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.

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 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). Interpretation: 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. Funding: The Science, Technology and Economic Commission of Shanghai Pudong New Area Municipality and Shanghai Haihe Biopharma Co., Ltd.