Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.
Phase I dose-escalation study of buparlisib (BKM120), an oral pan-class I PI3K inhibitor, in Japanese patients with advanced solid tumors.
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DOI：
10.1111/cas.12350
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发表时间：
2014-03
期刊：
影响因子：
5.7
通讯作者：
Doi T
中科院分区：
文献类型：
--
作者：
Ando Y;Inada-Inoue M;Mitsuma A;Yoshino T;Ohtsu A;Suenaga N;Sato M;Kakizume T;Robson M;Quadt C;Doi T
Buparlisib (BKM120) 是一种口服泛磷脂酰肌醇 3-激酶抑制剂，针对 I 类 PI3K 的所有四种亚型（α、β、γ 和 δ）。这项开放标签的 I 期剂量递增研究旨在确定日本晚期实体瘤患者连续每日使用 buparlisib 的最大耐受剂量。次要目标包括安全性和耐受性、药代动力学、抗肿瘤活性和药效标志物变化。 15 名患者接受了 25 毫克/天（n = 3）、50 毫克/天（n = 3）和 100 毫克/天（n = 9）剂量水平的治疗。 100 毫克/天时发生一种 4 级肝功能异常的剂量限制性毒性。考虑到在非日本患者中进行的 buparlisib 首次人体研究的安全性和最大耐受剂量，停止了进一步的剂量递增，并宣布 100 毫克/天为推荐剂量。最常见的治疗相关不良事件是皮疹、肝功能异常（包括转氨酶水平升高）、血液胰岛素水平升高和嗜酸性粒细胞计数增加。两名患者出现高血糖，一名 1 级和一名 4 级，三名患者出现情绪改变，两名 1 级和一名 2 级。药代动力学结果显示，buparlisib 以与剂量成比例的方式快速吸收。六名患者的最佳总体缓解是疾病稳定，其中包括一名未经证实的部分缓解。在这些患有晚期实体瘤的日本患者中，buparlisib 具有可控的安全性，其药代动力学与非日本患者相似。未来的 buparlisib 研究将用于日本患者的推荐剂量 100 毫克/天。
Buparlisib (BKM120) is an oral pan-phosphatidylinositol 3-kinase inhibitor, targeting all four isoforms of class I PI3K (α, β, γ and δ). This open-label Phase I dose-escalation study was conducted to determine the maximum tolerated dose of continuous daily buparlisib in Japanese patients with advanced solid tumors. Secondary objectives included safety and tolerability, pharmacokinetics, antitumor activity and pharmacodynamic marker changes. Fifteen patients were treated at 25 mg/day (n = 3), 50 mg/day (n = 3) and 100 mg/day (n = 9) dose levels. One dose-limiting toxicity of Grade 4 abnormal liver function occurred at 100 mg/day. Considering the safety profile and the maximum tolerated dose in the first-in-man study of buparlisib in non-Japanese patients, further dose escalation was stopped and 100 mg/day was declared the recommended dose. The most common treatment-related adverse events were rash, abnormal hepatic function (including increased transaminase levels), increased blood insulin levels and increased eosinophil count. Hyperglycemia was experienced by two patients, one Grade 1 and one Grade 4, and mood alterations were experienced by three patients, two Grade 1 and one Grade 2. Pharmacokinetic results showed that buparlisib was rapidly absorbed in a dose-proportional manner. Best overall response was stable disease for six patients, including one unconfirmed partial response. In these Japanese patients with advanced solid tumors, buparlisib had a manageable safety profile, with similar pharmacokinetics to non-Japanese patients. The recommended dose of 100 mg/day will be used in future studies of buparlisib in Japanese patients.
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