MF With Splenomegaly
Conditions
Brief summary
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.
Detailed description
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.
Interventions
DRUGWJ01024 tablet
5-20mg BID (dosage per investigator judgement)
Sponsors
Henan Cancer Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Masking description
open trial
Intervention model description
The study consisted of two phases: Phase IA and Phase IB. Phase IA: Patients with myelofibrosis who have relapsed, are refractory or intolerant after treatment with JAK inhibitors Phase IB: Patients with intermediate- or high-risk myelofibrosis who have not previously received JAK inhibitor treatment
Eligibility
Sex/Gender
ALL
Age
18 Days to No maximum
Healthy volunteers
No
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"
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| MTD | 12 months | Evaluate the Maximum tolerated dose |
| RP2D | 12 months | Evaluate the recommended dose for phase II |
| DLT | 12 months | Incidence of DLT |
| AE | 4 years | incidence and severity of adverse events(AEs) and serious adverse events(SAEs),as well as abnormal changes in clinical significance laboratory tests and other examinations |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| OS | 4 years | OS |
| LDH | 4 years | Evaluation of changes in serum LDH levels |
| Score in MPN-SAF-TSS | 4 years | Percentage reduction in Total Symptom Score(TSS) and proportion of subjects achieving ≥50% reduction (TSS50) assessed by Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) |
| Pharmacokinetic (PK) Parameter | 1.5 years | The blood concentration of WJ01024 |
| incidence and severity of adverse events and serious adverse events | 4 years | incidence and severity of adverse events nd serious adverse events,as well as abnormal changes in clinical significance laboratory tests and other examinations |
| SVR35 | 4 years | Percentage of subjects with spleen volume reduction of ≥35% (SVR35) |
| ORR：CR + PR + clinical improvement | 4 years | Overall response rate (ORR, CR + PR + clinical improvement) as determined by the investigator according to IWG-MRT criteria |
| LFS | 4 years | Leukemia-free survival (LFS) as assessed by the investigator |
| PFS | 4 years | Progression free survival (PFS) as assessed by the investigator |
Countries
China
Contacts
CONTACTShuai Guo
Outcome results
None listed