Inclusion Criteria:
All participants must:
1. Have signed the current relevant ICF prior to any study related procedures;
2. Understand and commit to comply with study requirements;
3. Be ≥18 years of age;
4. Be able to swallow and retain oral medications;
5. Be diagnosed with PMF according to the 2016 WHO criteria, or PPV-MF or PET-MF according to International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria;
6. Have Intermediate-1 to high-risk myelofibrosis (as per Dynamic International Prognostic Scoring System \[DIPSS\] risk categories) and be either JAKi-naïve or JAKi-resistant. JAKi-naïve patients include those with JAKi exposure of no more than 14 days. The JAKi-resistant patients need to meet 1 of the following criteria: a) Treatment with JAKi for 3 months with inadequate efficacy response defined as \< 10% spleen volume reduction (SVR) by Magnetic Resonance Imaging (MRI) or \<30% decrease from baseline in spleen size by palpation or regrowth to these parameters following an initial response; b) Treatment with JAKi for ≥28 days complicated by any of the following: development of a red blood cell transfusion requirement (at least 2 units/month for 2 months) or cytopenia-related intolerance requiring ≥2 dose reductions or discontinuation of a JAKi; or occurrence of ≥ Grade 3 non-haematological toxicity; c) Inadequate spleen and/or symptom response despite adequate attempt at therapy with JAKi, as judged by the investigator;
7. Not be intended to undergo stem cell transplantation for at least 6 months;
8. Have life expectancy per investigator assessment ≥ 12 weeks;
9. Have Eastern Cooperative Oncology Group (ECOG) score ≤ 2;
10. Have splenomegaly: palpable spleen extending at least 5 cm below the costal margin or unpalpable due to body habitus (obesity), but confirmed to be ≥450 cm³ by MRI (or computed tomography \[CT\] scan) at screening;
11. Have at least 2 symptoms with an average score ≥3 over the 7-day period prior to randomization or an average total score of ≥10 over the 7-day period prior to randomization using the Myelofibrosis Symptom Assessment Form (MFSAF) v4.0;
12. Have bone marrow blast cells ≤10% and peripheral blood blast cells ≤10%;
13. Have PLT ≥50 × 109 /L and absolute neutrophil count (ANC) ≥ 1.0 × 109 /L and hemoglobin (HGB) \>60 g/L without the assistance of CSF, EPO, TPO, or component blood transfusions. Have discontinued growth factors and platelets transfusions for more than 2 weeks before screening tests;
14. Have no overt significant disease involving heart, lungs, liver, kidneys, or pancreas (left ventricular ejection fraction ≥ 45%; serum direct bilirubin ≤2 × upper limit of normal \[ULN\]; serum creatinine ≤1.5 × ULN or Estimated Glomerular Filtration Rate \[eGFR\] by the 2021 chronic kidney disease-Epidemiology Collaboration formula ≥ 45 mL/min/1.73 m2; alanine aminotransferase \[ALT\] and aspartate aminotransferase \[AST\] ≤2.5 × ULN) or ≤5 × ULN if associated with liver MF involvement;
15. Have no severe coagulation dysfunction (prothrombin time \[PT\] or thrombin time \[TT\] ≤2 × ULN; activated partial thromboplastin time \[APTT\] ≤2 × ULN);
16. Have a normal thiamine level at the time of study entry;
17. Agree to comply with the relevant regulations of the treating institution and the research organization.
Exclusion Criteria:
Participants must not:
1. Have failure to recover from toxic effects of prior anticancer therapy to Grade 1 or below (except alopecia), or failure to fully recover from prior surgery (major surgery within 4 weeks);
2. Have known hypersensitivity to the investigational product or its excipients;
3. Have any significant clinical or laboratory abnormality that would interfere with accurate safety evaluation on study, including:
1. Uncontrolled diabetes with fasting blood glucose \>250 mg/dL (13.9 mmol/L);
2. Hypertension not controlled by one or two antihypertensive drugs to the following range: systolic \<160 mmHg, diastolic \<100 mmHg;
3. Peripheral neuropathy of Grade 2 or higher according to Common Terminology Criteria for Adverse Events (CTCAE) v6.0;
4. Thyroid dysfunction of Grade 2 or higher per CTCAE v6.0;
5. Any other relevant abnormality in the opinion of the investigator;
4. Have a history of congestive heart failure, unstable angina, myocardial infarction, cerebrovascular accident, or pulmonary embolism within the 6 months prior to screening;
5. Have impaired cardiac function including any of the following conditions as determined by echocardiogram or electrocardiogram (ECG): left ventricular ejection fraction less than 45%, or complete left bundle branch block with ST-segment depression greater than 1 mm or T-wave inversion across 2 or more leads. Other criteria include congenital ventricular arrhythmias, clinically significant tachycardia (greater than 100 beats per minute), bradycardia (less than 50 beats per minute) with accompanying clinical symptoms, heart rate less than 60 beats per minute with symptoms, an ECG Corrected QT Interval (QTc) interval greater than 450 ms, or clinically significant cardiac conditions such as unstable angina, congestive heart failure, or myocardial infarction occurring within the last 6 months. Patients with heart failure who meet New York Heart Association class III and IV definitions are ineligible for this study;
6. Have an active serious infection requiring systemic treatment in the 14 days prior to randomisation or active tuberculosis in the 48 weeks prior to randomization;
7. Have undergone splenectomy or who have received splenic irradiation within 6 months prior to screening;
8. Have Human Immunodeficiency Virus (HIV) positive, active Hepatitis B (Hepatitis B Surface Antigen \[HBsAg\] positive and Hepatitis B Virus \[HBV\]-DNA ≥1000 copies/mL), or positive for Hepatitis C Virus (HCV) antibodies or HCV-RNA at screening;
9. Have epilepsy or are taking psychotropic or sedative medications at screening;
10. Be women of childbearing potential (WOCBP): who are unwilling or unable to practice highly effective contraception before the initial dose/start of the first treatment, during the study, and for at least 6 months after the last dose. Highly effective contraceptive measures include:
i) Stable use of combined (estrogen and progestogen-containing) hormonal contraception (oral, intravaginal, transdermal) or progestogen-only hormonal contraception (oral, injectable, implantable) associated with inhibition of ovulation initiated 2 or more menstrual cycles before screening; ii) Intrauterine device; intrauterine hormone-releasing system; iii) Sexual abstinence; iv) Intercourse with a vasectomized partner (the male vasectomized partner is the sole sexual partner of the WOCBP study patient, the vasectomized partner has obtained medical assessment of surgical success for the procedure);
11. Be sexually active male patients with WOCBP partners who are unwilling to use 1 of the following forms of medically acceptable birth control at the start of the first treatment, during the study, and for at least 6 months after the last dose:
i) Vasectomy with medical assessment of surgical success or consistent use of a condom; ii) Male Participants must also agree not to donate sperm while receiving the investigational product and for at least 6 months after the last dose;
12. Have a history of malignancy within the 3 years prior to study screening (except for successfully treated basal cell carcinoma of the skin or carcinoma in situ of the cervix);
13. Have any other severe illnesses that the investigator feels may jeopardize Participant safety or compliance;
14. Have participated in an investigational agent or medical device study within 1 month prior to screening;
15. Have prior or concomitant treatment with any of the following: any myelofibrosis therapy (except hydroxyurea that may be stopped one day before first dose; prior JAKi is allowed with a ≥14 day washout); any immunomodulators (e.g., thalidomide); any immunosuppressants; androgenic steroids systemic corticosteroids ≥10 mg/day prednisone equivalent; or any growth factor (e.g., EPO) within 5 half lives or 2 weeks before enrollment (whichever is longer);
16. Have received potent or moderate cytochrome P450 (CYP)3A4 inhibitors (including but not limited to ketoconazole, clarithromycin, itraconazole, nefazodone, telithromycin) or potent CYP3A4 inducers (including but not limited to rifampin and St. John's wort) within 2 weeks before the first dose;
17. Have received concomitant QT-prolonging medications that cannot be discontinued or appropriately managed in accordance with the QTc Monitoring Plan;
18. Have received concomitant strong inhibitors/inducers of P-gp or Breast Cancer Resistance Protein (BCRP)；
19. Have congenital or acquired bleeding disorders;
20. Be alcohol dependent or drug abusers;
21. Consume grapefruit, starfruit, or their products within 48 hours of the first dose of study medication, or be unwilling to abstain from such products while on study as these substances may affect drug absorption, distribution, metabolism, or excretion;
22. Have any other severe and/or uncontrolled concomitant medical condition that in the opinion of the investigator could compromise participation in the study or analysis of study data.
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