Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel
Phase 1 study of the novel vascular disrupting agent plinabulin (NPI-2358) and docetaxel
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DOI：
10.1007/s10637-011-9642-4
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发表时间：
2012-06-01
影响因子：
3.4
通讯作者：
Spear, Matthew A.
中科院分区：
文献类型：
--
作者：
Millward, Michael;Mainwaring, Paul;Spear, Matthew A.
背景 普那布林 (NPI-2358) 是一种血管破坏剂 (VDA)，可破坏肿瘤血管内皮细胞结构的稳定性，导致已建立的肿瘤血管系统选择性崩溃，单独或与细胞毒性药物联合产生抗肿瘤活性。本研究的目的是评估普那布林联合多西他赛的推荐 2 期剂量 (RP2D)。患者和方法 患者在第 1 天接受 75 mg/m(2) 多西他赛，在第 1 天和第 8 天接受普那布林静脉注射，周期为 21 天。采用“3+3”设计，将普那布林从生物有效剂量（BED）13.5 mg/m(2) 升级至标准单药剂量30 mg/m(2)。结果 13 名患者入组。不良事件与单独使用两种药物的情况一致。疲劳、疼痛、恶心、腹泻和呕吐是最常见的事件。发生一剂量限制性毒性，包括恶心、呕吐、脱水和中性粒细胞减少。 RP2D 为 30 mg/m(2) 普那布林和 75 mg/m(2) 多西紫杉醇。药代动力学并未表明药物间相互作用。在 8 名可评估疗效的 NSCLC 患者中，2 名患者实现了部分缓解，4 名患者的肿瘤测量值下降幅度较小。结论 全剂量普那布林和多西他赛联合用药是可以耐受的。由于具有令人鼓舞的抗肿瘤活性，这支持了该组合的进一步开发。
Background Plinabulin (NPI-2358) is a vascular disrupting agent (VDA) that destabilizes tumor vascular endothelial cell architecture resulting in selective collapse of established tumor vasculature producing anti-tumor activity alone or in combination with cytotoxic agents. The objective of this study was to assess the recommended Phase 2 dose (RP2D) of plinabulin combined with docetaxel. Patients and Methods Patients received 75 mg/m(2) docetaxel on day 1 and plinabulin on days 1 and 8 intravenously in 21 day cycles. Plinabulin was escalated from the biologically effective dose (BED) of 13.5 mg/m(2) to the standard single agent dose of 30 mg/m(2) using a "3+3" design. Results Thirteen patients were enrolled. Adverse events were consistent with those of both agents alone. Fatigue, pain, nausea, diarrhea and vomiting were the most common events. One dose limiting toxicity of nausea, vomiting, dehydration and neutropenia occurred. The RP2D was 30 mg/m(2) of plinabulin with 75 mg/m(2) docetaxel. Pharmacokinetics did not indicate drug-drug interactions. Of the 8 patients with NSCLC evaluable for response, 2 achieved a partial response and 4 demonstrated lesser decreases in tumor measurements. Conclusions The combination of full doses of plinabulin and docetaxel is tolerable. With encouraging antitumor activity, this supported further development of this combination.