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.

Study Overview

• Status: Recruiting
• Conditions: Myeloid Malignancy; Relapsed/Refractory Acute Myeloid Leukaemia
• Intervention / Treatment: Drug: mitoxantrone hydrochloride liposome; Drug: Cytarabine; Drug: Venetoclax

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 72
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jie Jin, M.D.; Phone Number: +86 571-87236896; Email: jiej0503@163.com

Study Locations

• China
  • Zhejiang
    • Hangzhou, Zhejiang, China, 310003
      • Recruiting
      • The First Affiliated Hospital, Zhejiang University School of Medicine
      • Principal Investigator: Jie Jin, M.D.
      • Contact: Jie Jin; Phone Number: +86 571-87236896; Email: jiej0503@163.com
      • Sub-Investigator: Huafeng Wang, M.D.

Participation Criteria

Eligibility Criteria

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

Description

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.

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: MAV regimen; First induction: Mitoxantrone hydrochloride liposome injection, cytarabine combined with venetoclax. Second induction: Patients who achieved PR or MLFS after the first induction cycle will receive re-induction therapy with the same initial regimen. Consolidation: For patients with CR/CRi, allo-HSCT is recommended. For those currently ineligible for allo-HSCT, age- and fitness-adapted consolidation is advised. For intensive chemotherapy: Cytarabine (<60y: 2g/m² q12h d1-3; ≥60y: 1g/m² q12h d1-3) + Venetoclax 300mg d1-7, for 2-3 cycles. For non-intensive candidates, an appropriate regimen should be selected per investigator.

Drug: mitoxantrone hydrochloride liposome; Mitoxantrone hydrochloride liposome (30 mg/m^2) on day 1, every 4 weeks; Drug: Cytarabine; Cytarabine (100 mg/m^2 ) on day 1-7, every 4 weeks; Drug: Venetoclax; Venetoclax 100 mg on day 2，200 mg on day 3，400 mg on day 4-8, every 4 weeks

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite complete remission (CRc) rate	Complete remission plus complete remission with incomplete hematologic recovery (CR+CRi). Response is assessed according to the the European LeukemiaNet (ELN) 2022 criteria.	At the end of each cycle (each cycle is 28 days), up to 2 cycles

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall response rate (ORR)	CR+CRi+morphologic leukemia-free state+partial remission (CR+CRi+MLFS+PR). Response is assessed according to the the European LeukemiaNet (ELN) 2022 criteria.	At the end of each cycle (each cycle is 28 days), up to 2 cycles
Relapsed free survival (RFS)	Defined only for patients achieving CR or CRi. Measured from the date of achievement of remission until the date of hematologic relapse or death from any cause.	up to 12 months
Event free survival (EFS)	Defined for all patients in the study. Measured from day 1 of treatment to the date of treatment failure, hematologic relapse from CR/CRi or death from any cause, whichever occurs first.	up to 12 months
overall survival (OS)	Defined for all patients in the study. Measured from day 1 of treatment to the date of death from any cause.	up to 12 months
Rate of CR/CRi without minimal residual disease	Percentage of participants who achieve a CR MRD-/CRi MRD- as defined by investigators based on ELN 2022 criteria. MRD level is detected by flow cytometry and negtive MRD is defined as MRD value <0.1%.	At the end of each cycle (each cycle is 28 days), up to 2 cycles
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	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

Collaborators and Investigators

• Sponsor: First Affiliated Hospital of Zhejiang University
• Collaborators: CSPC Zhongnuo Pharmaceutical (Shijiazhuang) Co., Ltd.

Study record dates

Study Major Dates

• Study Start (Actual): July 5, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2027

Study Registration Dates

• First Submitted: September 29, 2024
• First Submitted That Met QC Criteria: September 29, 2024
• First Posted (Actual): October 1, 2024

Study Record Updates

• Last Update Posted (Estimated): September 16, 2025
• Last Update Submitted That Met QC Criteria: September 10, 2025
• Last Verified: September 1, 2025

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; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Arabinonucleosides; Cytarabine; venetoclax
• Other Study ID Numbers: CSPC-DED-AML-K16

Drug and device information, study documents

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