Phase IIa Study of Flonoltinib Maleate Tablets in the Treatment of Patients With Polycythemia Vera

An Open Label, Randomized, Parallel Controlled, Multicenter Phase IIa Study Evaluating the Safety, Efficacy, and Pharmacokinetics of Flonoltinib Maleate Tablets in the Treatment of Hydroxyurea or Interferon Resistant/Intolerant Polycythemia Vera

This trial adopts an open, randomized, parallel controlled, multicenter clinical trial design planning to enroll patients with polycythemia vera who are resistant/intolerant to hydroxyurea or interferon. The study divided into two stages: dose exploration stage: three dose groups are set, with three subjects in each group, totally nine subjects in each group; Dose expansion stage: Based on the safety, efficacy, and pharmacokinetic results of the comprehensive dose exploration stage, 2-3 dose groups are planned to be selected for dose expansion stage.

The treatment goal of polycythemia vera is to avoid initial or recurrent thrombosis, control disease-related symptoms, prevent post PV MF and/or acute leukemia transformation after polycythemia vera. Almost all PV patients have non receptor type Janus kinase 2 (JAK2) gene mutations, typically JAK2 V617F. This drug is intended for patients with myeloproliferative neoplasms (MPN), mainly including moderate to high-risk myelofibrosis (FM) (including primary myelofibrosis (PMF)), post polycythemia vera myelofibrosis (PPV-MF), and post thrombocytopenia myelofibrosis (PET-MF), polycythemia vera (PV), and primary thrombocytosis (ET).

Flonoltinib Maleate (FM), a triple target inhibitor of JAK2/FLT3/CDK6, has the potential to inhibit JAK2 signaling pathway activity and treat bone marrow proliferative tumors.

This trial adopts an open, randomized, parallel controlled, multicenter clinical trial design. The plan is to recruit patients with polycythemia vera who are resistant/intolerant to hydroxyurea or interferon. The study is divided into two stages: dose exploration stage: three dose groups are tentatively set, with three subjects in each group,for a total of 9 subjects; Dose expansion stage: Based on the safety, efficacy, and pharmacokinetic results of the comprehensive dose exploration phase, it is planned to select 2-3 dose groups for dose expansion stage.

Inclusion Criteria:

1. Age >= 18 years old and gender not limited when signing the informed consent form;
2. Diagnosed as PV according to WHO standards (2016 edition), and resistant/intolerant to hydroxyurea or interferon treatment (refer to attachments 1 and 2);
3. When screening, the peripheral blood blasts are 0%;
4. Meet any of the following criteria and achieve HCT<= 45% before randomization/enrollment:

1)At least 2 Phlebotomy and/or apheresis treatments have been performed within 24 weeks prior to screening, with a minimum interval of 4 weeks between each treatment, and at least 1 treatment has occurred within 16 weeks prior to screening; 2)At least one Phlebotomy and/or apheresis treatment has been performed within the 16 weeks and HCT>45% at the time of screening; 5.When screening, laboratory test indicators meet the following criteria: neutrophil count >= 1.0 × 10 ^ 9/L, platelet count >= 100 × 10 ^ 9/L and <= 1000 × 10 ^ 9/L; ALT and AST<= 2.5 × ULN; TBIL<=2.0×ULN; Serum creatinine <= 1.5 × ULN; 6.ECOG 0-2 points; 7.Can understand and voluntarily sign an informed consent form.

Exclusion Criteria:

1. Individuals with allergies or suspected allergies to the test drug and its excipients;
2. The toxic reactions of previous anti-cancer treatments have not recovered to grade 1 or below (excluding hair loss, blood routine and blood biochemical indicators refer to inclusion criteria 4 and 5), or have not fully recovered from previous surgeries (having undergone major surgery within 4 weeks);
3. In addition to PV, any other myeloproliferative neoplasms (MPN), including post polycythemia vera myelofibrosis (PPV-MF), may also be present;
4. Any active infections that require systemic treatment (oral, intravenous, subcutaneous, intramuscular, etc.) during screening;
5. Patients with swallowing difficulties, chronic diarrhea, or oral absorption disorders are included in the screening process;
6. Patients with basic diseases that are difficult to control in combination with drug treatment during screening, including but not limited to: diabetes, hypertension , peripheral neuropathy ;
7. Screening for individuals who have experienced congestive heart failure (NYHA class III or above), unstable angina, myocardial infarction, cerebrovascular accidents with functional impairment, or require treatment for arrhythmia within the past 6 months;
8. Individuals with QTcF>450 ms (male) and QTcF>470 ms (female) on electrocardiogram during screening;
9. Individuals who have experienced active tuberculosis infection within the past year prior to screening, or those whose tuberculosis related test results indicate latent infection during screening;
10. Patients who have undergone splenectomy or splenic radiotherapy in the past;
11. When screening, any of the following situations exist: a) Hepatitis B surface antigen (HbsAg) or hepatitis B core antibody (HbcAb) is positive, and HBV-DNA detection is positive or above the upper limit of normal value; b) HCV antibody positive and HCV-RNA detection positive; c) Positive for anti Treponema pallidum antibody (TP Ab) and positive for Treponema pallidum non-specific antibody (PRP or TRUST) detection; d) Positive for Human Immunodeficiency Virus Antibody (HIV Ab);
12. Individuals with epilepsy or mental illnesses requiring medication during screening (excluding insomnia);
13. Individuals who have suffered from other malignant tumors within the past 5 years prior to the first administration (excluding cured carcinoma in situ and basal cell carcinoma of the skin);
14. Patients with congenital or acquired bleeding disorders or active thrombotic disorders during screening;
15. Combining other serious diseases during screening may affect patient safety or compliance, according to researchers;
16. Within 2 weeks prior to trial administration or within 5 half lives (whichever is longer), any therapeutic PV drugs have been used, including hydroxyurea, recombinant interferon - α (long-acting recombinant interferon - α treatment needs to be discontinued for 4 weeks), JAK inhibitors (such as Ruxolitinib), 32P (needs to be discontinued for 8 weeks), Busulfan, etc;
17. Patients who receive treatment with other clinical trial drugs or clinical trial medical devices before screening and have not fully eluted for at least 5 half lives or 1 month (whichever is longer);
18. Pregnant or lactating women;
19. Individuals who have the ability to conceive but refuse to use contraceptive measures during the trial period ;and within 6 months after the trial ends;
20. Vaccination with active or attenuated vaccines within 4 weeks prior to screening;
21. Researchers believe that there are other factors that are not suitable for participating in the experiment.