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Primary Myelofibrosis

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Maleic acid

1 case，The starting dose，Take the medicine once on D1 ，D 5 through 21.

6 case，Increasing dose，Take the medicine once on D1 ，D 5 through 21.

1 case,The starting dose,Take the medicine once on D1,D 5-21.

flonoltinib 25mg

flonoltinib 50mg

flonoltinib 100mg

flonoltinib 150mg

flonoltinib 225mg

flonoltinib 325mg

Liangkun Sun, bachelor

Dan Wu, master

Gubo Li, Bachelor's degree

ting Niu, doctor

Yongsheng Wang, Doctor

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.The IC50 of JAK2 kinase inhibition by FM was as low as 0.8 nM, while the IC50 of JAK1, JAK3 and Tyk2 kinase inhibition was 690 nM, 557 nM and 65nM, respectively. The selectivity of JAK2 kinase inhibition by FM was 862.5, 696.3 and 81.3 times, respectively. Therefore, FM showed highly selective inhibition of JAK2 kinase.The IC50 for FLT3 kinase was 15 nM. FM has better inhibitory activity against JAK2 kinase than the listed Ruxolitinib and Fedratinib, and has better selectivity against JAK family.In order to determine whether FM has targets other than JAK2 and Flt3 kinases, we tested FM's inhibitory activity against 100 human kinases that are highly associated with tumors, including some common drug-resistant mutant kinases.The results showed that, except for CDK4/6, LCK and LN, FM had no obvious inhibitory activity against the screened kinases at 0.1 μm, and no other targets were found.

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.

Safety of Flunotinib Maleate Tablets for the Treatment of Patients With Myeloproliferative

Safety of Flunotinib Maleate Tablets for the Treatment of Patients With Myeloproliferative Neoplasms Tolerability, Pharmacokinetics, Pharmacodynamics, and Efficacy of the Phase I/II Trial

Estimation of maximum observed plasma concentration

Estimation of AUC from time zero to the last measured time point

Estimation of AUC from time zero extrapolated to infinity

Estimation of apparent volume of distribution

Estimation of terminal elimination half-life

Estimation of clearance when dosed orally

Estimation of apparent volume of distribution when dosed orally

Estimation of the elimination rate constant of a drug in the body

Chengdu Zenitar Biomedical Technology Co., Ltd

Neoplasms

Bone Marrow Neoplasms

6 case,Increasing dose,Take the medicine once on D1,D5 -21.

Lijuan Chen, doctor

Study of Flonoltinib Maleate Tablets in the Treatment of Proliferative Bone Marrow Tumors

A Phase I Study Evaluating the Safety, Tolerability, and Pharmacokinetic and Pharmacodynamic Dose-escalation of Flonoltinib Maleate Tablets in Patients With Bone Marrow Proliferative Tumors

Estimation of AUC from time zero extrapolated to infinity Estimation of AUC from time zero extrapolated to infinity Estimation of AUC from time zero extrapolated to infinity Estimation of AUC from time zero extrapolated to infinity Estimation of AUC from time zero extrapolated to infinity Estimation of AUC from time zero extrapolated to infinity

Estimation of apparent volume of distribution

Apparent volume of distribution

Apparent volume of distribution

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety of Flunotinib Maleate Tablets for the Treatment of Patients With Myeloproliferative	NCT05153343	Myeloproliferat... Myelofibrosis，M...	flonoltinib 25m... flonoltinib 50m... flonoltinib 100... flonoltinib 150... flonoltinib 225... flonoltinib 325...	18 Years -	Chengdu Zenitar Biomedical Technology Co., Ltd
Study of Flonoltinib Maleate Tablets in the Treatment of Proliferative Bone Marrow Tumors	NCT05115344	Myeloproliferat... Myelofibrosis，M...	flonoltinib 25m... flonoltinib 50m... flonoltinib 100... flonoltinib 150... flonoltinib 225... flonoltinib 325...	18 Years -	Guizhou Bailing Group Pharmaceutical Co Ltd
Study of Flonoltinib Maleate Tablets in the Treatment of Proliferative Bone Marrow Tumors	NCT05115344	Myeloproliferat... Myelofibrosis，M...	flonoltinib 25m... flonoltinib 50m... flonoltinib 100... flonoltinib 150... flonoltinib 225... flonoltinib 325...	18 Years -	Guizhou Bailing Group Pharmaceutical Co Ltd
Safety of Flunotinib Maleate Tablets for the Treatment of Patients With Myeloproliferative	NCT05153343	Myeloproliferat... Myelofibrosis，M...	flonoltinib 25m... flonoltinib 50m... flonoltinib 100... flonoltinib 150... flonoltinib 225... flonoltinib 325...	18 Years -	Chengdu Zenitar Biomedical Technology Co., Ltd

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