A Phase II, Single-arm, Open-label, Multicenter Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of TQ05105 Tablets in Subjects With Intermediate/High-risk Myelofibrosis
试验速览
- 阶段
- 2 期
- 状态
- 招募中
- 入组人数
- 51
- 试验地点
- 24
- 主要终点
- Proportion of subjects with ≥35% reduction in spleen volume from baseline at week 24 (SVR35)
研究概览
简要总结
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Voluntary and signed informed consent, good compliance.
- •Age ≥18 years (at time of signing informed consent); Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2; life expectancy ≥24 weeks.
- •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.
- •Intermediate or high risk per Dynamic International Prognostic Scoring System (DIPSS).
- •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.
- •Spleen enlargement (except Cohort 1).
- •Peripheral blood and bone marrow blasts ≤10%.
- •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.
- •Adequate major organ function within 7 days before first dose per protocol (renal function not restricted for Cohort 1).
- •Agreement to use effective contraception during the study and for 6 months after; negative pregnancy test for females of childbearing potential; non-lactating.
排除标准
- •Prior allogeneic stem cell transplantation, or autologous stem cell transplantation within 3 months before first dose, or planned stem cell transplantation.
- •Prior treatment with 2 or more Janus kinase (JAK) inhibitors (except Cohort 1).
- •Prior splenectomy or splenic radiotherapy within 6 months before first dose.
- •Other malignancies within 3 years before first dose or currently present (exceptions per protocol).
- •Factors affecting oral drug absorption.
- •Non-hematologic toxicity from prior therapy not recovered to ≤ grade 1 (excluding hypertension and alopecia).
- •Major surgery or significant traumatic injury within 4 weeks before first dose.
- •Congenital bleeding or coagulation disorders.
- •Arterial/venous thrombosis event within 6 months before first dose.
- •History of substance abuse or mental disorder.
- •Active or uncontrolled severe infection.
- •Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection.
- •Grade ≥2 myocardial ischemia or infarction, arrhythmia, QT prolongation, or grade ≥2 congestive heart failure.
- •Uncontrolled hypertension despite standard therapy.
- •Renal failure requiring hemodialysis or peritoneal dialysis.
- •Newly diagnosed pulmonary interstitial fibrosis or drug-related interstitial lung disease within 3 months before first dose.
- •History of immunodeficiency or organ transplantation.
- •Epilepsy requiring treatment.
- •Use of protocol-prohibited myelofibrosis (MF) medications, immunomodulators, or immunosuppressants within specified time before first dose.
- •Use of Chinese patent medicines with anti-tumor indications approved by National Medical Products Administration (NMPA) within 2 weeks before first dose.
- •Uncontrolled pleural effusion, pericardial effusion, or ascites.
- •Live attenuated vaccine within 4 weeks before first dose or planned during the study.
- •Known hypersensitivity to study drug or excipients.
- •Diagnosis of active autoimmune disease within 2 years before first dose.
- •Participation in another interventional clinical trial with investigational drug within 4 weeks before first dose.
- •Any condition that, in the investigator's judgment, seriously endangers subject safety or interferes with study completion.
研究组 & 干预措施
TQ05105 Tablets
TQ05105 Tablets, 28 days as a treatment cycle.
干预措施: TQ05105 Tablets (Rovadicitinib Tablets) (Drug)
结局指标
主要结局
Proportion of subjects with ≥35% reduction in spleen volume from baseline at week 24 (SVR35)
时间窗: up to 24 weeks
SVR35 at week 24 as assessed by Independent Review Committee (IRC)
Peak concentration (Cmax)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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-∞)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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)
时间窗: 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).
次要结局
- Best response rate of spleen volume reduction(up to 48 weeks)
- Onset time of splenic response(up to 48 weeks)
- Duration of maintenance of at least 35% Reduction in Spleen Volume (DoMSR)(up to 48 weeks)
- Percentage change in spleen volume from baseline at planned visits(up to 48 weeks)
- SVR35 at each planned visit time point(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.(up to 48 weeks)
- Percentage change in MPN-SAF TSS from baseline at planned visits(up to 48 weeks)
- Proportion of subjects with at least one occurrence of ≥50% reduction in MPN-SAF TSS from baseline(up to 48 weeks)
- Time to first ≥50% reduction in MPN-SAF TSS from baseline(up to 48 weeks)
- Duration of ≥50% reduction in MPN-SAF TSS from baseline(up to 48 weeks)
- Objective response rate (ORR)(up to 48 weeks)
- Progression-free survival (PFS)(From first dose to event (up to study completion) , an average of 3 years)
- Leukemia free survival (LFS)(From first dose to event (up to study completion) , an average of 3 years)
- Overall Survival (OS)(From first dose to event (up to study completion) , an average of 3 years)
- Incidence of adverse events (AEs)(From baseline up to 4 weeks after last dose)
- Severity of AEs(From baseline up to 4 weeks after last dose)
- Urinary excretion amount (Ae0-24)(Pre-dose (-24-0 hours), 0-3, 3-6, 6-9, 9-12, 12-24 hours post-dose)
- Cumulative urinary excretion rate (Ae0-24%)(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(Up to 24 weeks)
- Proportion of subjects receiving platelet transfusion within 24 weeks(Up to 24 weeks)