Lee Je-Hwan, Faderl Stefan, Pagel John M, Jung Chul Won, Yoon Sung-Soo, Pardanani Animesh D, Becker Pamela S, Lee Howard, Choi Jeongeun, Lee Kyoungjune, Kim Minkyoung, Cortes Jorge E
Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
Hackensack University Cancer Center, Hackensack, NJ.
Blood Adv. 2020 May 12;4(9):2032-2043. doi: 10.1182/bloodadvances.2019000757.
CWP232291 (CWP291) is a small-molecule inhibitor of Wnt signaling that causes degradation of β-catenin via apoptosis induction through endoplasmic reticulum stress activation. This first-in-human, open-label, dose-escalation study to evaluate the safety, maximum tolerated dose (MTD), and preliminary efficacy of CWP291 enrolled 69 patients with hematologic malignancies (acute myeloid leukemia [AML], n = 64; myelodysplastic syndrome, n = 5) in 15 dose-escalation cohorts of 4 to 334 mg/m2 using a modified 3+3 design and 1 dose-expansion cohort. CWP291 was administered IV daily for 7 days every 21 days. The most common treatment-emergent adverse events (TEAEs) were nausea (n = 44, 64%), vomiting (n = 32, 46%), diarrhea (n = 25, 36%), and infusion-related reactions (n = 20, 29%). Grade ≥3 TEAEs in >3 patients (5%) were pneumonia (n = 8, 12%); hypophosphatemia (n = 6, 8%); leukocytosis, nausea, cellulitis, sepsis, and hypokalemia (n = 5 each, 7% each); and hypertension (n = 4, 6%). Dose-limiting toxicities included nausea (n = 3) and abdominal pain, anaphylactic reaction, myalgia, and rash (n = 1, each); the MTD was defined at 257 mg/m2. CWP232204, the active metabolite of CWP291, showed pharmacokinetic linearity on both days 1 and 7, and a terminal half-life of ∼12 hours. Among 54 response-evaluable AML patients, there was one complete response at a dose of 153 mg/m2 and one partial response at 198 mg/m2; bone marrow blast percentage reduced from a median of 58.3% to 3.5% and 15.0% to 4.2%, respectively. Future studies will explore CWP291, with a mechanism of action aimed at eradication of earlier progenitors via Wnt pathway blockade, as combination therapy. This trial was registered at www.clinicaltrials.gov as #NCT01398462.
CWP232291（CWP291）是一种Wnt信号通路的小分子抑制剂，通过激活内质网应激诱导凋亡，导致β-连环蛋白降解。这项首次人体开放标签剂量递增研究旨在评估CWP291的安全性、最大耐受剂量（MTD）和初步疗效，该研究采用改良的3+3设计，在15个剂量递增队列（4至334mg/m²）和1个剂量扩展队列中纳入了69例血液系统恶性肿瘤患者（急性髓系白血病[AML]，n = 64；骨髓增生异常综合征，n = 5）。CWP291每21天静脉注射7天。最常见的治疗中出现的不良事件（TEAE）为恶心（n = 44，64%）、呕吐（n = 32，46%）、腹泻（n = 25，36%）和输液相关反应（n = 20，29%）。≥3级TEAE且发生在超过3例患者（5%）中的有肺炎（n = 8，12%）；低磷血症（n = 6，8%）；白细胞增多、恶心、蜂窝织炎、败血症和低钾血症（各n = 5，各7%）；以及高血压（n = 4，6%）。剂量限制性毒性包括恶心（n = 3）和腹痛、过敏反应、肌痛及皮疹（各n = 1）；MTD定义为257mg/m²。CWP291的活性代谢产物CWP232204在第1天和第7天均显示出药代动力学线性，终末半衰期约为12小时。在54例可评估反应的AML患者中，153mg/m²剂量时有1例完全缓解，198mg/m²剂量时有1例部分缓解；骨髓原始细胞百分比分别从中位数58.3%降至3.5%和从15.0%降至4.2%。未来研究将探索CWP291作为联合治疗方案，其作用机制旨在通过阻断Wnt通路根除早期祖细胞。该试验已在www.clinicaltrials.gov注册，编号为#NCT01398462。
