BMS-911543，一种选择性 JAK2 抑制剂：骨髓纤维化的多中心 1/2a 期研究,Blood

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BMS-911543，一种选择性 JAK2 抑制剂：骨髓纤维化的多中心 1/2a 期研究
Blood ( IF 21.0 ) Pub Date : 2013-11-15 , DOI: 10.1182/blood.v122.21.664.664
Animesh Pardanani ₁ , Andrew W. Roberts ₂ , John F. Seymour ₃ , Kate Burbury ₄ , Srdan Verstovsek ₅ , Hagop M. Kantarjian ₆ , Kebede Begna ₇ , Hiroyuki Yoshitsugu ₈ , Toni Ann Gestone ₈ , Penny Phillips ₈ , Guan Xing ₈ , Gerson Peltz ₈ , Matthew V Lorenzi ₈ , Leila Alland ₈ , Adrian Woolfson ₈ , Ayalew Tefferi ₇

Affiliation

背景 BMS-911543 是一种口服选择性 JAK2 小分子抑制剂 (IC50=1.1nM)，在依赖 JAK2 信号传导的细胞系和体内模型中具有有效的抗增殖和药效学作用。在体外，BMS-911543 在 JAK 家族（JAK1 [IC50=356nM]、JAK3 [IC50=73nM] 或 TYK2 [IC50=66nM]）和大型激酶组（BMS-911543 浓度为 1 µM 时）表现出高选择性，451 种激酶中只有 8 种被显着抑制 [≥67%]）它在依赖于其他 JAK 家族通路的细胞中也几乎没有活性。在使用从 JAK2 V617F 阳性真性红细胞增多症 (PV) 患者分离的原代祖细胞进行的集落生长测定中，使用 BMS-911543 观察到抗增殖反应 (Leukemia 2012;26:280)。方法在一项多中心 1/2a 期研究中，BMS-911543 使用 BID 给药方案口服给药，用于血小板计数≥50,000/mm3 的高、中 2 或中 1 风险症状性原发性或继发性 MF（JAK2 WT 或突变型）患者。患者不需要有可触及的脾肿大。该研究的目的是确定 BMS-911543 的安全性、最大耐受剂量 (MTD)、药代动力学、药效学和初步疗效。使用 NCI-CTCAE 4.0 版评估安全性。使用国际工作组 (IWG) 反应标准、MF-SAF、BFI、体格检查、MRI 评估脾脏和肝脏体积、骨髓形态、核型、V617F 突变等位基因负荷、血浆细胞因子分析、循环 CD34+ 细胞评估治疗效果和其他分子参数。当前状态迄今为止，84 名患者接受了治疗（剂量递增 [n=42]；剂量扩展 [n=42]），最大耐受剂量 (MTD) 定义为 200mg BID。下面的总结代表了 36 名来自剂量递增阶段的患者的中期数据分析，这些患者以 5、10、20、40、80、120、160 和 200mg BID 给药。36 名患者中有 15 名 (42%) 之前接受过 Jak 抑制剂 (Jaki)，其中 3 名接受了≥2 种 Jak 抑制剂。PK、PD、安全性、耐受性和有效性重复给药后，Cmax 和 AUC 的增加大于剂量成比例，并且在剂量≥40mg BID 时观察到药物蓄积。PD 分析表明外周血单核细胞中 JAK/STAT 通路信号活性受到抑制，并调节了几种可溶性外周血蛋白，包括 IL-6、EPO 和瘦素。11 名患者 (31%) 出现药物相关 AE。9 种血液学 AE 包括 3 种贫血（1 种 3 级和 2 种 2 级）；3 中性粒细胞减少症（4 级）；和单次白细胞减少症（4 级）、血小板减少症（4 级）和血小板计数减少（2 级）。9 次非血液学 AE 包括 3 次恶心（1/2 级）；淀粉酶升高（3 级）和脂肪酶升高（3 级）各 1 个；疲劳、肌肉痉挛、失眠、勃起功能障碍各1级。10 名患者 (28%) 停止治疗：4 名归因于疾病进展，2 名归因于缺乏疗效，2 名应患者要求，1 名依从性差，1 名归因于不相关的 AE。在 Jaki 失败和 Jaki 天真患者中观察到 MRI 的脾体积减少 (SVR)。在接受 160 和 200 毫克治疗的 11 名患者中，8 名患者 (73%) 在 3 个月时的 SVR 大于 35%。相比之下，4 名接受 120mg 治疗的患者中有 1 名接受低于 120mg 的治疗，SVR 超过 35%。在接受 160mg 和 200mg 治疗的患者中，超过 50% 的 MF-SAF 降低 > 50%。总体而言，3 名患者（8.3%；2 名以 10mg BID 治疗，1 名以 200mg BID 治疗）血红蛋白增加≥2g/dL；。临床活动的其他迹象包括 V617F 突变等位基因负荷、白细胞增多、白细胞增多症、循环 CD34+ 细胞和 LDH 的减少。结论 BMS-911543 通常耐受性良好，具有可接受的安全性和有效性特征。BMS-911543 可快速控制有症状的 MF 患者的全身症状和脾肿大，包括以前接受过一种或多种 Jak 抑制剂治疗的患者。在剂量递增和持续扩大阶段接受治疗的所有 84 名患者的更新数据，包括脾脏和肝脏体积的 MRI 评估、V617F 突变等位基因负荷和选定血浆细胞因子的水平，将被呈现。披露：Pardanani：JW Pharmaceutical Corp.：临床试验支持、临床试验支持其他；PharmaMar：临床试验支持、临床试验支持其他；赛诺菲：临床试验支持、出版支持服务、临床试验支持、出版支持服务其他；百时美施贵宝：临床试验支持其他。标签外使用：在临床试验环境中使用 BMS-911543、鲁索替尼、莫罗替尼、费德拉替尼和泊马度胺治疗骨髓纤维化。罗伯茨：艾伯维公司：研究资金；基因泰克：研究资金；Walter and Eliza Hall Institute of Medical Research：雇员，收到与 ABT-199 相关的商业收入，雇员，收到与 ABT-199 其他、就业相关的商业收入。Seymour：基因泰克：咨询，实体董事会或咨询委员会的成员。Verstovsek：Incyte 公司：研究资金。Yoshitsugu：百时美施贵宝：就业，股权。Gestone：百时美施贵宝：就业，股权。菲利普斯：百时美施贵宝：就业，股权。Xing：百时美施贵宝：就业，股权。Peltz：百时美施贵宝：就业、股权。Lorenzi: Bristol-Myers Squibb: 股权，以前的工作其他。Alland：百时美施贵宝：就业，股权。Woolfson：Bristol-Myers Squibb：股权，以前的工作其他。Verstovsek：Incyte 公司：研究资金。Yoshitsugu：百时美施贵宝：就业，股权。Gestone：百时美施贵宝：就业，股权。菲利普斯：百时美施贵宝：就业，股权。Xing：百时美施贵宝：就业，股权。Peltz：百时美施贵宝：就业、股权。Lorenzi: Bristol-Myers Squibb: 股权，以前的工作其他。Alland：百时美施贵宝：就业，股权。Woolfson：Bristol-Myers Squibb：股权，以前的工作其他。Verstovsek：Incyte 公司：研究资金。Yoshitsugu：百时美施贵宝：就业，股权。Gestone：百时美施贵宝：就业，股权。菲利普斯：百时美施贵宝：就业，股权。Xing：百时美施贵宝：就业，股权。Peltz：百时美施贵宝：就业、股权。Lorenzi: Bristol-Myers Squibb: 股权，以前的工作其他。Alland：百时美施贵宝：就业，股权。Woolfson：Bristol-Myers Squibb：股权，以前的工作其他。百时美施贵宝：就业，股权。Lorenzi: Bristol-Myers Squibb: 股权，以前的工作其他。Alland：百时美施贵宝：就业，股权。Woolfson：Bristol-Myers Squibb：股权，以前的工作其他。百时美施贵宝：就业，股权。Lorenzi: Bristol-Myers Squibb: 股权，以前的工作其他。Alland：百时美施贵宝：就业，股权。Woolfson：Bristol-Myers Squibb：股权，以前的工作其他。

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BMS-911543, A Selective JAK2 Inhibitor: A Multicenter Phase 1/2a Study In Myelofibrosis

Background BMS-911543 is an oral, selective small-molecule inhibitor of JAK2 (IC50=1.1nM) with potent anti-proliferative and pharmacodynamic effects in cell lines and in vivo models dependent upon JAK2 signaling. In vitro , BMS-911543 demonstrates high selectivity within the JAK family (JAK1 [IC50=356nM], JAK3 [IC50=73nM] or TYK2 [IC50=66nM]) and across a large kinase panel (at 1 µM concentration of BMS-911543, only 8 of 451 kinases were markedly inhibited [≥67%]) It also has little activity in cells dependent on other JAK family pathways. Anti-proliferative responses were observed with BMS-911543 in colony growth assays using primary progenitor cells isolated from patients with JAK2 V617F-positive polycythemia vera (PV) ( Leukemia 2012;26:280 ). Methods In a multicenter phase 1/2a study, BMS-911543 was administered orally using a BID dosing schedule, in patients with high-, intermediate-2 or intermediate-1 risk symptomatic primary or secondary MF (JAK2 WT or mutant) with platelet counts ≥50,000/mm3. Patients were not required to have palpable splenomegaly. The aim of the study is to determine safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and preliminary efficacy of BMS-911543. Safety was assessed using NCI-CTCAE version 4.0. Treatment effect was assessed using the International Working Group (IWG) response criteria, MF-SAF, BFI, physical examination, spleen and liver volume assessment by MRI, bone marrow morphology, karyotype, V617F mutant allele burden, plasma cytokine analysis, circulating CD34+ cells and other molecular parameters. Current status To date, 84 patients have been treated (dose escalation [n=42]; dose expansion [n=42]) and the maximum tolerated dose (MTD) was defined as 200mg BID. The summary below represents an interim data analysis of 36 patients from the dose escalation phase dosed at 5, 10, 20, 40, 80, 120, 160, and 200mg BID. Fifteen of 36 (42%) patients had received prior Jak inhibitors (Jaki) including 3 who had received ≥2 Jak inhibitors. PK, PD, Safety, Tolerability and Efficacy After repeat dosing, greater than dose-proportional increase in the Cmax and AUC, and drug accumulation was observed at doses ≥40mg BID. PD analysis indicated inhibition of JAK/STAT pathway signaling activity in peripheral blood mononuclear cells, and modulation of several soluble peripheral blood proteins including IL-6, EPO and Leptin. Eleven patients (31%) had drug-related AEs. The nine hematological AEs included 3 anemia (1 grade 3 and 2 grade 2); 3 neutropenia (grade 4); and single leukopenia (grade 4), thrombocytopenia (grade 4), and reduction in platelet count (grade 2). Nine non-hematological AEs included 3 nausea (grade1/2); amylase increased (grade 3) and lipase increased (grade 3) one each; and grade 1 fatigue, muscle spasms, insomnia, erectile dysfunction one each. Ten patients (28%) discontinued treatment: 4 were attributed to disease progression, 2 to lack of efficacy, 2 at patient’s request, 1 to poor compliance, and 1 to unrelated AE. Spleen volume reductions (SVR) by MRI were observed in Jaki failure and in Jaki naive patients. Of 11 patients treated at 160 and 200mg, 8 patients (73%) had SVR greater than 35% at 3 months. In contrast, 1 of 4 patients treated at 120mg and none treated below 120mg had SVR greater than 35%. Of the patients treated at 160mg and 200mg, more than 50% had MF-SAF reductions > 50%. Overall, 3 patients (8.3%; 2 treated at 10mg BID and 1 at 200mg BID) had an increase in hemoglobin of ≥2g/dL;. Other signs of clinical activity included reductions in V617F mutant allele burden, leukocytosis, leukoerythroblastosis, circulating CD34+ cells, and LDH. Conclusion BMS-911543 was generally well tolerated and has an acceptable safety and efficacy profile. BMS-911543 induced rapid control of constitutional symptoms, and splenomegaly in patients with symptomatic MF, including those previously treated with one or more Jak inhibitors. Updated data from all 84 patients who have been treated in the dose escalation and ongoing expansion phases, including MRI assessments of spleen and liver volume, V617F mutant allele burden and levels of select plasma cytokines, will be presented. Disclosures: Pardanani: JW Pharmaceutical Corp.: Clinical trial support, Clinical trial support Other; PharmaMar: Clinical trial support, Clinical trial support Other; Sanofi: Clinical trial support, Publication support services, Clinical trial support, Publication support services Other; Bristol Myers Squibb: Clinical trial support Other. Off Label Use: Use of BMS-911543, Ruxolitinib, Momelotinib, Fedratinib and Pomalidomide for treatment of Myelofibrosis in Clinical Trial setting. Roberts: AbbVie, Inc.: Research Funding; Genentech: Research Funding; Walter and Eliza Hall Institute of Medical Research: Employee, recieves commercial income related to ABT-199, Employee, recieves commercial income related to ABT-199 Other, Employment. Seymour: Genentech: Consultancy, Membership on an entity’s Board of Directors or advisory committees. Verstovsek: Incyte Corporation: Research Funding. Yoshitsugu: Bristol-Myers Squibb: Employment, Equity Ownership. Gestone: Bristol-Myers Squibb: Employment, Equity Ownership. Phillips: Bristol-Myers Squibb: Employment, Equity Ownership. Xing: Bristol-Myers Squibb: Employment, Equity Ownership. Peltz: Bristol-Myers Squibb: Employment, Equity Ownership. Lorenzi: Bristol-Myers Squibb: Equity Ownership, Former employment Other. Alland: Bristol-Myers Squibb: Employment, Equity Ownership. Woolfson: Bristol-Myers Squibb: Equity Ownership, Former employment Other.

更新日期：2013-11-15

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