Background: Bimiralisib is a pan-PI3K/mTOR inhibitor demonstrating antitumor efficacy in preclinical models. The objectives of this study were to identify a maximum tolerated dose (MTD), pharmacokinetics (PK), a dosing schedule, and adverse events (AEs) in patients with advanced solid tumors. Patients and Methods: Patients received oral bimiralisib to determine the MTD of one continuous (once daily) and two intermittent schedules (A: Days 1, 2 weekly; B: Days 1, 4 weekly) until progression or unacceptable AEs occurred. Results: The MTD for the continuous schedule was 80 mg, with grade three fatigue as the dose-limiting toxicity (DLT). No MTD was reached with intermittent schedules, with only one DLT in schedule B. PK analysis suggested that 140 mg (schedule A) was within the biologically active dose range and was selected for further exploration. The most frequent treatment-emergent AEs were hyperglycemia (76.2%) in the continuous schedule, and nausea (56–62.5%) in schedules A and B. The most frequent treatment-emergent > grade three AE for all schedules combined was hyperglycemia (28.6%, continuous schedule; 12.0%, schedule A; 12.5%, schedule B). There was one partial response in a head and neck squamous cancer patient with a NOTCH1T1997Mmutation. Conclusions: Bimiralisib demonstrated a manageable AE profile consistent with this compound class. Intermittent schedules had fewer > grade three AEs, while also maintaining favorable PK profiles. Intermittent schedule A is proposed for further development in biomarker-selected patient populations.
背景：Bimiralisib是一种泛PI3K/mTOR抑制剂，在临床前模型中显示出抗肿瘤活性。本研究旨在确定晚期实体瘤患者的最大耐受剂量（MTD）、药代动力学（PK）、给药方案以及不良事件（AEs）。患者与方法：患者口服bimiralisib，以确定一种连续给药方案（每日一次）和两种间歇给药方案（A：每周第1、2天；B：每周第1、4天）的MTD，直至疾病进展或出现不可接受的AEs。结果：连续给药方案的MTD为80 mg，剂量限制性毒性（DLT）为3级疲劳。间歇给药方案未达到MTD，仅在方案B中出现一例DLT。PK分析表明，140 mg（方案A）处于生物活性剂量范围内，被选择用于进一步探索。最常见的治疗相关AEs在连续方案中为高血糖（76.2%），在方案A和B中为恶心（56–62.5%）。所有方案合并最常见的治疗相关≥3级AE为高血糖（连续方案：28.6%；方案A：12.0%；方案B：12.5%）。一例携带NOTCH1 T1997M突变的头颈部鳞癌患者出现部分缓解。结论：Bimiralisib表现出可控的AE特征，与该类药物一致。间歇给药方案的≥3级AEs更少，同时保持了良好的PK特征。建议在生物标志物筛选的患者群体中进一步开发间歇给药方案A。
肿瘤(癌症)患者之家