Pevonedistat (TAK924) is a Nedd8-activating enzyme inhibitor with preclinical activity in non-Hodgkin lymphoma (NHL). This open-label, Phase I, multicenter, investigator-sponsored study enrolled patients with relapsed/refractory (R/R) NHL and chronic lymphocytic leukemia (CLL). The primary objective was safety. Pevonedistat was given intravenously on days 1, 3, 5 of a 21-day cycle for 8 cycles at five dose levels (15 to 50 mg/m2); ibrutinib was administered at 420 or 560 mg orally daily continuously. Eighteen patients with NHL were enrolled, including 8 patients with mantle cell lymphoma (MCL) and 4 patients with CLL. One dose-limiting toxicity (mediastinal hemorrhage) occurred at 50 mg/m2 of pevonedistat which is the estimated maximum tolerated dose. Bruising and diarrhea were the most common adverse events (56% and 44%). Atrial fibrillation occurred in 3 patients (17%). Grade ≥3 toxicities included arthralgia, atrial fibrillation, bone pain, diarrhea, hypertension, and mediastinal hemorrhage (one patient each). The overall response rate (ORR) was 65% (100% ORR in MCL). Pevonedistat disposition was not modified by ibrutinib. scRNA-Seq analysis showed that pevonedistat downregulated NFκB signaling in malignant B-cells in vivo. Thus, pevonedistat combined with ibrutinib demonstrated safety and promising early efficacy in NHL and CLL. NAE inhibition downregulated NFκB signaling in vivo.
Pevonedistat（TAK924）是一种Nedd8激活酶抑制剂，在非霍奇金淋巴瘤（NHL）临床前研究中显示出活性。这项开放标签、I期、多中心、研究者发起的研究纳入了复发/难治性（R/R）NHL和慢性淋巴细胞白血病（CLL）患者。主要目标是评估安全性。Pevonedistat在每个21天周期的第1、3、5天静脉给药，共8个周期，设五个剂量水平（15至50毫克/平方米）；伊布替尼按420或560毫克剂量每日连续口服给药。研究共纳入18例NHL患者，包括8例套细胞淋巴瘤（MCL）患者和4例CLL患者。在50毫克/平方米（估计最大耐受剂量）的pevonedistat剂量下发生1例剂量限制性毒性（纵隔出血）。瘀伤和腹泻是最常见的不良事件（分别为56%和44%）。3例患者（17%）出现心房颤动。≥3级毒性包括关节痛、心房颤动、骨痛、腹泻、高血压和纵隔出血（各1例）。总缓解率（ORR）为65%（MCL患者的ORR为100%）。伊布替尼未改变pevonedistat的体内处置。单细胞RNA测序分析显示，pevonedistat在体内下调了恶性B细胞的NFκB信号传导。因此，pevonedistat联合伊布替尼在NHL和CLL中显示出安全性及良好的早期疗效。NAE抑制在体内下调了NFκB信号传导。
肿瘤(癌症)患者之家