A Clinical Trial to Evaluate the Efficacy, Safety, and Pharmacokinetics of TQ05105 Tablets in Subjects With Intermediate/High-risk Myelofibrosis

Официальное название

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

Обзор

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.

Вмешательства

• Препарат TQ05105 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).

Первичные конечные точки

• Proportion of subjects with ≥35% reduction in spleen volume from baseline at week 24 (SVR35) [Срок оценки: up to 24 weeks]
• Peak concentration (Cmax) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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-∞) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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) [Срок оценки: 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)]

Вторичные конечные точки (12)

• Best response rate of spleen volume reduction [Срок оценки: up to 48 weeks]
• Onset time of splenic response [Срок оценки: up to 48 weeks]
• Duration of maintenance of at least 35% Reduction in Spleen Volume (DoMSR) [Срок оценки: up to 48 weeks]
• Percentage change in spleen volume from baseline at planned visits [Срок оценки: up to 48 weeks]
• SVR35 at each planned visit time point [Срок оценки: 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. [Срок оценки: up to 48 weeks]
• Percentage change in MPN-SAF TSS from baseline at planned visits [Срок оценки: up to 48 weeks]
• Proportion of subjects with at least one occurrence of ≥50% reduction in MPN-SAF TSS from baseline [Срок оценки: up to 48 weeks]
• Time to first ≥50% reduction in MPN-SAF TSS from baseline [Срок оценки: up to 48 weeks]
• Duration of ≥50% reduction in MPN-SAF TSS from baseline [Срок оценки: up to 48 weeks]
• Objective response rate (ORR) [Срок оценки: up to 48 weeks]
• Progression-free survival (PFS) [Срок оценки: From first dose to event (up to study completion) , an average of 3 years]

Критерии участия

Критерии включения

• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 24 центра

• The First Affiliated Hospital of University of Science and Technology of China — Хэфэй
• Fujian Medical University Union Hospital — Фучжоу
• Guangzhou First Municipal People's Hospital — Гуанчжоу
• The First Affiliated Hospital of Guangxi Medical University — Nanning
• Cangzhou People's Hospital rovince — Cangzhou
• Affiliated Hospital of Chengde Medical College — Chengde
• The Second Hospital of Hebei Medical University — Shijiazhuang
• Xingtai People's Hospital — Xingtai
• … и ещё 16 центров

Идентификаторы

NCT: NCT07551427 · TQ05105-II-08

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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