Department of Clinical Pharmacology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Oncology Medicine Department, Jules Bordet Institute, Université Libre de Bruxelles, Brussels, Belgium.
Br J Cancer. 2021 Feb;124(4):728-735. doi: 10.1038/s41416-020-01151-6. Epub 2020 Nov 24.
This open-label, phase 1 trial (NCT02316197) aimed to determine the maximum-tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of peposertib (formerly M3814), a DNA-dependent protein kinase (DNA-PK) inhibitor in patients with advanced solid tumours. Secondary/exploratory objectives included safety/tolerability, pharmacokinetic/pharmacodynamic profiles and clinical activity.
Adult patients with advanced solid tumours received peposertib 100-200 mg once daily or 150-400 mg twice daily (BID) in 21-day cycles.
Thirty-one patients were included (median age 66 years, 61% male). One dose-limiting toxicity, consisting of mainly gastrointestinal, non-serious adverse events (AEs) and long recovery duration, was reported at 300 mg BID. The most common peposertib-related AEs were nausea, vomiting, fatigue and pyrexia. The most common peposertib-related Grade 3 AEs were maculopapular rash and nausea. Peposertib was quickly absorbed systemically (median T 1.1-2.5 h). The p-DNA-PK/t-DNA-PK ratio decreased consistently in peripheral blood mononuclear cells 3-6 h after doses ≥100 mg. The best overall response was stable disease (12 patients), lasting for ≥12 weeks in seven patients.
Peposertib was well-tolerated and demonstrated modest efficacy in unselected tumours. The MTD was not reached; the RP2D was declared as 400 mg BID. Further studies, mainly with peposertib/chemo-radiation, are ongoing.
NCT02316197.
这项开放标签、1 期试验（NCT02316197）旨在确定晚期实体瘤患者中 DNA 依赖性蛋白激酶（DNA-PK）抑制剂 peposertib（前身为 M3814）的最大耐受剂量（MTD）和/或推荐的 2 期剂量（RP2D）。次要/探索性目标包括安全性/耐受性、药代动力学/药效学特征和临床活性。
接受治疗的晚期实体瘤成年患者每天一次接受 100-200mg 或每天两次（BID）接受 150-400mg peposertib，21 天为一个周期。
共纳入 31 例患者（中位年龄 66 岁，61%为男性）。300mg BID 组报告了 1 例剂量限制性毒性，主要为胃肠道、非严重不良事件（AE）和较长的恢复时间。最常见的 peposertib 相关 AE 为恶心、呕吐、疲劳和发热。最常见的 peposertib 相关 3 级 AE 为斑丘疹和恶心。peposertib 全身吸收迅速（中位 T 1.1-2.5h）。外周血单核细胞中 p-DNA-PK/t-DNA-PK 比值在剂量≥100mg 后 3-6h 持续下降。最佳总体缓解为疾病稳定（12 例），7 例患者的缓解持续时间≥12 周。
peposertib 耐受性良好，在未选择的肿瘤中显示出适度的疗效。未达到最大耐受剂量；推荐的 2 期剂量为 400mg BID。正在进行主要与 peposertib/放化疗联合的进一步研究。
NCT02316197。
