Fan Zhengfu, Wang Jin, Liu Dan, Shen Lin, Fang Meiyu, Johnson Patrick, Tun Han, Sommerhalder David, Yang Jilong, Yang Yun, Munozi Javier, Zhu Jun, Gao Tian, Li Zhiming, Li Xian'an, Ma Qiuying, Lv Chao, Yu Songda, Li Fugen, Song Yuqin, Gong Jifang
Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Bone and Soft Tissue Tumour, Peking University Cancer Hospital & Institute, Beijing, China.
Department of Bone & Soft Tissue Oncology, Sun Yat-sen University Cancer Centre, Guangzhou, China.
EClinicalMedicine. 2025 Aug 7;86:103398. doi: 10.1016/j.eclinm.2025.103398. eCollection 2025 Aug.
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).
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.
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 events (TRAEs) of any grade occurred in 58 patients (95.1%). The most common TRAEs were diarrhoea (n = 31, 50.8%), blood bilirubin increased (n = 29, 47.5%) and anaemia (n = 23, 37.7%). The most common TRAEs of grade ≥3 included anaemia (n = 7, 11.5%), diarrhoea (n = 5, 8.2%), and platelet count decreased (n = 4, 6.6%). No treatment-related deaths were reported. Among 57 efficacy-evaluable patients, 17 (27.9%) achieved an objective response, with four complete responses and 13 partial responses. Ten of 17 objective responses (58.8%) were observed in patients with epithelioid sarcoma (ES). The objective response rate in patients with ES was 31.3% (95% confidence interval [CI], 16.0-50.0), and the median progression-free survival was 16.0 months (95% CI, 5.2-19.1).
HH2853 showed a manageable safety profile and encouraging antitumour activity in refractory solid tumours and NHLs, with particularly promising antitumour activity in ES. Further trials are needed. A phase II trial of HH2853 in patients with ES is underway.
The Science, Technology and Economic Commission of Shanghai Pudong New Area Municipality and Shanghai Haihe Biopharma Co., Ltd.
HH2853是一种新型的EZH1/2双重抑制剂，在各种临床前模型中，与他泽司他相比，具有更强的抗肿瘤活性。在此，我们评估了HH2853在难治性晚期实体瘤和非霍奇金淋巴瘤（NHL）患者中的安全性、药代动力学（PK）、药效学（PD）及初步疗效。
本开放标签、全球多中心的I期研究在中国和美国的12个中心开展，纳入复发或难治性实体瘤或NHL患者（年龄≥18岁）。对于剂量递增，采用标准贝叶斯最优区间加速滴定设计，评估了HH2853的7个预定义剂量水平（50、100、200、400、600、800、1000mg，口服，每日两次，共28天）。选择两个剂量水平进行剂量扩展。主要终点为安全性、剂量限制性毒性（DLT）、最大耐受剂量（MTD）和推荐的II期剂量（RP2D）。次要终点和探索性终点包括PK/PD曲线和初步疗效。本研究已在ClinicalTrials.gov注册，注册号为NCT04390737。
2020年9月8日至2023年2月28日期间，61例患者接受了HH2853治疗。截至2024年1月5日，中位随访时间为15.7个月（四分位间距[IQR]，13.8 - 17.7）。在800mg剂量水平的患者中观察到2例DLT。未达到MTD。选择400mg和600mg剂量水平进行剂量扩展，RP2D确定为每日两次400mg。58例患者（95.1%）发生了任何级别的治疗相关不良事件（TRAE）。最常见的TRAE为腹泻（n = 31，50.8%）、血胆红素升高（n = 29，47.5%）和贫血（n = 23，37.7%）。≥3级最常见的TRAE包括贫血（n = 7，11.5%）、腹泻（n = 5，8.2%）和血小板计数降低（n = 4，6.6%）。未报告与治疗相关的死亡。在57例可评估疗效的患者中，17例（27.9%）获得客观缓解，其中4例完全缓解，13例部分缓解。17例客观缓解中有10例（58.8%）出现在上皮样肉瘤（ES）患者中。ES患者的客观缓解率为31.3%（95%置信区间[CI]，16.0 - 50.0），中位无进展生存期为16.0个月（95%CI，5.2 - 19.1）。
HH2853在难治性实体瘤和NHL中显示出可控的安全性和令人鼓舞的抗肿瘤活性，在ES中尤其具有显著的抗肿瘤活性。需要进一步开展试验。一项针对ES患者的HH285II期试验正在进行中。
上海市浦东新区科学技术和经济委员会及上海海和生物制药有限公司
