A Clinical Trial of TQ05105 Tablets Combined With TQB3617 Capsules in the Treatment of Myelofibrosis (MF)

Study Overview
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Brief Summary
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This is an open, single-arm, multi-center clinical study designed to evaluate the efficacy and safety of TQ05105 Tablets combined with TQB3617 Capsules in patients with intermediate- and high-risk Myelofibrosis.

Official Title
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A Phase Ib/II Clinical Trial of TQ05105 Tablets Combined With TQB3617 Capsules in the Treatment of Intermediate- and High-risk Myelofibrosis

Conditions
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Myelofibrosis

Intervention / Treatment
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* Drug: TQ05105 Tablets
* Drug: TQB3617 Capsules


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Voluntary and signed informed consent, good compliance. Age: 18 or above (when signing the informed consent form); Eastern Cooperative Oncology Group (ECOG) performance status (PS) score of 0 or 2; Life expectancy ≥ 24 weeks. Patients diagnosed with Primary myelofibrosis (PMF), post polycythemia vera myelofibrosis (post PV MF), or post essential thrombocythemia myelofibrosis (post ET MF) According to the dynamic international prognostic scoring system (DIPSS), patients with intermediate or high risk of bone marrow fibrosis were evaluated. Patients with poor efficacy of JAK inhibitors (for phase Ib and phase II cohort 2) Patients who had not received JAK inhibitor treatment (for phase II cohort 1). Spleen enlargement. Peripheral blood primary cells and bone marrow primary cells were ≤10%. No growth factor, colony stimulating factor, thrombopoietin or platelet transfusion was received within 2 weeks before the examination, and the blood routine indexes met the requirements within 7 days before the first administration. The Main organ function is normal. Men and women of childbearing age should agree to use contraceptive measures (such as intrauterine devices, contraceptives, or condoms) during the study period and within 6 months after the end of the study. Serum human chorionic gonadotrophin (HCG) test is not negative within 7 days before the first administration and must be non-lactating patients. Exclusion Criteria: Patients who have previously received allogeneic stem cell transplantation, or received autologous stem cell transplantation within 3 months before the first administration, or recently planned stem cell transplantation; Previous treatment with BET inhibitors; Patients who have previously undergone splenectomy, or received splenic radiotherapy within 6 months before the first administration; Use of any MF medications, any immunomodulators, androgens, any immunosuppressive agents, erythropoietin, aspirin > 100 mg/day within 2 weeks prior to first administration; Other malignancies within 3 years prior to first administration or currently present. Patients with multiple factors (such as inability to swallow, postoperative gastrointestinal resection, acute and chronic diarrhea, intestinal obstruction, etc.) affecting oral or absorption of drugs; Major surgical treatment or significant traumatic injury within 4 weeks prior to first administration; Presence of congenital bleeding disorder and congenital coagulopathy; Patients who had arterial/venous thrombosis events within 6 months before the first administration. Have a history of mental drug abuse, or have a mental disorder. Active or uncontrolled severe infection; Active hepatitis B virus (HBV) infection, or hepatitis C virus (HCV) infection and HCV RNA positive, or active Corona Virus Disease 2019 (COVID-19) infection; Patients with grade III or above congestive heart failure, unstable angina pectoris or myocardial infarction, or arrhythmia requiring treatment, or QT interval prolongation within 6 months before the first administration; Unsatisfactory blood pressure control despite standard therapy; Patients with renal failure requiring hemodialysis or peritoneal dialysis; Patients newly diagnosed with pulmonary interstitial fibrosis or drug-related interstitial lung disease within 3 months before the first administration; Patients with a history of immunodeficiency disease or organ transplantation; Patients with epilepsy requiring treatment; Patients who have received Chinese patent medicines with anti-tumor indications specified in the approved drug package insert of China National Medical Products Administration (NMPA) within 2 weeks before the first administration; Patients with uncontrolled pleural effusion, pericardial effusion or ascites; There was a history of attenuated live vaccine inoculation within 4 weeks before the first administration, or attenuated live vaccine inoculation was planned during the study period. People with known hypersensitivity to the study drug and excipients; Patients diagnosed as active autoimmune diseases within 2 years before the first administration; Those who participated in and used other anti-tumor clinical trial drugs within 4 weeks before the first administration (except JAK inhibitor-related clinical trials). According to the judgment of the investigators, some situations seriously endanger the safety of the subjects or affect the subjects to complete the study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TQ05105 Tablets + TQB3617 Capsules<br>TQ05105 Tablets combined with TQB3617 Capsules, orally administered. 21 days as a treatment cycle. | Drug: TQ05105 Tablets<br>* TQ05105 Tablets is a Janus kinase 1 (JAK1) and Janus kinase 2 (JAK2) Inhibitor.<br>Drug: TQB3617 Capsules<br>* TQB3617 Capsules is a Bromodomain and Extra-Terminal (BET) Inhibitor<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximal tolerance dose (MTD) | If dose limiting toxicity (DLT) occurs in 2 or more subjects in a given dose group, the dose level in the previous dose group is considered MTD. | Up to 2 years. | 
| Recommended phase II dose (RP2D) | The RP2D is defined as the lower dose level to MTD based on the safety profile. | Up to 2 years | 
| ≥35% reduction in spleen volume (SVR35) | The proportion of subjects with a ≥35% reduction in spleen volume from baseline at the end of treatment at week 24. | Up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SVR35 | The proportion of subjects with a ≥35% reduction in spleen volume compared to baseline after treatment. | Up to 120 weeks | 
| Optimum effective rate | The proportion of subjects with at least once spleen volume reduction ≥ 35% from baseline. | Up to 120 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 baseline. | Up to 120 weeks | 
| Duration of maintenance of at least 35% Reduction in Spleen Volume (DoMSR) | 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 is < 35% from baseline. | Up to 120 weeks | 
| Myeloproliferative neoplasm - Symptom Assessment Form - Total Symptom Score (MPN-SAF TSS) | The proportion of subjects whose total symptom score of MPN-SAF TSS decreased by more than 50% from baseline. MPN-SAF-TSS is an effective tool for evaluating the disease burden of patients with myeloproliferative neoplasms. 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 10 symptom scores is MPN-SAF-TSS score. The higher the score, the more severe the symptoms are. | Up to 60 weeks | 
| MPN-SAF TSS change | The total score of MPN-SAF TSS decreased compared with baseline. MPN-SAF-TSS is an effective tool for evaluating the disease burden of patients with myeloproliferative neoplasms. 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 10 symptom scores is MPN-SAF-TSS score. The higher the score, the more severe the symptoms are. | Up to 120 weeks | 
| Variant allele frequency (VAF) | The proportion of subjects whose VAF decreased compared with baseline. | Up to 48 weeks | 
| The proportion of subjects with gene mutation achieving SVR35 | The proportion of subjects with gene mutation achieving SVR35 | Up to 48 weeks | 
| The proportion of subjects with gene mutation whose MPN-SAF TSS scale decreased by ≥ 50% | The proportion of subjects with gene mutation whose MPN-SAF TSS scale decreased by ≥ 50% compared with baseline. | Up to 48 weeks. | 
| Progression-free survival (PFS) | The time interval from the first dose to the date of the occurrence of any of the following events, whichever occurs first:(1) Spleen volume increased by ≥25% compared with the screening period ; (2) Death caused by any cause. | Up to 120 weeks | 
| Leukemia free survival (LFS) | The time interval from the date of the first dose to the date of any of the following events, whichever occurs first: (1) the date of the first bone marrow smear showing the original cell ≥20% ;(2) The first peripheral blood smear showed that the original cells ≥ 20% and the absolute value of the original cells ≥1×10^9/L and lasted for at least 2 weeks; (3) Death caused by any reason. | Up to 120 weeks | 
| Overall Survival (OS) | OS is defined as the time from the first time the subject received treatment to death due to any cause. | Up to 120 weeks | 
| Incidence of adverse events (AEs) | Incidence rate of all adverse medical events that occur after the subject receives the investigational drug, evaluated according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) | Baseline up to 120 weeks | 
| Severity of adverse events (AEs) | Severity of all adverse medical events that occur after the subject receives the investigational drug, evaluated according to the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE v5.0) | Baseline up to 120 weeks |