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2908 A Phase I/II Trial of the FLT3 Kinase Inhibitor XY0206 in Patients with Relapsed/Refractory Acute Myeloid Leukemia

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster II
Hematology Disease Topics & Pathways:
Acute Myeloid Malignancies, AML, Research, clinical trials, Clinical Research, drug development, Diseases, Therapies, Myeloid Malignancies
Sunday, December 10, 2023, 6:00 PM-8:00 PM

Junyuan Qi, MD1*, Lin Song, MD2*, Xudong Wei3*, Zhimin Zhai, MD4, Anyou Wang, MD5*, Daozi Jiang, MD6*, Yang Liang, MD7*, Fei Li8*, Zhongxing Jiang, MD9*, Xuejun Zhang, MD10*, Qunyi Guo11*, Hongmei Jing, MD12, Yajing Xu, MD13*, Xiangmin Tong, MD14* and Jianxiang Wang, MD15

1State Key Laboratory of Experimental Hematology, National Clinical Research Center for Hematologic Disorders, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin, China
2Institute of Hematology, Blood Disease Hospital, Chinese Academy of Medical Sciences, Pekiing Union College, Tianjin, China
3Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
4The Second Affiliated Hospital of Anhui Medical University, Hefei, China
5Department of Hematology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
6Department of Hematology, Hubei Provincial People's Hospital, Wuhan, China
7Department of Hematologic Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-sen University Cancer Center, Guangzhou, China
8The First Affiliated Hospital of Nanchang University, Nanchang, China
9Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
10Department of Hematology, The Second Hospital of Hebei Medical University,, Shijiazhuang, China
11Department of Hematology, Taizhou Hospital of Zhejiang Province, Wenzhou Medical College, Taizhou, China
12Peking University Third Hospital, Beijing, China
13Department of Hematoogy, Xiangya Hospital, Central South University, Changsha, China
14Department of Hematology, Hangzhou First People's Hospital, Hangzhou, Chile
15State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China


Background: The FMS-like tyrosine kinase 3 (FLT3) mutations occur in approximately 30% of acute myeloid leukemia (AML) patients, which are associated with worse survival and higher relapse risk. XY0206 is a novel oral FLT3 inhibitor with preclinical activity against FLT3 internal tandem duplication mutations (FLT3-ITD). The Phase Ⅰ/Ⅱ clinical trail with XY0206 (NCT04471064) is currently underway to explore the initial efficacy, safety and pharmacokinetic (PK) of XY0206 in patients with relapsed/refractory AML (R/R AML).

Methods: This open-label, multicenter, dose-escalation and dose-expansion Phase Ⅰ/Ⅱ trail enrolled subjects from August 2020 to September 2022 who were aged ≥18 years with R/R AML. Six dose-escalation or dose-expansion cohorts (12.5, 25, 37.5, 50, 62.5 mg per day, or 25 mg twice a day) were set up to explore the safety/tolerability and antileukemic activity of XY0206, and to determine the maximal tolerated dose (MTD) of XY0206. Safety and tolerability were assessed by monitoring dose-limiting toxicities (DLT), treament-emergent adverse events (TEAE) and adverse drug reaction (ADR). Cohort expansion was based on safety and antileukemic activity.

Results: As of December 14, 2022, a total of 61 subjects were enrolled (37 with FLT3 mutation-positive). Demographics and baseline characteristics of patients are presented in Table 1. MTD of XY0206 was established as 50 mg when two of the three patients enrolled in the 62.5 mg dose-escalation cohort could not tolerate continuous medication. The 37.5 mg, 50 mg and 25 mg BID dose cohorts were further expanded. Antileukemic activity was assessed in the Full Analysis Set (FAS, n=61), with overall response rate (ORR) was 34.4% (n=21/61), composite complete remission (CRc) was 32.8% (n=20/61), complete remission (CR) was 6.6% (n=4/61) and CR with partial hematologic recovery (CRh) was 9.8% ( n=6/61 ). Among the patients with FLT3 mutation-positive (FLT3mut+, n= 37), ORR was 48.6%(n=18/37), CRc was 45.9% ( n=17/37), CR was 2.7% (n=1/37) and CRh was 16.2% (n=6/37). Among the patients with FLT3-ITD mutation (n=30), ORR was 56.7% (n=17/30), CRc was 53.3% (n=16/30), CR was 3.3% (n=1/30) and CRh was 20%( n=6/30). The 37.5 mg dose cohort as the target dose was further expanded to include FLT3mut+ patients only. CRc in FLT3mut+ patients ( n= 19 ) and FLT3-ITD mutation patients (n=16) was 57.9% (n=11/19) and 68.8% (n=11/16 ), CR was 5.3% (n=1/19) and 6.3% (n=1/16), CRh was 26.3% (n=5/19 ) and 31.3% (n=5/16), respectively. In terms of safety, the overall incidence and severity of TEAE/ADR in 61 subjects did not correlate with dose significantly. The most common grade 3 and above adverse events (≥ 50% ) were leukopenia (65.6% ), thromobocytopenia (63.9%), neutropenia (62.3%), animia (52.5%) and hypokalemia (50.8%). The fatal adverse event was disease progression, which was mostly related to AML.

Conclusion: XY0206 is a novel FLT3 inhibitor that showed a good safety profile, a potent anti-leukemic activity and improved efficacy in patients with FLT3mut+ R/R AML.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH