Flonoltinib maleate tablets for adults with polycythemia vera (dose-finding and expansion)

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 will test whether flonoltinib maleate tablets help adults with polycythemia vera who are resistant or intolerant to hydroxyurea or interferon.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 60 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Chengdu Zenitar Biomedical Technology Co., Ltd (Industry-sponsored)
• Drugs / interventions: Ruxolitinib, Flonoltinib
• Locations: 1 site (Tianjin)
• Trial ID: NCT07232290 on ClinicalTrials.gov

What this trial studies

This is an open-label, randomized, parallel-controlled, multicenter Phase IIa trial enrolling adults with polycythemia vera who are resistant or intolerant to hydroxyurea or interferon. The first stage is a dose-exploration phase with three planned dose groups (75 mg, 100 mg, 125 mg) using small cohorts (three participants per dose, nine total) to characterize safety, pharmacokinetics, and preliminary efficacy. Based on those results, 2–3 doses will move into a dose-extension phase to expand safety and efficacy data. Flonoltinib maleate is a small-molecule triple inhibitor targeting JAK2, FLT3, and CDK6 aimed at suppressing abnormal JAK2 signaling in myeloproliferative neoplasms.

Who should consider this trial

Good fit: Adults (≥18) with WHO-defined polycythemia vera who are resistant or intolerant to hydroxyurea or interferon, meet the laboratory criteria (including neutrophils ≥1.0×10^9/L and platelets 100–1000×10^9/L), and can achieve HCT ≤45% before randomization are the intended participants.

Not a fit: Patients who respond well to hydroxyurea or interferon, have active leukemic transformation, uncontrolled severe cytopenias, or other exclusionary medical conditions are unlikely to benefit from this trial.

Why it matters

Potential benefit: If successful, flonoltinib could offer an additional oral treatment option that better controls blood counts and symptoms and reduces the need for phlebotomy in hydroxyurea- or interferon-resistant/intolerant PV patients.

How similar studies have performed: Approved JAK2 inhibitors such as ruxolitinib have shown benefit in hydroxyurea-resistant PV, but flonoltinib's triple-target JAK2/FLT3/CDK6 profile is a novel approach that has not yet been proven clinically.

Eligibility criteria

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 primitive cells are 0%;
4. Meet any of the following criteria and achieve HCT\<= 45% before randomization/enrollment:

1)At least 2 venous bloodletting 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 venous bloodletting 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.

Where this trial is running

Tianjin

• Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences (IHCAMS) — Tianjin, China (Recruiting)

Study contacts

• Principal investigator: Lei Zhang, Doctor — Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences (IHCAMS)
• Study coordinator: Fangmei Wang

Conditions Polycythemia Vera