Aclarubicin Plus With Azacitidine and Venetoclax in the Treatment of Acute Myeloid Leukemia

A Multicenter, Open-Label, Phase 1/2 Clinical Study of the Safety and Efficacy of Aclarubicin Combined With Azacitidine and Venetoclax in the Treatment of Acute Myeloid Leukemia

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Acute Myeloid Leukemia (AML); Refractory Acute Myeloid Leukemia (AML); Relapse Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Aclarubicin; Drug: Venetoclax; Drug: Azacitidine

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 112
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Yunxiang Zhang; Phone Number: +86-13564516004; Email: zyx12103@rjh.com.cn

Study Locations

• China
  • Shanghai, China
    • Tongren Hospital, Shanghai Jiao Tong University School of Medicine
    • Contact: Li Yang; Phone Number: +8618017280986; Email: 2512034560@qq.com
  • Shanghai, China
    • Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai
    • Contact: Yunxiang Zhang; Phone Number: +86-13564516004; Email: zyx12103@rjh.com.cn
  • Shanghai, China
    • Shanghai Jing'an District Beizhan Hospital
    • Contact: Zhanyun Liu; Phone Number: lzy7706@126.com
  • Shanghai, China
    • Shanghai Traditional Chinese Medicine Hospital
    • Contact: Yuanfei Mao; Email: morfycell@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Aclarubicin + Venetoclax + Azacitidine; Aclarubicin will be used in a dose escalation and dose expansion approach. Venetoclax and aclarubicin will be used in a fixed dose throughout the phases. Phase I dose-escalation: a standard "3+3" approach for aclarubicin. Phase II: Cohort A will enroll patients same as in phase I and Cohort B will enroll patients with relapsed/refractory AML after intensive chemotherapy. Aclarubicin will be used at the dose determined by the dose escalation.

Drug: Aclarubicin; Induction (Cycle1) Phase I starting dose 20mg/m^2 D1-D2 (dose group 1), 20mg/m2 D1-D3 (dose group 2), 20mg/m2 D1-D4 (dose group 3), ivgtt, Qd The Phase II dose was determined based on the Phase I results Consolidation (Cycle 2-6) Phase I starting dose 20mg/m^2 D1-D2 (dose group 1), 20mg/m2 D1-D3 (dose group 2), 20mg/m2 D1-D4 (dose group 3), ivgtt, Qd The Phase II dose was determined based on the Phase I results; Drug: Venetoclax; Cycle 1 (Induction) 100mg on day 1, 200mg on day 2, 400mg on days 3-14 Cycles 2-6 (Consolidation) 400 mg orally daily on days 1-7; Drug: Azacitidine; Cycle 1 (Induction) 75 mg/m^2 SC on days 1-7 of each cycle Cycles 2-6 (Consolidation) 75 mg/m^2 SC on days 1-7 of each cycle Cycles 7-18 (Maintenance) 50 mg/m^2 SC on days 1-5 of each cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose (MTD)	MTD for aclarubicin (primary outcome measure of phase I)	28 days after first dose of aclarubicin
Recommended Phase 2 Dose (RP2D)	RP2D for aclarubicin (primary outcome measure of phase I)	28 days after first dose of aclarubicin
Event-free survival (EFS)	primary outcome measure of phase II, cohort A	From date of enrollment until the date of induction treatment failure , relapse for patients who achieved induction treatment success, or death from any cause, whichever came first, assessed up to 24 months
Composite Complete Remission (CCR)	primary outcome measure of phase II, cohort B	Proportion of patients who achieved CR+CRi+CRh at the end of Cycle 2 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Complete Remission (CCR)	Preliminary efficacy assessment (secondary outcome measure of phase I). Proportion of patients who achieved CR+CRi+CRh.	Proportion of patients who achieved CR+CRi+CRh at the end of Cycle 2 (each cycle is 28 days)
Complete Remission Rate (CRR)	Preliminary efficacy assessment (secondary outcome measure of phase I). Proportion of patients who achieved CR.	Proportion of patients who achieved CR at the end of Cycle 2 (each cycle is 28 days)
Adverse Events	Number of participants with treatment-related adverse events as assessed by CTCAE v6.0	From enrollment through 28 days after the end of the last dose of aclarubicine

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Association between baseline genomic alterations and composite complete remission (CCR)	Baseline genomic alterations will be assessed using next-generation sequencing. Composite Complete Remission (CCR) will be evaluated according to standard response criteria, and associations with genomic alterations will be analyzed.	From baseline to first documented composite complete remission, assessed up to 24 weeks
Change in quality of life as measured by the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30) global health status score	Quality of life will be assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (EORTC QLQ-C30). The global health status score ranges from 0 to 100, with higher scores indicating better quality of life. Scores will be calculated according to the EORTC scoring manual and summarized as change from baseline.	From enrollment through 28 days after the end of the last dose of aclarubicine
Cancer-related fatigue as measured by the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue score	Cancer-related fatigue will be assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) Fatigue questionnaire. Scores are reported as T-scores standardized to a reference population, with higher scores indicating greater fatigue (worse outcome). Changes from baseline will be summarized.	From enrollment through 28 days after the end of the last dose of aclarubicine

Collaborators and Investigators

• Sponsor: Shanghai Jiao Tong University School of Medicine
• Collaborators: Washington University School of Medicine; Fred Hutchinson Cancer Center; Leiden University Medical Center
• Investigators: Principal Investigator: Junmin Li, Professor, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai

Study record dates

Study Major Dates

• Study Start (Estimated): March 15, 2026
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2028

Study Registration Dates

• First Submitted: March 12, 2026
• First Submitted That Met QC Criteria: March 17, 2026
• First Posted (Actual): March 20, 2026

Study Record Updates

• Last Update Posted (Actual): March 20, 2026
• Last Update Submitted That Met QC Criteria: March 17, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: acute myeloid leukemia; Aclarubicin; Azacitidine and Venetoclax; ineligible for intensive chemotherapy
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Hematologic Diseases; Leukemia, Myeloid; Leukemia; Hemic and Lymphatic Diseases; Leukemia, Myeloid, Acute; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Hydrocarbons; Hydrocarbons, Cyclic; Carbohydrates; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Polycyclic Compounds; Glycosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Anthracyclines; Naphthacenes; Aminoglycosides; Azacitidine; venetoclax; Aclarubicin
• Other Study ID Numbers: AVAIL 2025

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No