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

Sponsor
The First Affiliated Hospital of Soochow University (Other)
Overall Status
Recruiting
CT.gov ID
NCT05566054
Collaborator
Jining Medical University (Other), The Second People's Hospital of Huai'an (Other), First Affiliated Hospital Bengbu Medical College (Other), Northern Jiangsu Province People's Hospital (Other), Affiliated Hospital of Nantong University (Other), Suzhou Hospital of Traditional Chinese Medicine (Other), Taizhou University (Other)
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Study Details

Study Description

Brief Summary

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

Condition or Disease Intervention/Treatment Phase
Phase 2

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 Design

Study Type:
Interventional
Anticipated Enrollment :
92 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date :
Mar 1, 2022
Anticipated Primary Completion Date :
Sep 30, 2024
Anticipated Study Completion Date :
Sep 30, 2025

Arms and Interventions

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)

Outcome Measures

Primary Outcome Measures

  1. Composite Complete Remission Rate [At the end of Cycle 1 or 2 (each cycle is 28 days)]

    The composite complete remission rate(complete remission plus complete remission with incomplete blood cell count recovery)

  2. Overall response rate (ORR) [At the end of Cycle 1 or 2 (each cycle is 28 days)]

    The overall response (completed remission without minimal residual disease, completed remission with incomplete blood count recovery, morphologic leukemia-free state and partial remission)

Secondary Outcome Measures

  1. Duration of Response (DOR) [1 year]

    It is measured the time from initial response to subsequent disease progression or relapse

  2. Overall Survival (OS) [1 year]

    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

  3. Progression-Free Survival (PFS) [1 year]

    It is measured from the time from randomization to progression or death

  4. Adverse reactions in hematology [At the end of Cycle 1 (each cycle is 28 days)]

    Record of adverse events in hematological system during and after VEN+AZA+Chidamide regimen induction (agranulocytosis days, PLT/RBC transfusion units)

  5. Nonhematological adverse reactions [At the end of Cycle 1 (each cycle is 28 days)]

    Record of adverse events in other organs or systmes during and after VEN+AZA+Chidamide regimen induction (infection and organ injury)

Eligibility Criteria

Criteria

Ages Eligible for Study:
18 Years and Older
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
No
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).

  1. Must meet the laboratory requirements per the protocol.

  2. 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.

  3. 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.

  4. Did not receive radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation within 4 weeks before enrollment;

  5. Other comorbidities that are not suitable for intensive chemotherapy;

  6. The patient refused to receive intensive chemotherapy;

  7. 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

Contacts and Locations

Locations

Site City State Country Postal Code
1 The First Affliated Hospital of Soochow University Suzhou Jiangsu China 215006

Sponsors and Collaborators

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

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.
Responsible Party:
Sheng-Li Xue, MD, Principal Investigator, The First Affiliated Hospital of Soochow University
ClinicalTrials.gov Identifier:
NCT05566054
Other Study ID Numbers:
  • SZAMLM5
First Posted:
Oct 4, 2022
Last Update Posted:
Oct 5, 2022
Last Verified:
Oct 1, 2022
Individual Participant Data (IPD) Sharing Statement:
No
Plan to Share IPD:
No
Studies a U.S. FDA-regulated Drug Product:
No
Studies a U.S. FDA-regulated Device Product:
No
Keywords provided by Sheng-Li Xue, MD, Principal Investigator, The First Affiliated Hospital of Soochow University
Additional relevant MeSH terms:

Study Results

No Results Posted as of Oct 5, 2022