Flonoltinib Maleate (FM) targets Janus kinase 2 (JAK2) and FMS-like tyrosine kinase 3 (FLT3). FM is a dual target inhibitor of JAK2/FLT3.FM has the activity of inhibiting JAK2 signaling pathway, and pharmacodynamics evaluation also confirmed that FM has a good therapeutic effect on the primary splenomegaly model of mice induced by JAK2V617 mutation.Therefore, FM has the potential to treat bone marrow proliferative tumors.The drug is intended to be used in patients with MPN, mainly including medium-risk or high-risk myelofibrosis (FM) (including primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (PostPV-MF) and post-primary thrombocythemia myelofibrosis (postET-MF)), Polycythemia vera (PV) and essential thrombocythemia (ET) were the primary causes of thrombocythemia and thrombocythemia. FM has high inhibitory activity against JAK family and FLT3 kinase, suggesting that FM may have a certain therapeutic effect on AML disease. In vitro experiments on the proliferation of JAK2-dependent and Flt3-related tumor cell lines with FM showed that the tumor cell lines had a significant inhibitory effect. The IC50 of half of the tumor cell lines was less than 0.5 μm, which was better than or equal to the similar drugs Ruxolitinib and Fedratinib. The effect of FM on tumor cells from MPN patients indicated that FM has the potential to treat MPN disease. In multiple animal models of bone marrow proliferative tumors with JAK2V617F mutations, FM showed superior efficacy and low toxicity (no obvious VISCAL toxicity) than existing drugs on the market, and the tumor inhibition effect of FM showed a good dose-dependent relationship. Objectives of Study Main Purpose: 1. Tolerance and safety of flonoltinib maleate Tablets tablets in patients with bone marrow proliferative tumors; 2. To observe the possible dose-limiting toxicity(DLT) of flonoltinib maleate tablets in patients with bone marrow proliferative tumors,To determine the maximum tolerated dose(MTD) of flonoltinib maleate tablets,To provide the basis for the recommended dose and design scheme of the later clinical trial. Secondary Purpose: 1. To evaluate the pharmacokinetic characteristics of single and repeated oral administration of flonoltinib maleate tablets in patients with bone marrow proliferative tumors; 2. To evaluate the primary efficacy of single and multiple oral flonoltinib maleate tablets in patients with bone marrow proliferative tumors.
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Flonoltinib Maleate Pharmacokinetics (PK)：Cmax
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：Tmax
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：AUC0-72h
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：AUC0-∞
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：MRT
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：Vd
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：t1/2
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：CLz/F
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：Vz/F
Timeframe: 72hours
Flonoltinib Maleate Pharmacokinetics (PK)：Ke
Timeframe: 72hours