Study of BEBT-507 Injection in Subjects With Polycythemia Vera (PV)

This is a multicenter, open-label Phase I clinical trial of BEBT-507 in subjects with polycythemia vera(PV). Phase Ia is a single-agent dose-escalation study designed to evaluate the safety, tolerability, pharmacokinetics (PK), preliminary efficacy, and pharmacodynamics of BEBT-507 in subjects with PV . Based on the results of Phase Ia, two doses will be selected for further evaluation in Phase Ib to assess the efficacy, safety, and PK profile of BEBT-507 in subjects with PV , and to recommend a dose for Phase III clinical trials.

Inclusion Criteria: 1. Male and female subjects aged 18-75 years (inclusive); 2. Subjects diagnosed with polycythemia vera (PV) according to the 2016 world health organization (WHO) criteria; 3. Hydroxyurea-resistant/intolerant and/or interferon α-resistant/intolerant: 1)Hydroxyurea-resistant or -intolerant Must meet the definition of hydroxyurea (HU) resistance or intolerance in the 2024 chinese society of clinical oncology (CSCO) Guidelines for the diagnosis and treatment of malignant hematological diseases and satisfy at least one of the following criteria:a) Resistance: Despite ≥3 months of HU treatment at a dose of ≥2 g/d, phlebotomy is still required to maintain HCT \400×10⁹/L and WBC \>10×10⁹/L); after ≥3 months of HU treatment at a dose of ≥2 g/d, a palpable massive splenomegaly fails to reduce by \>50% or splenomegaly-related clinical symptoms do not fully resolve;b) Intolerance: At the minimum hydroxyurea (HU) dose required to achieve a complete or partial clinical hematologic response for the disease, absolute neutrophil count (ANC) \2.0×Upper Limit of Normal (ULN), total bilirubin（TBIL）\>1.5×ULN;b) Renal function tests: estimated glomerular filtration rate (eGFR)\1000×10⁹/L, WBC count\>25×10⁹/L;d) Coagulation tests: international normalized ratio (INR)\>1.5×ULN;e) Others: presence of peripheral blood blasts. 8. Subjects with symptomatic splenomegaly (e.g., splenic infarction, left upper quadrant fullness or pain, early satiety, portal hypertension). 9. Due to potential genotoxicity, mutagenicity, and teratogenicity of the study drug, exclude:a) Men and women planning to conceive within 5 years without prior in vitro sperm/ovum preservation;b) Pregnant or breastfeeding women;c) Women within 2 years of menopause unwilling to use acceptable contraception until 6 months after the last study drug dose. 10. Presence of other active malignancies requiring treatment that may interfere with the study. 11. Comorbid conditions:a) Poorly controlled diabetes (random glucose≥11.1mmol/L or HbA1c≥8.5% despite antidiabetic treatment) assessed by the investigator;b) Severe pulmonary disease (CTCAE V5.0 grade III-IV);c) Severe cardiac disease (defined as any of the following:Left ventricular ejection fraction (LVEF) \450 ms for males or \>470 ms for females;Unstable angina;Symptomatic pericarditis;Myocardial infarction within the past 6 months with persistent elevation of cardiac enzymes or evidence of persistent regional wall abnormalities on LVEF assessment;History of congestive heart failure (new york heart association functional class III-IV) or cardiomyopathy;d) Significant renal or hepatic impairment;e) Poorly controlled active hepatitis B or C, or other diseases with clinically significant active infections, including hepatitis B (HBV), hepatitis C (HCV), or syphilis. Active HBV is defined as Hepatitis B Surface Antigen (HBsAg) or Hepatitis B e Antigen (HBeAg) positivity with HBV DNA≥2000 IU/ml (10⁴ copies/ml). If HBV DNA is below this level, antiviral therapy is required until one year post - study. Active HCV is defined as HCV RNA above the assay's upper limit. For syphilis, a positive non-treponemal test requires confirmation with a treponemal antibody test. If the latter is negative and the investigator confirms past infection with syphilitic cure, the subject can be included;f) Known human immunodeficiency virus （HIV） positivity or primary immunodeficiency;g) Deemed unsuitable for study participation due to a history of psychosis, family history of psychiatric illness, or mood disorders, as determined by the investigator or psychiatrist;h) Uncontrolled hypertension (systolic BP≥180mmHg and/or diastolic BP≥110mmHg);i) Severe medical conditions with a risk of major bleeding or history of major bleeding. 12. Concomitant use of drugs that may prolong the QT interval or cause torsades de pointes. 13. History of alcohol or drug abuse within the past year. 14. Subjects deemed unsuitable for this treatment regimen by the investigator.