Princess Margaret Cancer Centre and Mount Sinai Hospital, Toronto, ON, Canada.
Division of Oncology and Hematology, Faculty of Medicine, University of Toronto, Toronto, ON, Canada.
Invest New Drugs. 2020 Aug;38(4):1156-1165. doi: 10.1007/s10637-019-00869-2. Epub 2019 Nov 16.
Purpose MDM2 is a negative regulator of the tumor suppressor p53. RO6839921 is an inactive pegylated prodrug of idasanutlin, an MDM2 antagonist, developed for intravenous administration. On cleavage by plasma esterases, the active principle (AP = idasanutlin) is released. This phase 1 study investigated the safety, pharmacokinetics, and pharmacodynamics of RO6839921 in patients with advanced solid tumors (NCT02098967). Methods Patients were evaluated on a 5-day dosing schedule every 28 days. Dose escalation used the Bayesian new continual reassessment model. Accelerated dose titration was permitted until grade ≥2 drug-related AEs were observed. The target DLT rate to define the MTD was 16-25%. p53 activation was assessed by measuring macrophage inhibitory cytokine-1 (MIC-1). Results Forty-one patients received 14-120 mg AP; 39 were DLT evaluable. The MTD was 110-mg AP (8% DLT rate), whereas 120-mg AP had a 44% DLT rate. DLTs were neutropenia, thrombocytopenia, and stridor. The most common treatment-related AEs (≥30%) were nausea, fatigue, vomiting, and thrombocytopenia. Pharmacokinetic analyses indicated rapid conversion of prodrug to AP and an approximately linear and dose-proportional dose-exposure relationship, with a 2-fold increase in exposure between Days 1 and 5 of AP. MIC-1 increases were exposure dependent. Stable disease was observed in 14 patients (34%). Conclusions RO6839921 showed reduced pharmacokinetic exposure variability and a safety profile comparable with that of oral idasanutlin. Although this study indicated that RO6839921 could be administered to patients, the results did not provide sufficient differentiation or improvement in the biologic or safety profile compared with oral idasanutlin to support continued development.
目的 MDM2 是肿瘤抑制因子 p53 的负调节剂。RO6839921 是一种无活性的聚乙二醇化前药，是 MDM2 拮抗剂 idasanutlin 的静脉注射制剂。在血浆酯酶的裂解下，释放出活性成分（AP=idasanutlin）。这项 I 期研究旨在评估 RO6839921 在晚期实体瘤患者中的安全性、药代动力学和药效学（NCT02098967）。
方法 患者每 28 天接受为期 5 天的剂量方案评估。采用贝叶斯新连续再评估模型进行剂量递增。在观察到 2 级及以上与药物相关的不良事件（AE）时，允许加速剂量滴定。目标 DLT 率为 16-25%，以确定 MTD。通过测量巨噬细胞抑制细胞因子-1（MIC-1）评估 p53 激活。
结果 41 例患者接受了 14-120mg AP 的治疗；39 例患者可进行 DLT 评估。MTD 为 110mg AP（8% DLT 率），而 120mg AP 的 DLT 率为 44%。DLT 为中性粒细胞减少症、血小板减少症和喘鸣。最常见的治疗相关不良事件（≥30%）为恶心、疲劳、呕吐和血小板减少症。药代动力学分析表明，前药快速转化为 AP，且呈近似线性和剂量比例的剂量-暴露关系，AP 第 1 天和第 5 天的暴露量增加 2 倍。MIC-1 的增加与暴露量有关。14 例患者（34%）观察到疾病稳定。
结论 RO6839921 表现出较低的药代动力学暴露变异性和与口服 idasanutlin 相当的安全性特征。尽管该研究表明 RO6839921 可用于患者，但结果并未提供足够的区分度，与口服 idasanutlin 相比，在生物学或安全性特征方面没有足够的改善，不足以支持继续开发。
