SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial,The Lancet Haematology

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SHR2554, an EZH2 inhibitor, in relapsed or refractory mature lymphoid neoplasms: a first-in-human, dose-escalation, dose-expansion, and clinical expansion phase 1 trial
The Lancet Haematology ( IF 24.7 ) Pub Date : 2022-06-27 , DOI: 10.1016/s2352-3026(22)00134-x
Yuqin Song ₁ , Yanyan Liu ₂ , Zhi-Ming Li ₃ , Lanfang Li ₄ , Hang Su ₅ , Zhengming Jin ₆ , Xuelan Zuo ₇ , Jianyuan Wu ₈ , Hui Zhou ₉ , Kunyan Li ₁₀ , Chuan He ₁₁ , Jianfeng Zhou ₁₂ , Junyuan Qi ₁₃ , Siguo Hao ₁₄ , Zhen Cai ₁₅ , Yijing Li ₁₆ , Weiwei Wang ₁₆ , Xiaojing Zhang ₁₆ , Jianjun Zou ₁₆ , Jun Zhu ₁

Affiliation

Key Laboratory of Carcinogenesis and Transitional Research (Ministry of Education), Department of Lymphoma, Peking University Cancer Hospital & Institute, Beijing, China.
Lymphatic Comprehensive Internal Medicine Ward, Henan Cancer Hospital, Zhengzhou, China.
Medical Oncology, Sun Yat-sen University Cancer Centre, Guangzhou, China.
Department of Lymphoma, Tianjin Medical University Cancer Institute and Hospital, Tianjin, China.
The Fifth Medical Centre of the People's Liberation Army General Hospital, Beijing, China.
Department of Hematology, The First Affiliated Hospital of Soochow University, Suzhou, China.
Department of Hematopathology, Zhongnan Hospital of Wuhan University, Wuhan, China.
Clinical Trial Centre, Zhongnan Hospital of Wuhan University, Wuhan, China.
Department of Lymphoma & Hematology (Children's Tumour Centre), Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Early Clinical Trial Centre, Hunan Cancer Hospital & The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, China.
Department of Hematopathology, West China Hospital Sichuan University, Chengdu, China.
Department of Hematology, Tongji Hospital, Tongji Medical College of Huazhong University of Science and Technology, Wuhan, China.
Good Clinical Practice Ward, Blood Diseases Hospital, Chinese Academy of Medical Sciences, Tianjin, China.
Department of Hematology, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Bone Marrow Transplantation Centre, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
Clinical Research & Development, Jiangsu Hengrui Pharmaceuticals, Shanghai, China.

Background

Dysregulation of EZH2 has a crucial role in lymphomagenesis. We did a first-in-human study to assess the safety, pharmacokinetics, pharmacodynamics, and preliminary clinical activity of SHR2554, an oral EZH2 inhibitor, in patients with relapsed or refractory mature lymphoid neoplasms, including B-cell lymphomas, T-cell lymphomas, and classical Hodgkin lymphoma.

Methods

This was a multicentre, dose-escalation, dose-expansion, and clinical expansion phase 1 study done at 13 hospitals in China. Eligible patients had histologically or cytologically confirmed mature lymphoid neoplasms that had relapsed or were refractory to standard systemic therapies or had no standard-of-care. The study included a dose-escalation phase, at doses of SHR2554 from 50 mg to 800 mg twice daily; a dose-expansion phase, at two selected doses; and a subsequent clinical expansion phase at the recommended phase 2 dose in selected tumours. Primary endpoints were the safety, maximum tolerated dose, and recommended phase 2 dose. Objective response rate was a secondary endpoint. Safety and activity were assessed in all patients who received at least one dose of SHR2554 and had at least one post-baseline evaluation. This study is registered with ClinicalTrials.gov, NCT03603951, and follow-up is ongoing.

Findings

Between Aug 14, 2018, and July 13, 2021, 113 patients received SHR2554. At data cutoff (Sept 10, 2021), the median follow-up duration was 7·0 months (IQR 3·7–12·0). 71 (63%) patients were men and 42 (37%) were women, 110 (97%) were of Han ethnicity and 3 (3%) of other ethnicities, and 53 (47%) had received three or more lines of previous anticancer therapies. Dose-limiting toxicities occurred in two (67%) of three patients who received 400 mg SHR2554 twice daily and one (17%) of six patients who received 350 mg SHR2554 twice daily. The maximum tolerated dose and recommended phase 2 dose was determined to be 350 mg twice daily. The most common grade 3 or 4 treatment-related adverse events in all 113 patients were decreased platelet count (20 [18%]), decreased neutrophil count (ten [9%]), decreased white blood cell count (nine [8%]), and anaemia (seven [6%]). 18 (16%) patients had serious treatment-related adverse events. Two patients (2%) died due to treatment-related adverse events: one (1%) due to skin infection and toxic epidermal necrolysis and one (1%) due to respiratory failure. 107 (95%) of the 113 enrolled patients had post-baseline assessments for tumour response and were included in the activity analysis. 46 (43%; 95% CI 33–53) of these 107 patients had an overall response.

Interpretation

SHR2554 showed an acceptable safety proﬁle and promising antitumour activity in patients with relapsed or refractory lymphomas, providing evidence for future investigations.