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

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

doi:10.1016/j.medj.2025.100575

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

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

Authors

Lijuan Hu¹, Xudong Wei², Weili Zhao³, Yu Hu⁴, Juan Li⁵, Yugang Dong⁶, Tiejun Gong⁷, Xuhan Zhang⁸, Yajing Xu⁹, Yu Zhang¹⁰, Chongyuan Xu¹¹, Cheng Zhang¹², Zhen Cai¹³, Hongmei Jing¹⁴, Ruihua Mi², Wen Wu³, Wenjuan He⁴, Hehua Wang⁵, Qinghua Tang⁷, Zhiping Jiang⁹, Hui Liu¹⁰, Guo Chen¹², Jie Sun¹³, Jian Chen¹⁵, Sai Yan¹⁵, Huan Yan¹⁵, Jiaxuan Wangwu¹⁵, Zeyu Zhong¹⁵, Linfang Wang¹⁵, Songhua Fan¹⁵, Michael Shi¹⁵, Weiguo Su¹⁵, Xiaojun Huang¹⁶

Affiliations

¹ 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.
² Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University and Henan Cancer Hospital, Zhengzhou 450003, China.
³ Hematology Department, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.
⁴ Hematology Department, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China.
⁵ Hematology Department, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
⁶ Phase I Clinical Trial Center, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou 510080, China.
⁷ Department of Hematology, Harbin First Hospital Hematological Cancer Research Center, Harbin 150010, China.
⁸ Hematology Department, Division of Life Sciences and Medicine, The First Affiliated Hospital of USTC, University of Science and Technology of China, Hefei 230001, China.
⁹ Hematology Department, Xiangya Hospital Central South University, Changsha 410008, China.
¹⁰ Hematology Department, Southern Medical University Nanfang Hospital, Guangzhou 510515, China.
¹¹ Phase I Clinical Trial Center, Southern Medical University Nanfang Hospital, Guangzhou 510515, China.
¹² Hematology Department, The Second Affiliated Hospital of the Army Medical University of PLA, Chongqing 400037, China.
¹³ Hematology Department, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
¹⁴ Hematology Department, Peking University Third Hospital, Beijing 100191, China.
¹⁵ HUTCHMED Limited, Shanghai 201203, China.
¹⁶ 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; Peking Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China; State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100871, China. Electronic address: huangxiaojun@bjmu.edu.cn.

PMID: 39892383
DOI: 10.1016/j.medj.2025.100575

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.

Keywords: HMPL-306; Translation to patients; acute myeloid leukemia; mIDH1; mIDH2.

Publication types

Clinical Trial, Phase I
Multicenter Study

MeSH terms

Adult
Aged
Aged, 80 and over
Antineoplastic Agents* / administration & dosage
Antineoplastic Agents* / adverse effects
Dose-Response Relationship, Drug
Female
Humans
Isocitrate Dehydrogenase* / genetics
Leukemia, Myeloid, Acute* / drug therapy
Leukemia, Myeloid, Acute* / genetics
Leukemia, Myeloid, Acute* / mortality
Male
Maximum Tolerated Dose
Middle Aged
Mutation
Young Adult

Substances

Isocitrate Dehydrogenase
IDH1 protein, human
IDH2 protein, human
Antineoplastic Agents

Associated data

ClinicalTrials.gov/NCT04272957
ClinicalTrials.gov/NCT06387069