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
Author:
Jin Jie1, Wang Huafeng1, Yu Wen-Juan1, Ge Zheng2, Wei Xudong3, Li Yuhua4, Jiang Zhongxing5, Li Yiqing6, Du Xin7, Yang Linhua8, Lin Lie9, Wang Jishi10, Yao Yazhou11, Hu Xiaoping12, Lan Jianping13, Deng Xiuzhi14, Chen Tong15, Feng Xianqi16, Li Dengju17, Hou Ming18, Fu Rong19, Huang Siyong20, Wang Jingbo21, Du Xin22, Yang Hui23, Yang Haiping24, Jiang Yingzhi25, Wang Zhijie25, Li Deng25, Liu Bing25, Kang Ning25, Zhuang Yulei25, Zhang Yingjun25
Affiliation:
1. 1The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China 2. 2Zhongda Hospital, Southeast University, Nanjing, China 3. 3Department of Hematology, The Affiliated Cancer Hospital of Zhengzhou University, Henan Cancer Hospital, Zhengzhou, China 4. 4Department of Hematology, Zhujiang Hospital, Southern Medical University, Guangzhou, China 5. 5Department of Hematology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China 6. 6Sun Yat-sen Memorial Hospital of Sun Yat-sen University, Guangzhou, China 7. 7Guangdong Provincial People's Hospital, Guangzhou, China 8. 8The Second Hospital of Shanxi Medical University, Taiyuan, China 9. 9Hainan General Hospital, Haikou, China 10. 10Affiliated Hospital of Guizhou Medical University, Guiyang City, China 11. 11Baoji Central Hospital, Baoji, China 12. 12PKU Care Luzhong Hospital, Zibo, China 13. 13Department of Hematology, Zhejiang Provincial People's Hospital, Hangzhou, China 14. 14Weihai Municipal Hospital, Weihai, China 15. 15Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China 16. 16Affiliated Hospital of Qingdao University, qingdao, China 17. 17Tongji Hospital affiliated to Tongji Medical College of Huazhong University of Science & Technology, Wuhan, China 18. 18Qilu Hospital of Shandong University, Jinan, China 19. 19Tianjin Medical University General Hospital, Tianjin, China 20. 20Xi'an Gaoxin Hospital, Xi'an, China 21. 21Aerospace Center Hospital, Beijing, China 22. 22The Second People's Hospital of Shenzhen, Shenzhen, China 23. 23Shunde Hospital of Southern Medical University, Foshan, China 24. 24The First Affiliated Hospital of Henan University of Science and Technology, Luoyang, China 25. 25Sunshine Lake Pharma Co., Ltd, Dongguan, China
Abstract
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 t max 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
Publisher
American Society of Hematology
Subject
Cell Biology,Hematology,Immunology,Biochemistry
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