Venetoclax and Azacitidine Combined With Chidamide (VAC) for the Treatment of Newly Diagnosed Acute Monocytic Leukemia

A Multicenter, Randomized, Controlled Clinical Trial of Venetoclax, Azacytidine Combined With Chidamide for the Treatment of Newly Diagnosed Acute Monocytic Leukemia Patients That Are Ineligible for Intensive Chemotherapy

This study is to investigate the therapeutic efficacy and side effect of venetoclax, azacytidine combined with chidamide for newly diagnosed acute monocytic leukemia patients that are ineligible for intensive chemotherapy

Study Overview

• Status: Recruiting
• Conditions: Newly Diagnosed; Acute Monocytic Leukemia
• Intervention / Treatment: Drug: Chidamide; Drug: Azacitidine; Drug: Venetoclax

Detailed Description

Acute myeloid leukemia (AML) is one of the most aggressive blood cancers, with a very low survival rate and few options for patients who are unable to undergo intensive chemotherapy. Venetoclax in combination with hypomethylation agents or cytarabine has been approved by the Food and Drug Administration (FDA) for the treatment of patients with newly diagnosed AML unfit for intensive chemotherapy. However, resistance to venetoclax can be acquired through the upregulation of anti-apoptotic proteins in the BCL2 family, such as myeloid cell leukaemia 1 (MCL1). MCL1 plays a critical role in cell apoptosis regulation and high expression of MCL1 is observed in acute monocytic leukemia (AML-M5) . Chidamide, a newly designed selective histone deacetylase inhibitor, resulted in a decrease in the protein level of MCL1. This study is to investigate the therapeutic efficacy and side effect of venetoclax, azacytidine combined with chidamide for newly diagnosed AML-M5 patients that are ineligible for intensive chemotherapy.

• Study Type: Interventional
• Enrollment (Estimated): 92
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Sheng-Li Xue, M. D.; Phone Number: 008651267781139; Email: slxue@suda.edu.cn

Study Locations

• China
  • Jiangsu
    • Suzhou, Jiangsu, China, 215006
      • Recruiting
      • The First Affliated Hospital of Soochow University
      • Contact: Sheng-Li Xue, M.D.; Phone Number: +86 512 6778 1139; Email: slxue@suda.edu.cn

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

Confirmation of acute monocytic leukemia( AML-M5) diagnosis by the French-American-British (FAB) Classification and/or characterized for expression of monocytic and myeloid differentiation markers, have a projected life expectancy of at least 12 weeks, previously untreated, and ineligible for treatment with intensive chemotherapy.

Patients must be considered ineligible for induction therapy defined by the following:

1. >= 60 years of age

2. >=18 to 59years of age with at least one of the following comorbidities:

   Any other comorbidity that the physician judges to be incompatible with intensive chemotherapy:

   (A)Eastern Cooperative Oncology Group (ECOG) performance status of 2 or 3. (B)Cardiac history of congestive heart failure requiring treatment or ejection fraction <= 50% or chronic stable angina.

   (C)Diffusing capacity of the lung for carbon monoxide (DLCO) <= 65% or forced expiratory volume during the first second (FEV1) <= 65%.

   (D)Creatinine clearance >= 30 mL/min to < 45 mL/min. (E)Moderate hepatic impairment with total bilirubin > 1.5 to <= 3.0 × upper limit of normal (ULN).

3. Must meet the laboratory requirements per the protocol.
4. Female participant must not be pregnant or breastfeeding and is not considering becoming pregnant or donating eggs during the study or for approximately 90 days after the last dose of study drug.
5. Female participants of childbearing potential must agree to use at least 1 protocol-specified method of birth control and male participants, if sexually active with female partner(s) of childbearing potential, must agree to practice the protocol-specified contraception.
6. Did not receive radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation within 4 weeks before enrollment;
7. Other comorbidities that are not suitable for intensive chemotherapy;
8. The patient refused to receive intensive chemotherapy;
9. Ability to understand and willing to sign the informed consent for this trial.

Exclusion Criteria:

1. Patients who are allergic to the study drug or drugs with similar chemical structures
2. Pregnant or lactating women, and women of childbearing age who do not want to practice effective methods of contraception
3. Active infection
4. Active bleeding
5. Patients with new thrombosis, embolism, cerebral hemorrhage, or other diseases or a medical history within one year before enrollment
6. Patients with mental disorders or other conditions whereby informed consent cannot be obtained and where the requirements of the study treatment and procedures cannot be met
7. Liver function abnormalities (total bilirubin > 1.5 times the upper limit of the normal range, ALT/AST > 2.5 times the upper limit of the normal range or patients with liver involvement whose ALT/AST > 1.5 times the upper limit of the normal range), or renal anomalies (serum creatinine > 1.5 times the upper limit of the normal value)
8. Patients with a history of clinically significant QTc interval prolongation (male > 450 ms; female > 470 ms), ventricular heart tachycardia and atrial fibrillation, II-degree heart block, myocardial infarction attack within one year before enrollment, and congestive heart failure, and patients with coronary heart disease who have clinical symptoms and requiring drug treatment
9. Urgery on the main organs within the past six weeks
10. Drug abuse or long-term alcohol abuse that would affect the evaluation results
11. Patients who have received organ transplants (excepting bone marrow transplantation)
12. Patients not suitable for the study according to the investigator's assessment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: VAC group; Chidamide 10mg orally daily for 7 days (d1-d7), AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is PR/NR, the patient needs to withdraw from the trial, If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patients need to withdraw from the trial. If the patients were fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patients needs to withdraw from the trial if progression or recurrence of the disease.	Drug: Chidamide; Chidamide 10mg orally daily for 7 days (d1-d7); Drug: Azacitidine; azacytidine 75mg/m2 daily for 7 days (d1-d7); Drug: Venetoclax; Venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28)
Active Comparator: VA group; AZA 75mg/m2 daily for 7 days (d1-d7) and VEN orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28); If the bone marrow assessment is CR/CRi/MLFS/PR/NR on the 21th-28th day in the first cycle, the second cycle of treatment will be started; If the bone marrow assessment is still PR/NR, the patient needs to enter VEN+AZA+Chidamide group. If the bone marrow assessment is CR/CRi/MLFS, the patient will start post-remission therapy. For post-remission therapy, if the patients ineligible for intensive chemotherapy, continue with the same regimen until progression or recurrence of the disease, and the patient needs to withdraw from the trial. If the patients fit for intensive chemotherapy, patients will receive consolidation chemotherapy with other regimens or transplantation, and the patient needs to withdraw from the trial if progression or recurrence of the disease.	Drug: Azacitidine; azacytidine 75mg/m2 daily for 7 days (d1-d7); Drug: Venetoclax; Venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Complete Remission Rate	The composite complete remission rate(complete remission plus complete remission with incomplete blood cell count recovery)	At the end of Cycle 1 or 2 (each cycle is 28 days)
Overall response rate (ORR)	The overall response (completed remission without minimal residual disease, completed remission with incomplete blood count recovery, morphologic leukemia-free state and partial remission)	At the end of Cycle 1 or 2 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Duration of Response (DOR)	It is measured the time from initial response to subsequent disease progression or relapse	1 year
Overall Survival (OS)	It is measured from the time of entry into this trial to the date of death from any cause; patients not known to have died at last follow-up are censored on the date they were last known to be alive	1 year
Progression-Free Survival (PFS)	It is measured from the time from randomization to progression or death	1 year
Adverse reactions in hematology	Record of adverse events in hematological system during and after VEN+AZA+Chidamide regimen induction (agranulocytosis days, PLT/RBC transfusion units)	At the end of Cycle 1 (each cycle is 28 days)
Nonhematological adverse reactions	Record of adverse events in other organs or systmes during and after VEN+AZA+Chidamide regimen induction (infection and organ injury)	At the end of Cycle 1 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: The First Affiliated Hospital of Soochow University
• Collaborators: Northern Jiangsu Province People's Hospital; The Second People's Hospital of Huai'an; First Affiliated Hospital Bengbu Medical College; Jining Medical University; Affiliated Hospital of Nantong University; Suzhou Hospital of Traditional Chinese Medicine; Taizhou University

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Estimated): September 30, 2024
• Study Completion (Estimated): September 30, 2025

Study Registration Dates

• First Submitted: September 30, 2022
• First Submitted That Met QC Criteria: September 30, 2022
• First Posted (Actual): October 4, 2022

Study Record Updates

• Last Update Posted (Estimated): November 9, 2023
• Last Update Submitted That Met QC Criteria: November 7, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Keywords: Venetoclax; Azacitidine; Chidamide
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Leukemia; Leukemia, Monocytic, Acute; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Venetoclax; Azacitidine
• Other Study ID Numbers: SZAMLM5

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