Evaluating Safety ,Tolerability, Pharmacokinetic,Efficacy of WJ01024 or WJ01024 Combined With Ruxolitinib in Patients With Myelofibrosis

A Phase I Clinical Study Evaluating the Safety and Tolerability, Pharmacokinetic Characteristics and Preliminary Efficacy of Oral Administration of WJ01024 as a Monotherapy and in Combination With Ruxolitinib in Patients With Myelofibrosis

This is a Phase I clinical study to evaluate the safety and tolerability, pharmacokinetic characteristics and preliminary efficacy of oral WJ01024 administered as monotherapy and in combination with ruxolitinib in patients with myelofibrosis（MF）. The study will be conducted in two phases: Phase IA and Phase IB.

Phase IA is a dose-escalation and dose-expansion study of WJ01024 monotherapy in patients with MF after failure of JAK inhibitor (JAKi) therapy (relapsed/refractory/intolerant). Phase IB is a dose-escalation and dose-expansion study of WJ01024 in combination with ruxolitinib in JAKi-naïve patients with intermediate- or high-risk MF.

Phase IA is a dose-escalation and dose-expansion study of WJ01024 monotherapy in patients with MF after failure of JAK inhibitor (JAKi) therapy (relapsed/refractory/intolerant).Dose escalation is carried out by combining accelerated titration and the traditional 3+3 design. During the accelerated titration phase, if no dose-limiting toxicity (DLT) and no ≥2 episodes of grade ≥2 treatment-related adverse events (TRAEs) occur within the first cycle (DLT observation period), no further subjects are enrolled at that dose level, and the study proceeds to the traditional 3+3 phase starting with the 60 mg group. At present, it is expected that the dose will be increased in four groups . If the researchers elects to explore intermediate doses or higher doses during the trial, adjustments will be made based on the actual situation. It is planned to expand the dosage by two groups. The final expanded dosage will be determined based on emerging safety and efficacy data. Dose escalation is stratified by background therapy (with vs. without background medication). Phase IB involves dose escalation and dose expansion studies of WJ01024 combined with ruxolitinib. Phase IB is planned to be conducted in JAKi-naïve patients with intermediate- or high-risk MF. Initiation of Phase IB requires that the group in Phase IA has completed the DLT observation period. Two combination dose groups are planned. Intermediate or higher doses may be explored at the investigator's discretion.Two combination dose levels are planned for expansion ;final expansion dose(s) will be determined based on emerging safety and efficacy data.

Inclusion Criteria:

1. The subjects voluntarily participated in this study after obtaining full informed consent and signed the informed consent form.

2. Age ≥18 years old, gender not limited;

3. Patients diagnosed with primary myelofibrosis (PMF) according to the 2016 World Health Organization (WHO) criteria, or patients diagnosed with post-essential thrombocythemia MF (PET-MF) or post-polycythemia vera MF (PPV-MF) according to International Working Group for Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) criteria;

4. Patients evaluated as intermediate-1, intermediate-2, or high-risk according to the International Prognostic System (DIPSS) scoring system;;

5. Expected life expectancy is ≥ 24 weeks;

6. Eastern Cooperative Oncology Group (ECOG) score of 0-2 ;

7. No planned for stem cell transplantation in the near future.

8. Splenomegaly: Palpation of the spleen margin reaches or exceeds at least 5cm below the costal margin (the distance from the costal margin to the farthest point of the spleen protrusion), or spleen volume ≥450cm ³ by CT or MRI.

9. Adequate hematological and organ function within 7 days before the first administration of the study drug (no RBC transfusion, growth factors, colony-stimulating factors, platelet-generating factors ,or platelet transfusion within 14 days before the testing) :

   • Absolute neutrophil count (ANC) ≥1.5×109/L;
   • Platelet count ≥75×109/L(Phase IA); Platelet count ≥100×109/L(Phase IB); Hemoglobin ≥ 8.0g /dL; Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3.0× upper limit of normal (ULN); Total bilirubin ≤1.5×ULN; Creatinine ≤1.5×ULN.

10. For women of childbearing age, within 7 days before the first administration, if the serum pregnancy test is confirmed to be negative and they agree to use effective contraceptive measures during the study drug period and within 90 days after the last administration. For male subjects whose sexual partners are women of childbearing age, they must agree to take effective contraceptive measures during the use of the study drug and within 90 days after the last administration.

Exclusion Criteria:

• Peripheral blood blasts >5% or Bone marrow blasts >10%.
• Previous treatment with XPO1 inhibitors.
• Unable to cooperate with or unable to perform MRI or CT scans as deemed necessary by sponsor and investigator
• Treatment with strong CYP3A inhibitors or inducers within 14 days prior to initial administration"