Myelofibrosis
Conditions
Brief summary
This is an open-label, single-arm, multi-center phase II study consisting of two cohorts. Cohort 1 evaluates the pharmacokinetics (PK) of TQ05105 in myelofibrosis participants with normal, mild, or moderate renal impairment to guide dosing. Cohort 2 evaluates the efficacy and safety of TQ05105 in participants with intermediate/high-risk myelofibrosis who are refractory, relapsed, or intolerant to prior Janus kinase (JAK) inhibitor therapy.
Interventions
DRUGTQ05105 Tablets (Rovadicitinib Tablets)
TQ05105 is an inhibitor of Janus kinase 1 (JAK1), Janus kinase 2 (JAK2), and Rho-associated coiled-coil containing protein kinase 1 (ROCK1) and 2 (ROCK2).
Sponsors
Chia Tai Tianqing Pharmaceutical Group Co., Ltd.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Voluntary and signed informed consent, good compliance. 2. Age ≥18 years (at time of signing informed consent); Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2; life expectancy ≥24 weeks. 3. Diagnosis of primary myelofibrosis (PMF) per World Health Organization (WHO) 2016, or post-polycythemia vera myelofibrosis (post-PV-MF) or post-essential thrombocythemia myelofibrosis (post-ET-MF) per International Working Group for Myelofibrosis Research and Treatment (IWG-MRT) criteria; Janus kinase 2 (JAK2) mutation status not restricted. 4. Intermediate or high risk per Dynamic International Prognostic Scoring System (DIPSS). 5. Cohort 1: Renal function classified as normal, mild impairment, or moderate impairment. Cohort 2: Prior Janus kinase (JAK) inhibitor therapy with refractory, relapsed, or intolerant. 6. Spleen enlargement (except Cohort 1). 7. Peripheral blood and bone marrow blasts ≤10%. 8. No growth factors, colony-stimulating factors, thrombopoietin, or platelet transfusion within 2 weeks before first dose; and routine blood parameters meet requirements within 7 days before first dose. 9. Adequate major organ function within 7 days before first dose per protocol (renal function not restricted for Cohort 1). 10. Agreement to use effective contraception during the study and for 6 months after; negative pregnancy test for females of childbearing potential; non-lactating.
Exclusion criteria
1. Prior allogeneic stem cell transplantation, or autologous stem cell transplantation within 3 months before first dose, or planned stem cell transplantation. 2. Prior treatment with 2 or more Janus kinase (JAK) inhibitors (except Cohort 1). 3. Prior splenectomy or splenic radiotherapy within 6 months before first dose. 4. Other malignancies within 3 years before first dose or currently present (exceptions per protocol). 5. Factors affecting oral drug absorption. 6. Non-hematologic toxicity from prior therapy not recovered to ≤ grade 1 (excluding hypertension and alopecia). 7. Major surgery or significant traumatic injury within 4 weeks before first dose. 8. Congenital bleeding or coagulation disorders. 9. Arterial/venous thrombosis event within 6 months before first dose. 10. History of substance abuse or mental disorder. 11. Active or uncontrolled severe infection. 12. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection. 13. Grade ≥2 myocardial ischemia or infarction, arrhythmia, QT prolongation, or grade ≥2 congestive heart failure. 14. Uncontrolled hypertension despite standard therapy. 15. Renal failure requiring hemodialysis or peritoneal dialysis. 16. Newly diagnosed pulmonary interstitial fibrosis or drug-related interstitial lung disease within 3 months before first dose. 17. History of immunodeficiency or organ transplantation. 18. Epilepsy requiring treatment. 19. Use of protocol-prohibited myelofibrosis (MF) medications, immunomodulators, or immunosuppressants within specified time before first dose. 20. Use of Chinese patent medicines with anti-tumor indications approved by National Medical Products Administration (NMPA) within 2 weeks before first dose. 21. Uncontrolled pleural effusion, pericardial effusion, or ascites. 22. Live attenuated vaccine within 4 weeks before first dose or planned during the study. 23. Known hypersensitivity to study drug or excipients. 24. Diagnosis of active autoimmune disease within 2 years before first dose. 25. Participation in another interventional clinical trial with investigational drug within 4 weeks before first dose. 26. Any condition that, in the investigator's judgment, seriously endangers subject safety or interferes with study completion.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of subjects with ≥35% reduction in spleen volume from baseline at week 24 (SVR35) | up to 24 weeks | SVR35 at week 24 as assessed by Independent Review Committee (IRC) |
| Peak concentration (Cmax) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Maximum plasma concentration of TQ05105 and its metabolite(s). |
| Time to peak concentration (Tmax) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Time to reach maximum plasma concentration of TQ05105 and its metabolite(s). |
| Elimination half-life (t1/2) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Half-life of TQ05105 and its metabolite(s) in plasma. |
| Area under the curve from time 0 to last measurable concentration (AUC0-t) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | AUC from time 0 to the last measurable concentration of TQ05105 and its metabolite(s). |
| Area under the curve from time 0 to infinity (AUC0-∞) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | AUC from time 0 extrapolated to infinity for TQ05105 and its metabolite(s). |
| Total clearance (CLt) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Total body clearance of TQ05105 and its metabolite(s) from plasma. |
| Renal clearance (CLr) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Renal clearance of TQ05105 and its metabolite(s). |
| Apparent volume of distribution (Vd/F) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Apparent volume of distribution of TQ05105 and its metabolite(s) after oral administration. |
| Elimination rate constant (λz) | Pre-dose on Cycle 1 Day 1 and Day 7; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12, 24 hours post-dose on Cycle 1 Day 1; and 15, 30, 45 minutes, 1, 2, 3, 4, 6, 8, 12 hours post-dose on Cycle 1 Day 7. (28 days a cycle) | Terminal elimination rate constant of TQ05105 and its metabolite(s). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best response rate of spleen volume reduction | up to 48 weeks | Proportion of subjects with at least one occurrence of ≥35% reduction in spleen volume from baseline. |
| Onset time of splenic response | up to 48 weeks | The time interval from the first administration to the date when the spleen volume was reduced by ≥ 35 % from the baseline. |
| Duration of maintenance of at least 35% Reduction in Spleen Volume (DoMSR) | up to 48 weeks | Duration of spleen volume reduction ≥ 35% from baseline: the time between the date when the spleen volume reduction ≥ 35% from baseline occurs for the first time and the date when the spleen volume reduction \< 35% from baseline. |
| Percentage change in spleen volume from baseline at planned visits | up to 48 weeks | Percentage change in spleen volume relative to baseline at each planned visit. |
| SVR35 at each planned visit time point | up to 48 weeks | Proportion of subjects with ≥35% reduction in spleen volume from baseline at each planned visit. |
| The proportion of subjects whose total symptom score of Myeloproliferative neoplasm- Symptom Assessment Form- Total Symptom Score (MPN-SAF TSS) decreased by more than 50% compared with baseline. | up to 48 weeks | The proportion of subjects whose total symptom score of MPN-SAF TSS decreased by more than 50% compared with baseline. Myeloproliferative Neoplasm Symptom Assessment Form Total Symptom Score (MPN-SAF-TSS) is an effective tool for evaluating the disease burden of patients with myeloproliferative neoplasms. The higher the score, the more severe the symptoms. Each symptom is scored according to the severity, from asymptomatic (0 points) to the most serious (10 points), a total of 10 levels,The sum of the symptom scores is the MPN-SAF-TSS score. |
| Percentage change in MPN-SAF TSS from baseline at planned visits | up to 48 weeks | Percentage change in MPN-SAF TSS from baseline at planned visits. |
| Proportion of subjects with at least one occurrence of ≥50% reduction in MPN-SAF TSS from baseline | up to 48 weeks | Proportion of subjects with at least one occurrence of ≥50% reduction in MPN-SAF TSS from baseline. |
| Time to first ≥50% reduction in MPN-SAF TSS from baseline | up to 48 weeks | Time from first dose to first documentation of ≥50% reduction in MPN-SAF TSS from baseline. |
| Duration of ≥50% reduction in MPN-SAF TSS from baseline | up to 48 weeks | Time from first achievement of ≥50% reduction in MPN-SAF TSS to loss of this response. |
| Objective response rate (ORR) | up to 48 weeks | Proportion of subjects achieving complete remission (CR) or partial remission (PR). |
| Progression-free survival (PFS) | From first dose to event (up to study completion) , an average of 3 years | The time interval from the first medication to the date of the occurrence of any of the following events, whichever occurs first, shall prevail :(1) Spleen volume increased by≥25% compared with the screening period ; (2) Death caused by any cause. |
| Leukemia free survival (LFS) | From first dose to event (up to study completion) , an average of 3 years | Time from first dose to leukemic transformation or death. |
| Overall Survival (OS) | From first dose to event (up to study completion) , an average of 3 years | OS is defined as the time from the first time the subject received treatment to death due to any cause |
| Incidence of adverse events (AEs) | From baseline up to 4 weeks after last dose | Incidence of adverse events determined and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 6.0. |
| Severity of AEs | From baseline up to 4 weeks after last dose | All adverse medical events that occur after the subject receives the investigational drug may be manifested as symptoms, signs, disease, or laboratory abnormalities, but are not necessarily causally related to the investigational drug, evaluated according to the CTCAE v6.0. |
| Urinary excretion amount (Ae0-24) | Pre-dose (-24-0 hours), 0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose | Amount of drug excreted in urine within 24 hours after single and multiple oral doses of TQ05105. |
| Cumulative urinary excretion rate (Ae0-24%) | Pre-dose (-24-0 hours), 0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose | Percentage of the dose excreted in urine within 24 hours after single and multiple oral doses of TQ05105. |
| Proportion of subjects receiving red blood cell transfusion within 24 weeks | Up to 24 weeks | Proportion of subjects who receive red blood cell transfusion during the first 24 weeks of treatment. |
| Proportion of subjects receiving platelet transfusion within 24 weeks | Up to 24 weeks | Proportion of subjects who receive platelet transfusion during the first 24 weeks of treatment. |
Countries
China
Contacts
CONTACTChunkang Chang, Doctor
Outcome results
None listed