Liposomal Mitoxantrone Plus Azacitidine and Venetoclax in Newly Diagnosed Elderly or Unfit AML

A Phase Ib Study of Liposomal Mitoxantrone Combined With Azacitidine and Venetoclax in Newly Diagnosed Elderly or Unfit Patients With Acute Myeloid Leukemia

This prospective, open-label, multicenter phase Ib trial will evaluate the safety, tolerability, and RP2D of the VAM regimen (liposomal mitoxantrone + azacitidine [AZA] + venetoclax [VEN]) in elderly or unfit patients with newly diagnosed AML. A standard 3+3 dose escalation will enroll 12-30 patients, testing liposomal mitoxantrone at 8, 12, 16, and 20 mg/m². VEN duration (9 vs. 14 days) will be determined at the 8 mg/m² dose level, after which only liposomal mitoxantrone will be escalated while AZA and VEN will remain fixed.

Induction therapy will consist of up to two 28-day cycles. Responders achieving CR/CRi/MLFS will be eligible for up to 4 consolidation cycles (total ≤6 cycles), after which they will proceed to maintenance with either AZA+VEN or observation.

Study Overview

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

• Study Type: Interventional
• Enrollment (Estimated): 30
• Phase: Phase 1

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Subjects eligible for enrollment in this study must meet all of the following criteria:

  1. Diagnosis of acute myeloid leukemia (AML) according to the WHO 2022 or ICC criteria, excluding acute promyelocytic leukemia (APL).
  2. No prior therapy for AML, except hydroxyurea for the management of hyperleukocytosis.

  3. Meeting at least one of the following criteria:

     1. Age ≥ 75 years;
     2. Age 18-74 years with at least one of the following conditions precluding suitability for intensive chemotherapy:

     i. ECOG performance status 2-3; ii. Cardiac dysfunction with left ventricular ejection fraction (LVEF) ≤ 50%; iii. Pulmonary dysfunction with diffusing capacity of the lung for carbon monoxide (DLCO) ≤ 65% or forced expiratory volume in 1 second (FEV1) ≤ 65%; iv. Creatinine clearance 30-45 mL/min; v. Other major organ dysfunction or comorbidities that, in the investigator's judgment, render the patient unsuitable for intensive chemotherapy.

  4. ECOG performance status 0-3.
  5. Life expectancy ≥ 3 months.
  6. Patients of childbearing potential agree to use effective contraception during the treatment period and for at least 6 months after the last dose of study treatment.
  7. Voluntary written informed consent provided.

Exclusion Criteria:

• Subjects who meet any of the following criteria will not be eligible for enrollment in this study:

  1. Acute promyelocytic leukemia (APL)..
  2. Active central nervous system (CNS) leukemia.
  3. Prior targeted therapy or chemotherapy for AML, excluding hydroxyurea.
  4. Uncontrolled active infection.
  5. Uncontrolled cardiovascular disease: New York Heart Association (NYHA) class III-IV heart failure, myocardial infarction or unstable angina within 6 months before enrollment, or uncontrolled hypertension.
  6. Left ventricular ejection fraction (LVEF) < 40%.
  7. Concurrent active malignancy, except for cured non-melanoma skin cancer, carcinoma in situ of the cervix, or localized prostate cancer.
  8. Known hypersensitivity to the study drugs or their excipients.
  9. Pregnant or breastfeeding women.
  10. Any other condition that, in the investigator's judgment, would make the patient unsuitable for study participation.

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: Venetoclax, azacitidine combined with liposome mitoxantrone as induction regimen; The trial will employ a standard 3+3 dose escalation design, testing liposomal mitoxantrone at 8, 12, 16, and 20 mg/m². VEN duration (9 vs. 14 days) will be determined at the 8 mg/m² dose level, after which only liposomal mitoxantrone will be escalated while AZA and VEN will remain fixed. Venetoclax duration will be sequentially escalated (9 vs. 14 days), choosing the longest duration without dose-limiting toxicity (DLT) in 3-6 evaluable patients. The RP2D for liposomal mitoxantrone is the highest dose with ≤1 DLT in 6 patients; if DL4 is tolerated, RP2D = 20 mg/m² on day 1.

Drug: Liposome Mitoxantrone; Liposome Mitoxantrone: 8, 12, 16, and 20 mg/m², administered by intravenous drip (ivgtt) on day 1, every 4 weeks; Drug: Venetoclax; Venetoclax(9 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-9, administered orally (po), every 4 weeks Venetoclax(14 days): 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3-14, administered orally (po), every 4 weeks; Drug: Azacitidine; Azacitidine: 75 mg/m², administered subcutaneously (sc) on days 1-7, every 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose-Limiting Toxicity (DLT)	To evaluate the safety, tolerability, and RP2D of the VAM regimen in newly diagnosed elderly/unfit AML patients.	Cycle 1(up to 42 days)
Incidence of treatment-related adverse events	The safety of the drug was evaluated by NCI-CTC AE 5.0 standard which including hematologic and non-hematologic toxicity	From day 1 of treatment to 28 days after the last dose
Composite complete remission (CRc) rate	Proportion of patients with complete remission (CR), complete remission with incomplete hematologic recovery (CRi) or morphologic leukemia-free state (MLFS)	Up to approximately eight weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete remission (CR) rate	Proportion of patients with complete remission (CR)	Up to approximately eight weeks
Complete remission with incomplete hematologic recovery (CRi) rate	Proportion of patients with complete remission with incomplete hematologic recovery (CRi)	Up to approximately eight weeks
Morphologic leukemia-free state (MLFS) rate	Proportion of patients with morphologic leukemia-free state (MLFS)	Up to approximately eight weeks
Event-free survival (EFS)	It is defined as the time from the start of study treatment to the occurrence of induction failure or disease progression or death from any cause (whichever occurs first)	Up to approximately 5 years
Overall survival (OS)	It is defined as the time from the start of study treatment to the death from any cause	Up to approximately 5 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 5 years
Duration of Response (DoR)	It is defined as the time from the first documentation of CRc to relapse	Up to approximately 5 years
30-day postinduction mortality	It is defined as death from any cause within 30 days after the start of induction	Up to approximately 30 days
60-day postinduction mortality	t is defined as death from any cause within 60 days after the start of induction	Up to approximately 60 days
Measurable Residual Disease (MRD) negative rate by flow cytometry	Among those who have achieved CR/CRh/CRi after induction, proportion of patients who is MRD-negative by flow cytometry	Up to approximately eight weeks
Measurable Residual Disease (MRD) negative rate by molecular testing	Among those who have achieved CR/CRh/CRi after induction, proportion of patients who is MRD-negative by molecular testing	Up to approximately eight weeks

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China

Study record dates

Study Major Dates

• Study Start (Estimated): October 30, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): December 31, 2032

Study Registration Dates

• First Submitted: September 15, 2026
• First Submitted That Met QC Criteria: September 15, 2026
• First Posted (Actual): September 18, 2026

Study Record Updates

• Last Update Posted (Actual): September 18, 2026
• Last Update Submitted That Met QC Criteria: September 15, 2026
• Last Verified: August 1, 2026

More Information

Terms related to this study

• 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; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Aza Compounds; Nucleosides; Ribonucleosides; Azacitidine; venetoclax
• Other Study ID Numbers: IIT2026104

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