Clinical Study of Mitoxantrone Hydrochloride Liposome Injection in Subjects With Acute Myeloid Leukemia

This study is an open-label, single-arm, phase I/II clinical study. Phase I is a multi-center, dose-escalation study, aiming to explore the maximum tolerated dose (MTD) of venetoclax combined with mitoxantrone liposome in the treatment of relapsed or refractory acute myeloid leukemia (AML), and determine the recommended dose for phase II (RP2D); Phase II is a multi-center, exploratory study, aiming to explore efficacy of venetoclax combined with mitoxantrone liposome in the treatment of relapsed and refractory AML patients, and to explore the differences in the efficacy of this combination therapy with different gene mutations.

This study is an open-label, single-arm, phase I/II clinical study. Phase I is a multi-center, dose-escalation study. Following the "3+3" principle, it plans to recruit 9-18 patients with clinically diagnosed relapsed or refractory AML who will be treated with venetoclax and mitoxantrone liposome, in order to explore the MTD of mitoxantrone liposome, and determine the RP2D. Mitoxantrone liposome began to explore the dose from 24 mg/m\^2, and every 4 weeks (28 days) was a cycle. Three dose groups of 24, 30 and 36 mg/m\^2 were preseted; The trial phase includes screening period (within 28 days), treatment period (planned 2 cycles), follow-up period (RFS and OS follow-up, planned 1 year).

Phase II is a multi-center, exploratory study, aiming to explore efficacy of venetoclax combined with mitoxantrone liposome in the treatment of relapsed or refractory AML patients, and to explore the differences in the efficacy of this combination therapy with different gene mutations. After Phase I reaches MTD and the dose of Phase II is determined, Phase II clinical trials will be carried out. The phase II trial phase includes screening period (within 28 days) , treatment period (planned 6 cycles ) and a follow-up period (RFS and OS follow-up, planned for 1 year).

Eligibility Criteria:
Inclusion Criteria:

1. AML confirmed by bone marrow cytology and pathology;
2. Meet the diagnostic criteria for relapsed and refractory AML. Diagnostic criteria for relapsed AML: leukemia cells reappeared in peripheral blood after complete remission or blast cells in bone marrow \>0.05 (except for other reasons such as bone marrow regeneration after consolidation chemotherapy) or extramedullary leukemia cell infiltration. Diagnostic criteria for refractory AML: naive patients who were ineffective after 2 courses of standard regimens; patients who relapsed within 12 months after consolidation and intensive therapy after CR; patients who relapsed after 12 months but were ineffective after conventional chemotherapy; 2 or more Secondary relapse; persistent extramedullary leukemia;
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2;
4. Liver and kidney function: Alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤2.5 x upper limit of normal (ULN) (≤5 x ULN for patients with liver infiltrates); Total bilirubin ≤1.5 x ULN (≤3 x ULN for patients with liver infiltration); Serum creatinine ≤1.5 x ULN;
5. Normal cardiac function: left ventricular ejection fraction (LVEF) ≥ 45% assessed by echocardiography or radionuclide active angiography (MUGA);
6. Pulmonary function: dyspnea ≤ CTC AE grade 1 and SaO2 ≥ 92% in indoor air environment;
7. The expected survival time is greater than 3 months;
8. Patients voluntarily participated in this study and signed the informed consent.

Exclusion Criteria:

1. The subject had previously received any of the following anti-tumor treatments: a)Those who have previously received mitoxantrone or mitoxantrone liposome; b)Previously received doxorubicin or other anthracycline treatment, and the total cumulative dose of doxorubicin is more than 360 mg/m\^2 (1 mg doxorubicin converted from other anthracycline drugs is equivalent to 2 mg daunorubicin or 0.5 mg idarubicin); c)Have received anti-tumor treatment (including chemotherapy, targeted therapy, hormone therapy, taking traditional Chinese medicine with anti-tumor activity, etc.) or participated in other clinical trials and received clinical trial drugs within 4 weeks before the first use of the study drugs;
2. Heart function and disease meet one of the following conditions: a)Long QTc syndrome or QTc interval \> 480 ms; b)Complete left bundle branch block, grade II or III atrioventricular block; c)Serious and uncontrolled arrhythmias requiring drug treatment; d)New York Heart Association grade ≥ II; e)A history of myocardial infarction, unstable angina pectoris, severe unstable ventricular arrhythmia or any other arrhythmia requiring treatment, a history of clinically serious pericardial disease, or ECG evidence of acute ischemia or active conduction system abnormalities within 6 months before recruitment.
3. Identify patients with central nervous system invasion;
4. Other malignancies, except for effectively controlled non melanoma skin basal cell carcinoma, breast / cervical carcinoma in situ, and other malignancies that have been effectively controlled without treatment in the past five years;
5. Non controlled systemic diseases (such as active infection, non controlled hypertension, diabetes, etc.);
6. Human immunodeficiency virus (HIV) infection (HIV antibody positive);
7. Active hepatitis B and C infection (hepatitis B test: if there is a positive hepatitis B surface antigen or core antibody, add HBV DNA, and the hepatitis B virus DNA exceeds 1x10\^3 copies/mL to exclude; hepatitis C: if the hepatitis C antibody is positive, further test HCV RNA, hepatitis C Viral RNA exceeding 1x10\^3 copies/mL was excluded);
8. Hypersensitivity to any study drug or its components;
9. Pregnant women, lactating women, patients who refused to take effective contraceptive measures during the study;
10. Serious neurological or psychiatric history;
11. Unsuitable subjects for this study determined by the investigator.