Institute for Drug Development, San Antonio, Texas, USA.
Clin Cancer Res. 2010 Dec 1;16(23):5892-9. doi: 10.1158/1078-0432.CCR-10-1096.
Plinabulin (NPI-2358) is a vascular disrupting agent that elicits tumor vascular endothelial architectural destabilization leading to selective collapse of established tumor vasculature. Preclinical data indicated plinabulin has favorable safety and antitumor activity profiles, leading to initiation of this clinical trial to determine the recommended phase 2 dose (RP2D) and assess the safety, pharmacokinetics, and biologic activity of plinabulin in patients with advanced malignancies.
Patients received a weekly infusion of plinabulin for 3 of every 4 weeks. A dynamic accelerated dose titration method was used to escalate the dose from 2 mg/m² to the RP2D, followed by enrollment of an RP2D cohort. Safety, pharmacokinetic, and cardiovascular assessments were conducted, and Dynamic contrast-enhanced MRI (DCE-MRI) scans were performed to estimate changes in tumor blood flow.
Thirty-eight patients were enrolled. A dose of 30 mg/m² was selected as the RP2D based on the adverse events of nausea, vomiting, fatigue, fever, tumor pain, and transient blood pressure elevations, with DCE-MRI indicating decreases in tumor blood flow (Ktrans) from 13.5 mg/m² (defining a biologically effective dose) with a 16% to 82% decrease in patients evaluated at 30 mg/m². Half-life was 6.06 ± 3.03 hours, clearance was 30.50 ± 22.88 L/h, and distributive volume was 211 ± 67.9 L.
At the RP2D of 30 mg/m², plinabulin showed a favorable safety profile, while eliciting biological effects as evidenced by decreases in tumor blood flow, tumor pain, and other mechanistically relevant adverse events. On the basis of these results additional clinical trials were initiated with plinabulin in combination with standard chemotherapy agents.
Plinabulin（NPI-2358）是一种血管破坏剂，可引起肿瘤血管内皮结构不稳定，导致已建立的肿瘤血管选择性塌陷。临床前数据表明，plinabulin 具有良好的安全性和抗肿瘤活性特征，因此启动了这项临床试验，以确定推荐的 2 期剂量（RP2D）并评估 plinabulin 在晚期恶性肿瘤患者中的安全性、药代动力学和生物学活性。
患者每 4 周的 3 周内每周接受一次 plinabulin 输注。采用动态加速剂量滴定法将剂量从 2mg/m² 增加到 RP2D，然后招募 RP2D 队列。进行安全性、药代动力学和心血管评估，并进行动态对比增强 MRI（DCE-MRI）扫描以估计肿瘤血流变化。
共招募了 38 名患者。根据恶心、呕吐、疲劳、发热、肿瘤疼痛和短暂性血压升高的不良反应，选择 30mg/m² 作为 RP2D，DCE-MRI 显示肿瘤血流量（Ktrans）从 13.5mg/m²（定义为生物有效剂量）降低，30mg/m² 评估的患者中有 16%至 82%降低。半衰期为 6.06±3.03 小时，清除率为 30.50±22.88L/h，分布容积为 211±67.9L。
在 30mg/m² 的 RP2D 下，plinabulin 表现出良好的安全性，同时通过降低肿瘤血流、肿瘤疼痛和其他机制相关的不良事件证明了生物学效应。基于这些结果，启动了额外的临床试验，将 plinabulin 与标准化疗药物联合使用。
