Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms
Phase 2 study of gandotinib (LY2784544) in patients with myeloproliferative neoplasms
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DOI：
10.1016/j.leukres.2018.06.014
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发表时间：
2018-08-01
影响因子：
2.7
通讯作者：
Gerds, A. T.
中科院分区：
文献类型：
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作者：
Berdeja, J.;Palandri, F.;Gerds, A. T.
背景资料：费城染色体阴性骨髓增生性肿瘤（MPN）与Janus激酶2（JAK 2）信号转导增加相关，通常由JAK 2 V617 F突变引起。LY2784544（gandotinib）是一种有效的、选择性的JAK 2小分子抑制剂，对JAK 2 V617 F突变具有潜在的剂量依赖性选择性，并可在非临床试验中抑制其他JAK 2突变亚型。一项多中心、单组、门诊2期研究评价了MPN患者（包括真性红细胞增多症（PV）、原发性血小板增多症（ET）和骨髓纤维化（MF））接受gandotinib（120 mg，每日一次）给药的药代动力学（PK）。2012年5月至2015年3月，138例患者接受了至少一剂研究药物。结果：最常见的3级或4级治疗后出现的不良事件，被认为是研究药物相关的贫血（11.6%），高尿酸血症（3.2%），疲劳（2.9%），腹泻（2.2%）和血小板减少症（2.2%）。JAK 2 V617 F突变PV、ET和MF患者的总体缓解率（ORR）分别为95%、90.5%和9.1%，而不具有JAK 2 V617 F突变的ET和MF患者的ORR分别为43.7%和0%。LY 2784544在JAK 2 V617 F突变的MPN中表现出疗效，包括既往接受鲁索替尼治疗的患者，其ORR为3.3%。在1年访视时，44%的患者的MPN-症状评估表总症状评分改善>= 50%，26%的患者的简明疲劳量表评分降低50%。
Background: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPNs) are associated with increases in janus kinase 2 (JAK2) signaling, often resulting from the JAK2 V617F mutation. LY2784544 (gandotinib) is a potent, selective, small-molecule inhibitor of JAK2 that has potential dose-dependent selectivity for the JAK2 V617F mutation and may inhibit additional JAK2 mutant isoforms in nonclinical testing.Methods: A multicenter, single-arm, outpatient phase 2 study evaluated the efficacy, safety, and pharmacokinetics (PK) of gandotinib administered to patients (120 mg once daily) with MPNs, including polycythemia vera (PV), essential thrombocythemia (ET), and myelofibrosis (MF). Between May 2012 and March 2015, 138 patients received at least one dose of study drug.Findings: Most frequent Grade 3 or 4 treatment-emergent adverse events that were considered study-drug related were anemia (11.6%), hyperuricemia (3.2%), fatigue (2.9%), diarrhea (2.2%), and thrombocytopenia (2.2%). Overall response rates (ORRs) in patients with JAK2 V617F-mutated PV, ET, and MF were 95%, 90.5%, and 9.1%, respectively, while patients with ET and MF without the JAK2 V617F mutations had ORRs of 43.7% and 0%, respectively.Interpretations: LY2784544 demonstrated efficacy in JAK2 V617F-mutated MPNs, including in patients previously on ruxolitinib therapy, who had an ORR of 3.3%. At the 1-year visit, 44% of patients experienced a >= 50% improvement in the MPN-Symptom Assessment Form Total Symptom Score, and 26% of patients had a 50% reduction in Brief Fatigue Inventory score.