Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies
Phase Ia/II, two-arm, open-label, dose-escalation study of oral panobinostat administered via two dosing schedules in patients with advanced hematologic malignancies
复制标题
DOI：
10.1038/leu.2013.38
复制
发表时间：
2013-08-01
期刊：
影响因子：
11.4
通讯作者：
Ottmann, O. G.
中科院分区：
文献类型：
--
作者：
DeAngelo, D. J.;Spencer, A.;Ottmann, O. G.
Panobinostat是一种有效的口服泛乙酰化酶抑制剂，可导致细胞内蛋白乙酰化，抑制细胞增殖并诱导白血病细胞系凋亡。一项Ia/II期研究旨在确定晚期血液恶性肿瘤患者每日panobinostat的最大耐受剂量（MTD），分两种方案给药：每周三次或每隔一周，治疗周期为28天。血液学剂量限制性毒性的标准在基线时与严重细胞减少相关的指征（白血病和髓系疾病）和与基线细胞减少不太常见的指征（淋巴瘤和骨髓瘤）患者之间存在差异。在白血病和髓系疾病患者中，每周和双周panobinostat的MTD为60 mg。在淋巴瘤和骨髓瘤患者中，每周panobinostat II期评估推荐剂量为40mg（正式MTD未确定），两周panobinostat推荐剂量为60mg。总体而言，panobinostat相关的3-4级不良事件包括血小板减少（41.5%）、疲劳（21%）和中性粒细胞减少（21%）。单药活性在几种适应症中观察到，包括霍奇金淋巴瘤和骨髓纤维化。这项Ia/II期研究广泛分析了单药panobinostat在血液恶性肿瘤患者中的安全性和有效性。
Panobinostat is a potent oral pandeacetylase inhibitor that leads to acetylation of intracellular proteins, inhibits cellular proliferation and induces apoptosis in leukemic cell lines. A phase Ia/II study was designed to determine the maximum-tolerated dose (MTD) of daily panobinostat, administered on two schedules: three times a week every week or every other week on a 28-day treatment cycle in patients with advanced hematologic malignancies. The criteria for hematologic dose-limiting toxicities differed between patients with indications associated with severe cytopenias at baseline (leukemia and myeloid disorders) and those less commonly associated with baseline cytopenias (lymphoma and myeloma). In patients with leukemia and myeloid disorders, 60 mg was the MTD for weekly as well as biweekly panobinostat. In patients with lymphoma and myeloma, 40 mg was the recommended dose for phase II evaluation (formal MTD not determined) of weekly panobinostat, and 60 mg was the MTD for biweekly panobinostat. Overall, panobinostat-related grade 3-4 adverse events included thrombocytopenia (41.5%), fatigue (21%) and neutropenia (21%). Single-agent activity was observed in several indications, including Hodgkin lymphoma and myelofibrosis. This phase Ia/II study provided a broad analysis of the safety profile and efficacy of single-agent panobinostat in patients with hematologic malignancies.