A Clinical Trial of TQ05105 Tablets in the Treatment of Moderate and High Risk Myelofibrosis

Study Overview
=================
Brief Summary
-----------------
Q05105 tablet is a Janus kinase 2 (JAK2) inhibitor, which can be used to treat JAK2 target related diseases, such as moderate or high-risk multiple myelofibrosis

Official Title
-----------------
A Randomized, Double Blind, Double Dummy, Parallel Controlled, Multicenter Phase II Clinical Trial of TQ05105 Tablets Versus Hydroxyurea Tablets in the Treatment of Moderate and High Risk Myelofibrosis

Conditions
-----------------
Moderate and High Risk Myelofibrosis

Intervention / Treatment
-----------------
* Drug: TQ05105 tablets
* Drug: Hydroxycarbamide tablets


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: The subjects volunteered to join the study and signed informed consent, with good compliance; Age: 18-75 years old (when signing the informed consent form); Eastern Cooperative oncology Group (ECoG) Performance Status (PS) score: 0-2; The expected survival time is more than 24 weeks; Primary Myelofibrosis (PMF) was diagnosed according to World Health Organization (WHO) standard (2016 Edition), or Post Polycythemia Vera(PV)-MF or Post Essential Thrombocythemia (ET)-MF was diagnosed according to International Working Group-Myeloproliferative Neoplasms Research and Treatment (IWG-MRT) standard; JAK2 mutation or not was included in the study; According to Dynamic International Prognostic Scoring System (DIPSS) prognosis grading criteria, the patients with myelofibrosis were assessed as medium risk (including medium risk-1, medium risk-2) or high risk; Splenomegaly: palpate the splenic margin at least 5cm below the ribs (the distance from the costal margin to the farthest point of splenic protrusion); Peripheral blood primordial cells ≤ 10%; If anti myelofibrosis therapy (except JAK inhibitor) is being received before screening, the drug must be stopped at least 4 weeks before the random date; No growth factor, colony stimulating factor, thrombopoietin or platelet transfusion was received within 2 weeks before the examination, and hemoglobin (Hgb) ≥ 80g / L, platelet count (PLT) ≥ 100 within 7 days before the random date × 10^9 / L and neutrophil absolute value (neut) ≥ 1.0 × 10^9/L; The main organs were functional 7 days before the random date, which was in accordance with the following criteria: Total Bilirubin (TBIL) was less than 2 times the upper limit of normal value (ULN); Alanine aminotransferase (ALT) and Aspartate aminotransferase (AST) were less than 2.5 times of ULN; Serum creatinine (Cr) < 1.5 times of ULN or creatinine clearance rate (Ccr) ≥ 50ml/min; The blood coagulation function should be checked in accordance with: prothrombin time (PT), activated partial thromboplastin time (APTT), international standardized ratio (INR) < 1.5 × ULN (not anticoagulant treatment); Left ventricular ejection fraction (LVEF) evaluated by color Doppler ultrasonography ≥ 50%; Female subjects of childbearing age should agree to use contraceptive measures (such as intrauterine device, contraceptive or condom) during the study period and within 6 months after the end of the study; The serum pregnancy test was negative within 7 days before the date of randomization and must be non lactating subjects; Male subjects should agree to use contraception during the study period and within 6 months after the end of the study period. Exclusion Criteria: Those who have received allogeneic stem cell transplantation in the past, or autologous stem cell transplantation within 3 months before the random date, or recently planned stem cell transplantation; Patients who have received JAK inhibitors in the past; Those who had undergone splenectomy or received splenic radiotherapy within 6 months before the date of randomization (including internal and external radiotherapy); Other malignancies were present or present within 3 years before the date of randomization. The following two cases can be included: other malignant tumors treated by single operation have achieved 5-year disease-free survival (DFS) in a row; Cured cervical carcinoma in situ, non melanoma skin cancer and superficial bladder tumor [ta (non-invasive tumor), tis (carcinoma in situ) and T1 (tumor infiltrating basement membrane)]; 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; Non hematological toxicity caused by previous treatment did not return to ≤ 1 (excluding alopecia); Patients who received major surgical treatment or had obvious traumatic injury within 4 weeks before the date of randomization; At present, there are congenital bleeding or coagulation diseases, or are using anticoagulant therapy; Arteriovenous thrombotic events occurred within 6 months before the random date, such as cerebrovascular accident (including transient ischemic attack, cerebral hemorrhage, cerebral infarction), deep venous thrombosis and pulmonary embolism; A history of psychotropic substance abuse or mental disorder; Active or uncontrolled severe infection (≥ Common Terminology Criteria for Adverse Events(CTCAE)2 infection); Hepatitis B Virus (HBV) DNA≥ULN； Hepatitis C antibody positive and Hepatitis C Virus (HCV) RNA ≥ ULN; Myocardial ischemia or myocardial infarction, arrhythmia, QT interval prolongation (corrected QT interval (QTc) ≥ 450 ms for male, QTc ≥ 470 ms for female) and congestive heart failure (NYHA classification) of grade 2 or above; Blood pressure control is not ideal (systolic blood pressure ≥ 150 mmHg or diastolic blood pressure ≥ 100 mmHg); Renal failure requires hemodialysis or peritoneal dialysis; Newly diagnosed pulmonary fibrosis or drug-related interstitial lung disease within 3 months before the date of randomization; History of immunodeficiency, including Human Immunodeficiency Virus (HIV) positive or other acquired or congenital immunodeficiency diseases, or organ transplantation; Patients with epilepsy and need treatment; Had received chemotherapy, radiotherapy or other anti-cancer therapy within 4 weeks before the date of randomization; Within 2 weeks before the date of randomization, he received Chinese patent medicines (including compound cantharis capsule, Kang'ai injection, kang'laite capsule / injection, Aidi injection, Brucea javanica oil injection / capsule, Xiaoaiping tablet / injection, cinobufagin capsule, etc.) with anti-tumor indications specified in nmpa approved drug instructions; Uncontrolled pleural effusion, pericardial effusion or ascites; Patients with central nervous system involvement; There was a history of live attenuated vaccine inoculation within 4 weeks before the date of randomization or live attenuated vaccine inoculation was planned during the study period;

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 75 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: TQ05105 tablets + Hydroxyurea blank tablets<br>Take TQ05105 Tablets + Hydroxyurea blank tablets orally on an empty stomach, with an interval of at least 8 hours, and the best interval is 12 hours. Every 4 weeks is a period of administration | Drug: TQ05105 tablets<br>* TQ05105 tablet is a JAK2 inhibitor, which can be used to treat JAK2 target related diseases, such as moderate or high-risk multiple myelofibrosis.<br>|
| Active Comparator: TQ05105 blank tablets + Hydroxyurea tablets<br>Take TQ05105 blank tablets + Hydroxyurea tablets orally on an empty stomach, with an interval of at least 8 hours, and the best interval is 12 hours. Every 4 weeks is a period of administration | Drug: Hydroxycarbamide tablets<br>* Hydroxycarbamide tablet is a nucleoside diphosphate reductase inhibitor.<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Spleen Volume was Reduced by more than 35% from baseline（SVR35） assessed by Independent Review Committee (IRC) | Proportion of subjects whose spleen volume was reduced by more than 35% from baseline at the end of week 24 of IRC assessment (SVR35) | up to 24 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| SVR35 assessed by the researchers and objective response rate (ORR) | Proportion of subjects whose spleen volume was reduced by more than 35% from baseline to the end of the 24th week assessed by the researchers and ORR | up to 24 weeks | 
| optimal response rate of splenic response | Proportion of subjects with at least one reduction in spleen volume ≥ 35% from baseline. | up to 120 weeks | 
| onset time of splenic response | The time between the date of randomization and the date when the spleen volume decreased ≥ 35% from the baseline for the first time. | up to 120 weeks | 
| Duration of Maintenance of a Least 35% Reduction in Spleen Volume(DoMSR) | Duration of spleen volume reduction ≥ 35% from baseline (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 < 35% from baseline. | up to 120 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 | At the 24th week, the proportion of subjects whose total symptom score of MPN-SAF TSS) decreased by more than 50% compared with baseline. | up to 24 weeks | 
| The total symptom score of MPN-SAF TSS decreased compared with baseline | The total symptom score of MPN-SAF TSS decreased compared with baseline; | up to 24 weeks | 
| Progression-free survival (PFS) | The interval from the random date to the date of occurrence of any of the following events, whichever occurs first: ① the spleen volume increases by ≥ 25% compared with the lowest value during the treatment period (including the screening period); ② Death from any cause; ③ Start other anti-MF treatments; | up to 120 weeks | 
| Leukemia free survival (LFS) | The time interval between the random date and the date of any of the following events, whichever occurs first, shall prevail: ① the date when the first bone marrow smear showed that the number of primordial cells was more than or equal to 20%; ② The first peripheral blood smear showed that the number of primordial cells was more than or equal to 20% and the absolute value of primordial cells was more than or equal to 1% × 10^9 / L for at least 2 weeks; ③ Death from any cause; | up to 120 weeks | 
| Overall survival (OS) | The time interval between the random date and death from any cause | up to 120 weeks | 
| The incidence and severity of adverse events (AEs) occurred during the study | The incidence and severity of AEs occurred during the study | up to 120 weeks |