学（PD）以及根据2006年国际工作组标准评估的初步缓解情况。
45例患者接受ARRY - 614治疗，采用剂量递增方案（每日一次400、600、900或1200 mg；每日两次200或300 mg）或扩展队列。
每日两次300 mg的给药方案耐受性差，每日一次给药未达到最大耐受剂量（MTD）。与治疗相关的不良事件主要为1 - 2级，最常见的是皮疹、腹泻、皮肤干燥、疲劳和厌食。患者间PK变异性高，尽管暴露量足以使骨髓中p38 MAPK活化以及循环生物标志物水平降低。44例可评估患者中有14例（32%）观察到疾病缓解，其中13例（93%）之前接受过去甲基化药物治疗。所有谱系均观察到缓解，5例患者出现双谱系缓解。25例依赖红细胞输血（TD）的患者中有3例实现了输血独立（TI），7例血小板TD患者中有5例实现了TI。
ARRY - 614耐受性良好，具有足够的活性，值得在该患者群体中进一步评估。我们推荐每日一次1200 mg作为进一步研究的最佳剂量。
