Safety and efficacy of HH2853, a novel EZH1/2 dual inhibitor, in patients with refractory solid tumours or non-Hodgkin lymphomas: a phase I study

作者：Zhengfu Fan, Jin Wang, Dan Liu, Lin Shen, Meiyu Fang, P. Connor Johnson, Han Tun, David Sommerhalder, Jilong Yang, Yun Yang, Javier Munozi, Jun Zhu, Tian Gao, Zhiming Li, Xianan Li, Qiuying Ma, Chao Lv, Songda Yu, Fugen Li, Yuqin Song, Jifang Gong · 发表于：EClinicalMedicine · 年份：2025 · DOI：10.1016/j.eclinm.2025.103398 · 被引用次数：5 · 研究领域：Epigenetics and DNA Methylation、Cancer, Hypoxia, and Metabolism、Cancer-related gene regulation

Background: HH2853 is a novel dual EZH1/2 inhibitor that exhibits superior antitumour activity compared to tazemetostat across various preclinical models. Here, we evaluated the safety, pharmacokinetic (PK), pharmacodynamic (PD), and preliminary efficacy of HH2853 in patients with refractory advanced solid tumours and non-Hodgkin lymphomas (NHLs). Methods: This open-label, global multicentre, phase I study was conducted at 12 centres in China and the USA, enrolling patients (aged ≥18 years) with relapsed or refractory solid tumours or NHLs. For dose escalation, seven predefined dose levels of HH2853 (50, 100, 200, 400, 600, 800, 1000 mg, orally twice daily for 28 days) were evaluated using a standard Bayesian optimal interval with accelerated titration design. Two dose levels were selected for dose extension. Primary endpoints were safety, dose-limiting toxicity (DLT), maximum tolerated dose (MTD), and recommended phase II dose (RP2D). Secondary and exploratory endpoints included PK/PD profiles and preliminary efficacy. This study is registered with ClinicalTrials.gov, NCT04390737. Findings: Between Sept 8, 2020, and Feb 28, 2023, 61 patients received HH2853. As of Jan 5, 2024, the median follow-up was 15.7 months (interquartile range [IQR], 13.8-17.7). Two DLTs were observed in patients at 800 mg dose level. MTD was not reached. The dose levels of 400 mg and 600 mg were selected for dose extension, and the RP2D was determined as 400 mg twice daily. Treatment-related adverse ...