A Study to Evaluate Safety , Efficacy and Pharmacokinetics of WJ01024 Tablets Combined With Ruxolitinib in Patients With Myelofibrosis

This is a Phase Ib/II clinical study to evaluate the safety , efficacy and pharmacokinetics of WJ01024 tablets combined with Ruxolitinib tablets in patients with myelofibrosis.The study will be conducted in two phases: Phase 1b (dose escalation) and Phase 2 (dose extension ). Phase 1b was an open-label evaluation of the safety and recommended Phase 2 dose (RP2D) from three groups (40mg WJ01024 tablets plus 15/20mg BID rucotinib tablet, 60mg WJ01024 tablets plus15/20mg BID Ruxolitinib tablet and 80mg WJ01024 tablets plus 15/20mg BID Ruxolitinib tablet) using a standard 3+3 design and Phase II was an open-label evaluation of the safety and effecacy of WJ01024 tablets combined with Ruxolitinib tablets in patients with myelofibrosis.

Ruxolitinib tablets have been approved in China since April 2017 as the first-line treatment for most intermediate- and high-risk myelofibrosis (MF) patients with splenomegaly. Compared with supportive treatment alone, ruxolitinib tablets have the efficacy of reducing spleen size and improving the symptoms of myelofibrosis, as well as reducing the risk of death and prolonging the survival of MF patients.

Although the clinical efficacy of Ruxolitinib tablets has been confirmed, only about half of MF patients can achieve the ideal therapeutic effect (≥35% reduction in spleen volume and ≥50% improvement in disease symptoms at 24 weeks). Therefore, there is an urgent need for innovative drugs that can be combined with Ruxolitinib tablets to enhance therapeutic efficacy and meet clinical needs.

WJ01024 is a small molecule inhibitor of XPO-1, belonging to the same target small molecule compounds as Selinexor. Compared with Selinexor, the metabolism rate of this product is faster, which can reduce the toxicity in the body. In the Ba/F3-EPOR-JAK2-V617F cell model, the combination of this product and ruxolitinib tablets can enhance its anti-cell proliferation activity. In a clinical study initiated by researchers, this product has shown preliminary efficacy as a monotherapy in patients with myelofibrosis who have relapsed, are refractory to, or intolerant of JAK inhibitors, and is expected to have fewer toxic and side effects than drugs targeting the same site. Based on this, the following research is planned.

This is a Phase Ib/II clinical study to evaluate the safety , efficacy and pharmacokinetics of WJ01024 tablets combined with Ruxolitinib tablets in JAK inhibitor (JAKi) treatment-naïve myelofibrosis (MF) patients.The study will be conducted in two phases: Phase 1b (dose escalation) and Phase 2 (dose extension ). Phase 1b was an open-label evaluation of the safety and recommended Phase 2 dose (RP2D) from three groups (40mg WJ01024 tablets plus 15/20mg BID rucotinib tablet, 60mg WJ01024 tablets plus15/20mg BID Ruxolitinib tablet and 80mg WJ01024 tablets plus 15/20mg BID Ruxolitinib tablet) and an intermediate dose or higher dose may be explored during the Phase Ib, if sponsor and researchers consider it necessary. Phase II was an open-label evaluation of the safety and effecacy of WJ01024 tablets combined with Ruxolitinib tablets in JAK inhibitor (JAKi) treatment-naïve myelofibrosis (MF) patients.It is expected to expand the group of 60mg WJ01024 tablets plus 15/20mg BID Ruxolitinib tablets, and finally expand dose to adjust as the actual situation.

Eligibility Criteria:
Inclusion Criteria:

* Subjects voluntarily participate in the study after receiving full informed consent and sign informed consent;
* Age ≥18 years old, gender unlimited;
* Patients diagnosed with primary myelofibrosis (PMF) according to WHO criteria (2016 edition), or with ET secondary myelofibrosis (PET-MF) or PV secondary myelofibrosis (PPV-MF) according to International Working Group on Myelofibrosis Research and Treatment (IWG-MRT) criteria; They could be included regardless of JAK2 mutation;
* Participants with international prognostic scoring system (DIPSS) risk category of intermediate-1, or intermediate-2, or high-risk;
* ECOG score 0\~2;
* No stem cell transplantation plan in the near future;
* Spleen enlargement: MRI or CT scan showed spleen volume ≥450cm3 before the first medication;
* Sufficient hematology and organ function;

Exclusion Criteria:

* More than 10% blasts in peripheral blood or bone marrow (accelerated or blast phase);
* Previous treatment with JAK inhibitors for MF;
* Previous treatment with XPO1 inhibitor;
* Unable to cooperate with or unable to perform MRI or CT scans as deemed necessary by sponsor and investigator;
* Treatment with a powerful CYP3A inhibitor or inducer within 14 days prior to initial administration;