Mitoxantrone Hydrochloride Liposome Combined With Chemotherapy in Untreated de Novo Acute Myeloid Leukemia

Study Overview
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Brief Summary
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The purpose of this study is to determine the safety, efficacy and pharmacokinetics of mitoxantrone hydrochloride liposome injection combined with chemotherapy in previously untreated de novo acute myeloid leukemia.

Detailed Description
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This is a prospective, multi-center, randomized, open-label, three-arm clinical study to explore the efficacy among three chemotherapy regimens combined with mitoxantrone hydrochloride liposome in previously untreated de novo acute myeloid leukemia. Patients will be randomized to different treatment group and be given different induction therapy in the first cycle. If patients do not achieve Morphologic Leukemia-free State (MLFS) after the first induction cycle, they will receive the second induction therapy with mitoxantrone hydrochloride liposome, cytarabine and venetoclax. Mitoxantrone hydrochloride liposome will be given on day 1 at the dose of 24 mg/m2 or 30 mg/m2 and be combined with cytarabine, venetoclax or homoharringtonine. A maximum of 2 cycles of induction therapy are planned.

Official Title
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A Clinical Study to Evaluate the Safety, Efficacy and Pharmacokinetics of Mitoxantrone Hydrochloride Liposome Injection Combined With Chemotherapy in Previously Untreated de Novo Acute Myeloid Leukemia

Conditions
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Acute Myeloid Leukemia

Intervention / Treatment
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* Drug: Mitoxantrone hydrochloride liposome injection
* Drug: Cytarabine
* Drug: Homoharringtonine
* Drug: Venetoclax


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Able to understand the study and voluntarily sign informed consent. Age: 18 65 (including 18) years old, gender unlimited. Patients diagnosed with acute myeloid leukemia according to The 2016 revision to the World Health Organization classification of myeloid neoplasms and acute leukemia who haven't been treated. Eastern Cooperative Oncology Group (ECOG) physical state score: 0-1. Fit for intensive chemotherapy. The function of main organs should meet the following standards before treatment: Kidney: Serum creatinine ≤ 1.5 × Upper limit of normal range (ULN) Liver: Total bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 3× ULN Patients should agree to use contraception (such as intrauterine device [IUD], contraceptive pill or condom) during the study period and within 6 months after the end of the study; Female patients must have a negative serum pregnancy test within 7 days before enrollment. Exclusion Criteria: Any of the following cases:(1) diagnosed as acute promyelocytic leukemia (APL);(2) chronic myelogenous leukemia in blast crisis;(3) AML with central nervous system leukemia. AML arising from prior cytotoxic chemotherapy or radiotherapy for other tumours. Patient has been previously diagnosed with another malignancy in last 5 years (except for cured basal cell carcinoma of skin or cervical carcinoma in situ). Has been previously treated with doxorubicin or other anthracyclines and drugs for AML. Allergic history of mitoxantrone hydrochloride injection or any other drugs used in this study. Those on systemic anti-infective therapy with poorly controlled infection (signs of infection progression within 1 week prior to the first dose, or as determined by the investigator). Patient who is suffering from severe hemorrhagic diseases, such as haemophilia A, haemophilia B, von Willebrand disease and any other spontaneous bleeding require medical treatment. The estimated survival time is less than 3 months. Any of the following conditions occurs in cardiac function:(1) Long QTc syndrome or QTc interval > 480 ms;(2) Complete left bundle branch block or severe atrioventricular block disease (without a pacemaker);(3) Serious and uncontrolled arrhythmias and unstable angina pectoris requiring drug treatment;(4) History of chronic congestive heart failure, New York Heart Association (NYHA)≥grade 3;(5) The cardiac ejection fraction is less than 50% in Echocardiography;(6)Uncontrollable hypertension (defined as multiple measurements of systolic blood pressure > 150 mmHg or diastolic blood pressure > 90 mmHg under drug control);(7) History of myocardial infarction, unstable angina pectoris, viral myocarditis or severe pericardial disease, ECG evidence of acute ischemia or active conduction system abnormalities within 6 months before first dose. Patients have thromboembolic events within 6 months prior to first dose, such as cerebrovascular accidents (including transient ischemic attack) and pulmonary embolism. HBsAg/HBcAb positive with HBV-DNA higher than the lower limit of the detection value of the research center , hepatitis C antibody-positive with HCV-RNA higher than the lower limit of the detection value of the research center, or HIV antibody positive in the preliminary screening. Patients who have been treated with strong/moderate CYP3A inducers/inhibitors or P-gp inhibitors within 7 days prior to first dose (for treatment group 3 only). Patients who cannot take oral medications or have absorption disorder (for treatment group 3 only). Patient is suffering from any serious and /or non-controllable disease, or the investigator determines that the disease might affect the participation of patients in the study, including (but not limited to, uncontrolled diabetes, dialysis related kidney diseases, severe liver diseases, life-threatening autoimmune diseases and hemorrhagic diseases, drug abuse, neurological diseases, etc.). Pregnant or lactating female. Patients who are not suitable for this study as decided by the investigator due to other reasons.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group 1<br>Patients will receive mitoxantrone hydrochloride liposome injection combined with standard-dose of cytarabine. | Drug: Mitoxantrone hydrochloride liposome injection<br>* intravenous infusion on day 1 in a 4-week treatment cycle.<br>Drug: Cytarabine<br>* intravenous infusion<br>|
| Experimental: Treatment group 2<br>Patients will receive mitoxantrone hydrochloride liposome injection combined with intermediate-dose of cytarabine and homoharringtonine. | Drug: Mitoxantrone hydrochloride liposome injection<br>* intravenous infusion on day 1 in a 4-week treatment cycle.<br>Drug: Cytarabine<br>* intravenous infusion<br>Drug: Homoharringtonine<br>* intravenous infusion<br>|
| Experimental: Treatment group 3<br>Patients will receive mitoxantrone hydrochloride liposome injection combined with standard-dose of cytarabine and venetoclax. | Drug: Mitoxantrone hydrochloride liposome injection<br>* intravenous infusion on day 1 in a 4-week treatment cycle.<br>Drug: Cytarabine<br>* intravenous infusion<br>Drug: Venetoclax<br>* orally once a day<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (TEAEs) |  | Up to approximately one month | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Complete remission rate（CR） | Proportion of patients with complete remission | Up to approximately nine weeks | 
| Complete remission or complete remission with partial hematologic recovery (CR/CRh) | Proportion of patients with complete remission or complete remission with partial hematologic recovery. | Up to approximately nine weeks | 
| Composite remission rate (CRc) | Proportion of subjects with complete remission (CR) or complete remission with partial hematologic recovery (CRh) or complete remission with incomplete hematologic recovery (Cri). | Up to approximately nine weeks | 
| Minimal Residual Disease (MRD)-negative composite remission rates | Among those who have achieved composite remission, proportion of patients who is MRD-negative. | Up to approximately nine weeks | 
| Event-free survival (EFS) | It is defined as the time from the start of randomization to the occurrence of induction failure or disease progression or death from any cause (whichever occurs first). | Up to approximately 3 years. | 
| Relapse-free Survival (RFS) | It is defined as the time from the start of achieving remission to disease progression, death from any cause or the last follow-up | Up to approximately 3 years. | 
| Overall survival (OS) | It is defined as the time from the start of randomization to the death from any cause. | Up to approximately 3 years. | 
| Blood concentrations of total and free mitoxantrone. |  | 30 minutes before administration and 5min, 6, 24, 72, 144, 288, 432, 648 hours after administration of Mitoxantrone hydrochloride liposome on day 1 |