Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors.
Phase I Dose-Escalation Study of Taselisib, an Oral PI3K Inhibitor, in Patients with Advanced Solid Tumors.
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DOI：
10.1158/2159-8290.cd-16-1080
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发表时间：
2017-07
期刊：
影响因子：
28.2
通讯作者：
Baselga J
中科院分区：
文献类型：
--
作者：
Juric D;Krop I;Ramanathan RK;Wilson TR;Ware JA;Sanabria Bohorquez SM;Savage HM;Sampath D;Salphati L;Lin RS;Jin H;Parmar H;Hsu JY;Von Hoff DD;Baselga J
Taselisib 是一种通过抑制 PI3K 通路而有效的选择性肿瘤生长抑制剂。 34 名患有局部晚期或转移性实体瘤的患者接受了治疗（I 期研究，改良的 3+3 剂量递增；5 个队列；每日一次 3-16 mg taselisib 胶囊）。 Taselisib 的药代动力学与剂量成正比；平均半衰期为40小时。常见的剂量依赖性、治疗相关不良事件包括腹泻、高血糖、食欲下降、恶心、皮疹、口腔炎和呕吐。在 12 和 16 mg 剂量水平下，观察到剂量限制毒性 (DLT)，并在第 1 周期 DLT 评估窗口后累积更高级别的不良事件。药效学研究结果显示，患者肿瘤样本中 ≥3 mg 的途径受到抑制，与临床前 PIK3CA 突变肿瘤异种移植模型一致。对于具有可测量疾病的 PIK3CA 突变肿瘤患者（5/14：4 名乳腺癌，[3 名患者，12 mg]；1 名非小细胞肺癌），确认的缓解率为 36%，其中从 3 mg 开始有缓解，而在没有已知 PIK3CA 热点突变的肿瘤患者中，确认的缓解率为 0% (0/15)。
Taselisib is a potent and selective tumor growth inhibitor through PI3K pathway suppression. Thirty-four patients with locally advanced or metastatic solid tumors were treated (phase I study, modified 3+3 dose escalation; 5 cohorts; 3-16 mg taselisib once daily capsule). Taselisib pharmacokinetics were dose-proportional; mean half-life was 40 hours. Frequent dose-dependent, treatment-related adverse events included diarrhea, hyperglycemia, decreased appetite, nausea, rash, stomatitis, and vomiting. At 12 and 16 mg dose levels, dose limiting toxicities (DLT) were observed, with an accumulation of higher-grade adverse events after the cycle 1 DLT assessment window. Pharmacodynamic findings showed pathway inhibition at ≥3 mg in patient tumor samples, consistent with preclinical PIK3CA-mutant tumor xenograft models. Confirmed response rate was 36% for PIK3CA-mutant tumor patients with measurable disease (5/14: 4 breast cancer, [3 patients at 12 mg]; 1 NSCLC) where responses started at 3 mg, and 0% in patients with tumors without known PIK3CA hotspot mutations (0/15).