South Texas Accelerated Research Therapeutics, San Antonio, Texas.
Celgene Corporation, San Francisco, California.
Clin Cancer Res. 2019 Jan 1;25(1):90-98. doi: 10.1158/1078-0432.CCR-18-1203. Epub 2018 Sep 10.
Avadomide is a novel, small-molecule therapeutic agent that modulates cereblon E3 ligase activity and exhibits potent antitumor and immunomodulatory activities. This first-in-human phase I study (NCT01421524) evaluated the safety and clinical activity of avadomide in patients with advanced solid tumors, non-Hodgkin lymphoma (NHL), and multiple myeloma.
Thirty-four patients were treated with avadomide in 7 dose-escalation cohorts using a 3 + 3 design (0.5-3.5 mg, 28-day continuous dosing cycles). The primary objectives were to determine the dose-limiting toxicity (DLT), nontolerated dose (NTD), maximum tolerated dose (MTD), recommended phase II dose, and pharmacokinetics of avadomide. The secondary objective was to determine preliminary avadomide efficacy. Exploratory objectives included evaluation of pharmacodynamic effects of avadomide.
DLTs were reported in 2 patients, and grade ≥3 treatment-emergent adverse events (TEAEs) occurred in 14 patients (41%). The most common TEAEs (≥15%) were fatigue, neutropenia, and diarrhea. The NTD and MTD were 3.5 and 3.0 mg, respectively. Of 5 patients with NHL, 1 achieved a complete response, and 2 had partial responses. Although no objective responses were observed in patients with solid tumors, 5 of 6 patients with brain cancer experienced nonprogression of ≥6 months. A dose-dependent relationship between Aiolos degradation in peripheral B and T cells occurred within 5 hours of the first dose of avadomide administered, starting at 0.5 mg.
Avadomide monotherapy demonstrated acceptable safety and favorable pharmacokinetics in patients with solid tumors, NHL, and multiple myeloma. In addition, 3 objective responses were observed in NHL.
阿伐达泊是一种新型小分子治疗药物，可调节 cereblon E3 连接酶的活性，并具有强大的抗肿瘤和免疫调节活性。这项首次人体 I 期研究（NCT01421524）评估了阿伐达泊在晚期实体瘤、非霍奇金淋巴瘤（NHL）和多发性骨髓瘤患者中的安全性和临床活性。
34 名患者在 7 个剂量递增队列中接受阿伐达泊治疗，采用 3 + 3 设计（0.5-3.5mg，28 天连续给药周期）。主要目的是确定剂量限制性毒性（DLT）、不可耐受剂量（NTD）、最大耐受剂量（MTD）、推荐的 II 期剂量和阿伐达泊的药代动力学。次要目标是确定阿伐达泊的初步疗效。探索性目标包括评估阿伐达泊的药效学效应。
2 名患者报告 DLT，14 名患者（41%）发生≥3 级治疗后出现的不良事件（TEAE）。最常见的 TEAEs（≥15%）是疲劳、中性粒细胞减少和腹泻。NTD 和 MTD 分别为 3.5mg 和 3.0mg。5 名 NHL 患者中，1 名患者达到完全缓解，2 名患者有部分缓解。尽管在实体瘤患者中未观察到客观缓解，但 6 名脑癌患者中有 5 名的疾病无进展时间≥6 个月。阿伐达泊首次给药后 5 小时内，外周 B 和 T 细胞中的 Aiolos 降解出现剂量依赖性，起始剂量为 0.5mg。
阿伐达泊单药治疗在实体瘤、NHL 和多发性骨髓瘤患者中表现出可接受的安全性和良好的药代动力学。此外，在 NHL 中观察到 3 例客观缓解。
