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4281 Efficacy and Safety of Clifutinib, a Novel, Highly Selective, Oral FLT3 Inhibitor, in Patients with FLT3-Mutated Relapsed or Refractory Acute Myeloid Leukemia:Updated Results from a Phase I Study

Program: Oral and Poster Abstracts
Session: 616. Acute Myeloid Leukemias: Investigational Therapies, Excluding Transplantation and Cellular Immunotherapies: Poster III
Hematology Disease Topics & Pathways:
Research, clinical trials, Clinical Research
Monday, December 11, 2023, 6:00 PM-8:00 PM

Jie Jin1, Huafeng Wang1*, Wen-Juan Yu1*, Zheng Ge2, Xudong Wei3*, Yuhua Li4*, Zhongxing Jiang, MD5*, Yiqing Li6*, Xin Du7*, Linhua Yang, MD8*, Lie Lin, MD9*, Jishi Wang, PhD10, Yazhou Yao11*, Xiaoping Hu12*, Jianping Lan13*, Xiuzhi Deng14*, Tong Chen15, Xianqi Feng16*, Dengju Li17*, Ming Hou18*, Rong Fu19*, Siyong Huang20*, Jingbo Wang21*, Xin Du, MD22*, Hui Yang23*, Haiping Yang24*, Yingzhi Jiang25*, Zhijie Wang25*, Deng Li25*, Bing Liu25*, Ning Kang25*, Yulei Zhuang25* and Yingjun Zhang25*

1The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China
2Zhongda Hospital, Southeast University, Nanjing, China
3Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China
4Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China
5The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
6Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China
7Guangdong Provincial People's Hospital, Guangzhou, China
8The Second Hospital of Shanxi Medical University, Taiyuan, China
9Hainan General Hospital, Haikou, China
10Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang City, China
11Baoji Central Hospital, Baoji, China
12PKU Care Luzhong Hospital, Zibo, China
13Department of Hematology, Zhejiang Provincial People’s Hospital, Hangzhou, China
14Weihai Municipal Hospital, Weihai, China
15Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China
16Affiliated Hospital of Qingdao University, qingdao, China
17Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China
18Qilu Hospital of Shandong University, Jinan, China
19Tianjin Medical University General Hospital, Tianjin, China
20Xi'an Gaoxin Hospital, Xi'an, China
21Aerospace Center Hospital, Beijing, China
22Shenzhen Second People's Hospital, The First Affiliated Hospital of Shenzhen University, Shenzhen, China
23Shunde Hospital of Southern Medical University, Foshan, China
24The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China
25Sunshine Lake Pharma Co., Ltd, Dongguan, China

Background: Patients with relapsed/ refractory (R/R) FLT3-internal tandem duplication positive (FLT3-ITD+) acute myeloid leukemia (AML) have limited treatment options and poor prognosis. Clifutinib is a novel, highly selective, oral FLT-3 inhibitor with potent activity against FLT3-ITD(+) leukemic models both in vitro and in vivo. This study is a first-in-human study of clifutinib, with the purpose of evaluating the safety, tolerability, efficacy, and pharmacokinetic (PK) profile in Chinese patients with R/R FLT3-mutated AML (NCT04827069).

Methods: Patients aged ≥18 years with AML who were refractory to ≥ 2 cycles of standard induction chemotherapy or relapsed after achieving remission from previous treatments were enrolled. Previous use of FLT3 inhibitors were allowed. The study included two parts, a dose-escalation part (10 to 100 mg/day cohorts) and a dose-expansion part (40 and 70 mg/day cohorts). The primary endpoints were safety and tolerability, and the secondary endpoints were efficacy [CR(complete remission)/CRh (complete remission with partial hematologic recovery) rate, composite complete remission (CRc: CR+CRh+CRi, CRi defined as complete remission with incomplete hematological recovery) rate, TTR (time to remission), duration of remission (DOR), and overall survival (OS)] and pharmacokinetics (PK).

Results: As of May 2023, 75 patients (pts) were enrolled (Figure 1), with a median age of 55 years (range:18-80), and 96.0% pts were FLT3-ITD(+) or TKD(+) [80.0% with ITD(+)/TKD(-), 9.3% with ITD(+)/TKD(UK), 5.3% with ITD(+)/TKD(+), 1.3% with ITD(-)/TKD(+)], 58.7% pts had received ≥2 lines of previous treatment, and 32.0% pts exposed to FLT3 inhibitors. 3 pts experienced dose-limiting toxicities (DLT): one out of 6 pts in the 55 mg/day cohort (Grade 3 QTcF prolongation with ΔQTcF =71 ms) and 2 out of 6 pts in the 100 mg/day cohort (Grade 3 nausea and Grade 3 atrial fibrillation). Therefore, the maximum tolerated dose of clifutinib was 70 mg/day. The most common (rate ≥20%) treatment-related adverse events (TRAEs) included leukopenia (70.7%), thrombocytopenia (68%), neutropenia (64%), anemia (48%), lymphopenia (26.7%), pneumonia (26.7%), hypokalemia (26.7%), aspartate aminotransferase increased (22.7%), alkaline phosphatase increased (21.3%) and alanine aminotransferase increased (20.0%). Grade ≥3 TRAEs occurring in ≥20% pts were leukopenia, thrombocytopenia, neutropenia, anemia, lymphopenia, and pneumonia. Approximately dose-proportional PK parameters were observed across 40-100 mg/day dose range for both single and repeat dosing (the parent drug might approach saturation at 100 mg/day), and median tmax ranged from 2 to 6 hours.

For efficacy, responses occurred in 28 (40.6%) of 69 FLT3-ITD(+) or TKD(+) efficacy evaluable pts, including 5 (7.2%) CR, 5(7.2%) CRh, 17 (24.6%) CRi, 1 (1.4%) MLFS, and the median TTR was 32 days (range: 26-149 days). The efficacy was better in the 40 mg/day group compared to 70 mg/day and 40-100 mg/day groups, with CR/CRh rate of 21.2% (7/33) vs 8.3% (2/24) vs 14.5% (10/69), CRc rate of 48.5% (16/33) vs 33.3% (8/24) vs 39.1% (27/69), and median DOR of CR/CRh was 3.2 months (95% CI:1.9, NA) vs 0.9 months (95% CI: NA, NA ) vs 3.2 months (95% CI: 0.9, 7.4 ), the median OS was 6.5 months vs 5.4 months vs 6.3 months, respectively. Among FLT3-ITD(+)/TKD(-) subjects administered with clifutinib 40 mg/day, the CR/CRh rate was 23.1% (6/26) with 3 patients achieved CR, median DOR of CR/CRh was 3.7 months, the CRc rate was 53.8% (14/26), and median OS was 7.4 months. Compared to FLT3-ITD(+) or TKD(+) pts, 40 mg dose group exhibited better efficacy in FLT3-ITD(+)/TKD(-) pts. In addition, clifutinib exhibited more potent anti-leukaemic activity in patients received only one line of previous treatment. Among patients experienced only one line treatment of 40 mg dose group, the CR/CRh rate was 30.8% (4/13), the CRc rate was 53.8% (7/13), and the median OS was 7.9 months (Table 1) .

Conclusion: This phase 1 study has demonstrated an acceptable safety profile and a significant anti-leukaemic activity of clifutinib in FLT3 mutant R/R AML, with the best response at the dose of 40 mg/day in FLT3-ITD(+)/TKD(-) AML. A confirmatory phase 3 study is currently ongoing to further evaluate the efficacy and safety of clifutinib dosed at 40 mg/day in R/R AML pts after first-line therapy with FLT3-ITD(+)/TKD(-) (NCT05586074).

Keywords: Acute myeloid leukemia, FLT3 inhibitor, Clifutinib

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH