Acute myeloid leukemia Acute myeloid leukemia (AML) is a clonal hematopoietic cancer that disrupts normal hematopoiesis, ultimately leading to bone marrow failure and death. The annual incidence rate of AML is 4.1 per 100000 people in the US and is higher in patients older than 65 years. There has been a steady improvement in survival over the decades, more noticeably so in younger patients and in the last decade. Azacitidine and Venetoclax is now the standard treatment of newly diagnosed AML ineligible for intensive chemotherapy, while still facing the dilemma of relapse and refractory disease.

Anthracycline-based chemotherapeutics were wildly used in the treatment of fit AML patients. While the cardiovascular toxicity leading to morbidity and mortality limited the use of daunorubicin/idarubicin in unfit patients. Aclarubicin, also known as aclacinomycin A, is an anthracycline type of antibiotic with significant anti-cancer properties. Previous studies have shown that aclarubicin only induces histone eviction without causing DNA damage, and it stands out in pre-clinical models and clinical studies, as it potently kills AML cells. Meanwhile, aclarubicin lacks cardiotoxicity, and can be safely administered even after the maximum cumulative dose of either doxorubicin or idarubicin has been reached. CAG regimen, combined with low-dose cytarabine, aclarubicin and G-CSF has been widely used in China and Japan for treatment of AML.

The purpose of this study is to determine the maximum tolerated dose, safety and efficacy of aclarubicin combined with azacitidine and venetoclax for subjects with newly diagnosed and relapsed /refractory AML.

This will be a phase I/II, single-arm, open-label study. The study will have a phase I dose-escalation portion using a standard "3+3" approach to determine the MTD of aclarubicin in combination with established doses of azacitidine and venetoclax.

Phase I is open to patients with newly diagnosed AML who's not a candidate for, or refusal of intensive induction therapy. This will be followed by two parallel phase II expansion cohorts. Cohort A will enroll patients same as in phase I and Cohort B will enroll patients with relapsed/refractory AML after intensive chemotherapy.

The regimen consists of up to 6 cycles of the combination of azacitidine, venetoclax, and aclarubicin followed by maintenance azacitidine in none transplant cohort (up to 12 cycles). For patients eligible for allo-HCT, allo-HCT will be recommended, and the maintenance will be based on post-transplant schedule.

Inclusion Criteria:

1. Understand and voluntarily sign the informed consent form.

2. Age 18 or above.

3. Diagnosis (the diagnose is based on the 5th edition of the WHO classification of hematolymphoid tumors):

   1. Phase I cohort: Adults ≥18 years with newly diagnosed AML who's not a candidate for intensive chemotherapy (criteria include age ≥75, significant cardiac/pulmonary/hepatic/renal comorbidities, CGA assessment unfit for IC, etc.) or declines.
   2. Phase II cohort A: Adults ≥18 years with newly diagnosed AML who's not a candidate for intensive chemotherapy (criteria include age ≥75, significant cardiac/pulmonary/hepatic/renal comorbidities, CGA assessment unfit for IC, etc.) or declines.
   3. Phase II cohort B: Adults ≥18 years with relapsed/refractory AML after intensive chemotherapy (Exclude patients with FLT3 or IDH1/2 mutations who have not previously received targeted therapy).

4. Performance status < 3 (ECOG Scale).

5. Estimated survival ≥ 3 months.

6. White blood cell (WBC) count < 25 × 10^9 cells/L (hydroxyurea is permitted to control WBC count before treatment).

7. Adequate liver and renal function as defined by the following criteria:

   1. Total serum bilirubin < 2.5 x upper limit of normal (ULN), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the PI
   2. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) < 2.5 x ULN, unless due to the underlying leukemia approved by the PI
   3. Creatinine clearance ≥50 mL/min

8. Ability to swallow

9. Phase II Cohort B: Subjects have recovered from prior treatment toxicity to less than Grade 2 (per CTCAE v6.0), excluding the influence of the underlying disease. The following are excluded: alopecia, fatigue, hyperpigmentation, hypothyroidism stabilized with hormone replacement therapy, and peripheral neuropathy following chemotherapy.

10. Phase II Cohort B: Washout period from first dose of prior anti-cancer therapy

    1. at least 2 weeks after completion of cytotoxic chemotherapy
    2. at least 5 half-lives for non-cytotoxic drugs (if the 5 half-lives exceed 4 weeks, the washout period will still be calculated as 4 weeks). If the half-life is unclear, a washout period of >4 weeks will be considered
    3. at least 2 weeks after the first dose of anti-cancer traditional Chinese medicine.

11. Subjects of reproductive potential must use effective contraceptive measures from the time they sign the informed consent form until 6 months after the last dose of the trial medication. Furthermore, male subjects of reproductive potential must refrain from sperm donation from the time they sign the informed consent form until 6 months after the last dose of the trial medication.

Exclusion Criteria:

1. Prior therapies

   1. Phase I cohort: Patients with prior therapy are not eligible. Patients with a history of myeloproliferative disorders (MPNs), including primary myelofibrosis (PMF), polycythemia vera (PV), chronic myeloid leukemia (CML) excluding essential thrombocythemia (ET); or myelodysplasia-myeloproliferative neoplasms (MDS-MPNs), including chronic monocytic leukemia (CMML), atypical chronic myeloid leukemia (aCML), juvenile myelomonocytic leukemia (JMML), and acute promyelocytic leukemia (APL) are not eligible.

      Prior hydroxyurea or cytarabine given for purposes of cytoreduction is also allowed. Prior all trans-retinoic acid given for presumed acute promyelocytic leukemia is also allowed.

   2. Phase II cohort A: Same as for Phase I cohort.

   3. Phase II cohort B: Patients relapsed/refractory to prior lower intensity therapy for AML are not eligible. No restriction on number of prior therapies.

2. Patients suitable for and willing to receive intensive induction chemotherapy (for Phase I and Phase II cohort A).

3. Congenital long QT syndrome or QTcF >450 msec (male), >470 msec (female). Repeat EKGs after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria. In cases where QTcF >450/470 msec is considered to be falsely increased due to inaccurate automated reading and not clinically significant (e.g. due to bundle branch block), patients are still eligible if cardiologist reviews and documents that QTcF is ≤ 450 msec when manually measured.

4. Active serious infection not controlled by systemic antibiotics (e.g. persistent fever or lack of improvement despite antimicrobial treatment).

5. Active Grade III-V cardiac failure as defined by the New York Heart Association Criteria.

6. Active central nervous system leukemia, extramedullary AML (except liver/spleen/lymph nodes)

7. Known human immunodeficiency virus (HIV) seropositive. Known hepatitis B surface antigen seropositive or known or suspected active hepatitis C infection.

8. Patients who have received an allo-HCT within 60 days of first receiving study medication must discontinue all immunosuppressants during study treatment.

9. Patients who have previously received CAR-T therapy.

10. Subjects with malabsorption syndrome or other comorbidities that prevent them from swallowing capsules or taking medications via the enteral route.

11. Patients with a prior or concurrent malignancy whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the PI.

12. Treatment with any investigational antileukemic agents or chemotherapy agents in the last 7 days before study entry. Prior recent treatment with corticosteroids, hydroxyurea and/or cytarabine (given for cytoreduction) is permitted.

13. Pregnant /lactating women will not be eligible; women of childbearing potential should have a negative pregnancy test prior to entering on the study and be willing to practice methods of contraception throughout the study period and for at least 6 months after the last dose of study drugs. Women do not have childbearing potential if they have had a hysterectomy or are postmenopausal without menses for 6 months. In addition, men enrolled on this study should understand the risks to any sexual partner of childbearing potential and should practice an effective method of birth control throughout the study period and for at least 6 months after the last dose of study drugs.