HMPL-306用于复发或难治性异柠檬酸脱氢酶1和/或异柠檬酸脱氢酶2突变的急性髓系白血病：一项1期研究。

HMPL-306 in relapsed or refractory IDH1- and/or IDH2-mutated acute myeloid leukemia: A phase 1 study.

作者信息

Hu Lijuan, Wei Xudong, Zhao Weili, Hu Yu, Li Juan, Dong Yugang, Gong Tiejun, Zhang Xuhan, Xu Yajing, Zhang Yu, Xu Chongyuan, Zhang Cheng, Cai Zhen, Jing Hongmei, Mi Ruihua, Wu Wen, He Wenjuan, Wang Hehua, Tang Qinghua, Jiang Zhiping, Liu Hui, Chen Guo, Sun Jie, Chen Jian, Yan Sai, Yan Huan, Wangwu Jiaxuan, Zhong Zeyu, Wang Linfang, Fan Songhua, Shi Michael, Su Weiguo, Huang Xiaojun

机构信息

Hematology Department, Peking University People's Hospital, Peking University Institute of Hematology, National Clinical Research Center for Hematologic Disease, Beijing Key Laboratory of Hematopoietic Stem Cell Transplantation, Peking University, Beijing 100044, China.

Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450003, China.

出版信息

Med. 2025 Jun 13;6(6):100575. doi: 10.1016/j.medj.2025.100575. Epub 2025 Jan 31.

DOI:10.1016/j.medj.2025.100575

PMID:39892383

Abstract

BACKGROUND

HMPL-306 has equally high inhibitory activity against mutated isocitrate dehydrogenases 1 and 2 (mIDH1/2).

METHODS

This first-in-human, phase 1 dose-escalation/dose-expansion study (this study was registered at ClinicalTrials.gov: NCT04272957) enrolled patients with relapsed/refractory (R/R) acute myeloid leukemia (AML) harboring mIDH1 and/or mIDH2. Patients received 25-250 mg of HMPL-306 orally once daily (QD) in a 28-day treatment cycle. Primary objectives were safety, tolerability, and recommended phase 2 dose (RP2D), and the secondary objective was preliminary efficacy.

FINDINGS

A total of 76 patients were enrolled. No dose-limiting toxicities were observed, and the maximum tolerated dose was not reached. RP2D was 250 mg QD for cycle 1 and 150 mg QD from cycle 2 onward. Common (≥10%) grade ≥3 treatment-related adverse events included platelet count decreased, anemia, neutrophil count decreased, and white blood cell count decreased. In patients who received 150 mg, 250 mg, or the RP2D (N = 59), rates of complete remission (CR)+CR with partial hematologic recovery were 34.6% and 36.4% in the mIDH1 (n = 26) and mIDH2 (n = 33) subgroups, respectively, and among these, CR with minimal residual disease negative rates were 77.8% and 50.0%, respectively. The median overall survival was 13.4 months in patients with mIDH1 and 13.1 months in patients with mIDH2.

CONCLUSIONS

HMPL-306 showed an acceptable safety profile and promising preliminary efficacy. A phase 3, randomized study of HMPL-306 in R/R AML (this study was registered at ClinicalTrials.gov: NCT06387069) has been initiated.

FUNDING

HUTCHMED Limited, National Key Research and Development Program of China, National Natural Science Foundation of China, and Peking University Medicine Fund for world's leading discipline or discipline cluster development.

摘要

背景

HMPL-306对突变型异柠檬酸脱氢酶1和2（mIDH1/2）具有同样高的抑制活性。

方法

这项首次人体1期剂量递增/剂量扩展研究（本研究已在ClinicalTrials.gov注册：NCT04272957）纳入了携带mIDH1和/或mIDH2的复发/难治性（R/R）急性髓系白血病（AML）患者。患者在28天的治疗周期中，每天口服一次25 - 250 mg的HMPL-306（每日一次）。主要目标是安全性、耐受性和推荐的2期剂量（RP2D），次要目标是初步疗效。

研究结果

共纳入76例患者。未观察到剂量限制性毒性，未达到最大耐受剂量。第1周期的RP2D为每日250 mg，从第2周期起为每日150 mg。常见（≥10%）的≥3级治疗相关不良事件包括血小板计数降低、贫血、中性粒细胞计数降低和白细胞计数降低。在接受150 mg、250 mg或RP2D的患者中（N = 59），mIDH1（n = 26）和mIDH2（n = 33）亚组的完全缓解（CR）+伴有部分血液学恢复的CR率分别为34.6%和36.4%，其中，微小残留病阴性率的CR分别为77.8%和50.0%。mIDH1患者的中位总生存期为13.4个月，mIDH2患者为13.1个月。