Janku Filip, Choong Grace M, Opyrchal Mateusz, Dowlati Afshin, Hierro Cinta, Rodon Jordi, Wicki Andreas, Forster Martin D, Blagden Sarah P, Yin Jun, Reid Joel M, Muller Helene, Cmiljanovic Natasa, Cmiljanovic Vladimir, Adjei Alex A
The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
Mayo Clinic Rochester, Department of Oncology, Rochester, MN 55905, USA.
Cancers (Basel). 2024 Mar 13;16(6):1137. doi: 10.3390/cancers16061137.
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 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.
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 NOTCH1 mutation.
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.
比米拉西布是一种泛PI3K/mTOR抑制剂，在临床前模型中显示出抗肿瘤疗效。本研究的目的是确定晚期实体瘤患者的最大耐受剂量（MTD）、药代动力学（PK）、给药方案和不良事件（AE）。
患者接受口服比米拉西布，以确定一种连续给药方案（每日一次）和两种间歇给药方案（方案A：第1、2天，每周一次；方案B：第1、4天，每周一次）的MTD，直至疾病进展或出现不可接受的AE。
连续给药方案的MTD为80mg，三级疲劳为剂量限制性毒性（DLT）。间歇给药方案未达到MTD，方案B仅出现1例DLT。PK分析表明，140mg（方案A）在生物活性剂量范围内，因此被选择用于进一步研究。最常见的治疗中出现的AE在连续给药方案中是高血糖（76.2%），在方案A和B中是恶心（56 - 62.5%）。所有给药方案合并后最常见的治疗中出现的>三级AE是高血糖（连续给药方案中为28.6%；方案A中为12.0%；方案B中为12.5%）。一名NOTCH1突变的头颈部鳞状癌患者出现了部分缓解。
比米拉西布显示出与该化合物类别一致的可管理的AE谱。间歇给药方案的>三级AE较少，同时也保持了良好的PK谱。建议在生物标志物选择的患者群体中进一步开发间歇给药方案A。
