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.
Study Type
INTERVENTIONAL
Allocation
NA
Purpose
TREATMENT
Masking
NONE
Enrollment
51
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).
The First Affiliated Hospital of University of Science and Technology of China
Hefei, Anhui, China
RECRUITINGFujian Medical University Union Hospital
Fuzhou, Fujian, China
RECRUITINGGuangzhou First Municipal People's Hospital
Guangzhou, Guangdong, China
RECRUITINGThe First Affiliated Hospital of Guangxi Medical University
Nanning, Guangxi, China
Proportion of subjects with ≥35% reduction in spleen volume from baseline at week 24 (SVR35)
SVR35 at week 24 as assessed by Independent Review Committee (IRC)
Time frame: up to 24 weeks
Peak concentration (Cmax)
Maximum plasma concentration of TQ05105 and its metabolite(s).
Time frame: 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 peak concentration (Tmax)
Time to reach maximum plasma concentration of TQ05105 and its metabolite(s).
Time frame: 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)
Elimination half-life (t1/2)
Half-life of TQ05105 and its metabolite(s) in plasma.
Time frame: 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)
Area under the curve from time 0 to last measurable concentration (AUC0-t)
AUC from time 0 to the last measurable concentration of TQ05105 and its metabolite(s).
Time frame: 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)
Area under the curve from time 0 to infinity (AUC0-∞)
AUC from time 0 extrapolated to infinity for TQ05105 and its metabolite(s).
Time frame: 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 clearance (CLt)
Total body clearance of TQ05105 and its metabolite(s) from plasma.
Time frame: 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 (CLr)
Renal clearance of TQ05105 and its metabolite(s).
Time frame: 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 (Vd/F)
Apparent volume of distribution of TQ05105 and its metabolite(s) after oral administration.
Time frame: 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)
Elimination rate constant (λz)
Terminal elimination rate constant of TQ05105 and its metabolite(s).
Time frame: 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)
Best response rate of spleen volume reduction
Proportion of subjects with at least one occurrence of ≥35% reduction in spleen volume from baseline.
Time frame: up to 48 weeks
Onset time of splenic response
The time interval from the first administration to the date when the spleen volume was reduced by ≥ 35 % from the baseline.
Time frame: up to 48 weeks
Duration of maintenance of at least 35% Reduction in Spleen Volume (DoMSR)
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.
Time frame: up to 48 weeks
Percentage change in spleen volume from baseline at planned visits
Percentage change in spleen volume relative to baseline at each planned visit.
Time frame: up to 48 weeks
SVR35 at each planned visit time point
Proportion of subjects with ≥35% reduction in spleen volume from baseline at each planned visit.
Time frame: up to 48 weeks
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.
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.
Time frame: up to 48 weeks
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Cangzhou People's Hospital rovince
Cangzhou, Hebei, China
RECRUITINGAffiliated Hospital of Chengde Medical College
Chengde, Hebei, China
RECRUITINGThe Second Hospital of Hebei Medical University
Shijiazhuang, Hebei, China
RECRUITINGXingtai People's Hospital
Xingtai, Hebei, China
RECRUITINGHenan Cancer Hospital
Zhengzhou, Henan, China
RECRUITINGTongji Hospital affiliated to Tongji Medical College of Huazhong University of Science & Technology
Wuhan, Hubei, China
RECRUITING...and 14 more locations
Percentage change in MPN-SAF TSS from baseline at planned visits
Percentage change in MPN-SAF TSS from baseline at planned visits.
Time frame: up to 48 weeks
Proportion of subjects with at least one occurrence of ≥50% reduction in MPN-SAF TSS from baseline
Proportion of subjects with at least one occurrence of ≥50% reduction in MPN-SAF TSS from baseline.
Time frame: up to 48 weeks
Time to first ≥50% reduction in MPN-SAF TSS from baseline
Time from first dose to first documentation of ≥50% reduction in MPN-SAF TSS from baseline.
Time frame: up to 48 weeks
Duration of ≥50% reduction in MPN-SAF TSS from baseline
Time from first achievement of ≥50% reduction in MPN-SAF TSS to loss of this response.
Time frame: up to 48 weeks
Objective response rate (ORR)
Proportion of subjects achieving complete remission (CR) or partial remission (PR).
Time frame: up to 48 weeks
Progression-free survival (PFS)
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.
Time frame: From first dose to event (up to study completion) , an average of 3 years
Leukemia free survival (LFS)
Time from first dose to leukemic transformation or death.
Time frame: From first dose to event (up to study completion) , an average of 3 years
Overall Survival (OS)
OS is defined as the time from the first time the subject received treatment to death due to any cause
Time frame: From first dose to event (up to study completion) , an average of 3 years
Incidence of adverse events (AEs)
Incidence of adverse events determined and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) version 6.0.
Time frame: From baseline up to 4 weeks after last dose
Severity of AEs
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.
Time frame: From baseline up to 4 weeks after last dose
Urinary excretion amount (Ae0-24)
Amount of drug excreted in urine within 24 hours after single and multiple oral doses of TQ05105.
Time frame: Pre-dose (-24-0 hours), 0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose
Cumulative urinary excretion rate (Ae0-24%)
Percentage of the dose excreted in urine within 24 hours after single and multiple oral doses of TQ05105.
Time frame: Pre-dose (-24-0 hours), 0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose
Proportion of subjects receiving red blood cell transfusion within 24 weeks
Proportion of subjects who receive red blood cell transfusion during the first 24 weeks of treatment.
Time frame: Up to 24 weeks
Proportion of subjects receiving platelet transfusion within 24 weeks
Proportion of subjects who receive platelet transfusion during the first 24 weeks of treatment.
Time frame: Up to 24 weeks