Mitoxantrone Hydrochloride Liposome, Standard-dose of Cytarabine and Venetoclax in the Treatment of R/R AML

A Prospective, Multi-center, Phase 2 Study of Mitoxantrone Hydrochloride Liposome Injection Combined With Standard-dose Cytarabine and Venetoclax in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

The purpose of this prospective, multi-center, single-arm, phase 2 study is to evaluate the efficacy and safety of a combination regimen of mitoxantrone hydrochloride liposome injection, standard-dose of cytarabine and venetoclax (MAV) in the treatment of relapsed or refractory (R/R) AML. The study plan to enroll 72 R/R AML patients who are expected to receive laboratory tests of bone marrow and blood specimens at regular times after MAV treatment.

For patients with R/R AML, there is currently no established standard treatment. Previous research suggests that mitoxantrone could against venetoclax-resistant leukemia stem cells (LSCs) by modulating mitochondrial calcium levels. Based on the potentially synergistic killing effect of mitoxantrone and venetoclax, a phase 2 study is underway in R/R AML. Patients receive mitoxantrone hydrochloride liposome, moderate-dose of cytarabine (1.0 g/m^2, IV, q12h, d1, 3, 5) and venetoclax (MAV) when they were enrolled.

Here the investigator also conduct another phase 2 study of MAV regimen with standard-dose of cytarabine in relapsed or refractory (R/R) AML, aiming to evaluate the efficacy and safety of MAV regimen. All participants will receive MAV treatment including 30 mg/m^2 mitoxantrone hydrochloride liposome on day 1, 100 mg/m^2 cytarabine on days 1-7 and 400 mg venetoclax on days 2-8 with a dose escalation on days 2-4. Each cycle consists of 4 weeks. A maximum of 2 cycles of therapy are planned.

Inclusion Criteria:

1. Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study.

2. Age ≥18

3. Clinically diagnosed relapsed/refractory AML, excluding acute promyelocytic leukemia.

   1. Patients who failed after at least 1 courses of initial induction therapy.
   2. Bone marrow blasts≥5% after CR/CRi, or reappearance of blasts in the blood in at least 2 peripheral blood samples at least one week apart, or leukemia cell infiltration appeared in extramedullary.
   3. Conversion from MRD negativity to MRD positivity after CR/CRi.

4. Physical status score of Eastern Oncology Collaboration Group (ECOG) 0-2.

5. Life expectancy > 3 months.

6. AST/ALT≤2.5 ULN (for subjects with hepatic infiltration≤5 ULN); Total bilirubin≤1.5 ULN (for subjects with hepatic infiltration≤3 ULN); Serum creatinine≤1.5 ULN.

Exclusion Criteria:

1. Previous anti-tumor therapy meets one of the following criteria:

   1. Prior therapy with mitoxantrone or mitoxantrone liposome;
   2. Prior therapy with doxorubicin or anthracyclines, and the cumulative dose of doxorubicin > 360 mg/m^2 (1 mg doxorubicin was equivalent to 2 mg daunorubicin or 0.5 mg idarubicin);
   3. Have received other anti-tumor therapy (including chemotherapy, targeted therapy, hormone therapy, Chinese medicines with anti-tumor activity, except those that do not affect the efficacy of the study as determined by the investigator) or participated in other clinical trials and received clinical trial drugs within 4 weeks or 5 half-lives of the drug before the study;

2. Subjects who received strong or moderate CYP3A inducers/inhibitors or P-glycoprotein (P-gp) inhibitors within 7 days before starting study treatment;

3. Subjects who are unable to take oral medications or have malabsorption syndrome;

4. Cardiovascular diseases, including but not limited to:

   1. QTc interval >480 ms or long QTc syndrome in screening;
   2. Complete left bundle branch block, 2 or 3 grade atrioventricular block;
   3. Requiring treatment of serious and uncontrolled arrhythmia;
   4. New York Heart Association NYHA≥2;
   5. Cardiac ejection fraction (EF) was less than 50%;
   6. Myocardial infarction, unstable angina pectoris, severe unstable ventricular arrhythmia or any other history of arrhythmia or clinically serious pericardial disease that requires treatment within the first 6 months of enrollment, or electrocardiographic evidence of acute ischemic or active conduction system abnormalities.

5. Central nervous system leukemia;

6. Previous or current occurrence of other malignancies (in addition to non-melanoma basal cell carcinoma of the skin that is effectively controlled, breast/cervical carcinoma in situ, and other malignancies that have been effectively controlled without treatment within the past five years).

7. Subjects are suffering from any other uncontrollable disease (including but not limited to: uncontrolled diabetes and hypertension, and advanced infection);

8. HIV infection.

9. HBsAg or HBcAb positive, with HBV-DNA≥1x10^3 copies/mL; or HCV-RNA≥1x10^3 copies/mL;

10. A history of immediate or delayed allergy to similar drug and excipients of the investigate drug.

11. Pregnant, lactating female or subjects who refuse to use effective contraception during the study.

12. With a history of severe neurological or psychiatric illness.

13. Not suitable for this study as decided by the investigator.