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

Primary Purpose

Acute Monocytic Leukemia, Newly Diagnosed

Status
Recruiting
Phase
Phase 2
Locations
China
Study Type
Interventional
Intervention
Chidamide
Azacitidine
Venetoclax
Sponsored by
The First Affiliated Hospital of Soochow University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Acute Monocytic Leukemia focused on measuring Chidamide, Azacitidine, Venetoclax

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • The First Affliated Hospital of Soochow UniversityRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Active Comparator

Arm Label

VAC group

VA group

Arm Description

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.

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.

Outcomes

Primary Outcome Measures

Composite Complete Remission Rate
The composite complete remission rate(complete remission plus complete remission with incomplete blood cell count recovery)
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)

Secondary Outcome Measures

Duration of Response (DOR)
It is measured the time from initial response to subsequent disease progression or relapse
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
Progression-Free Survival (PFS)
It is measured from the time from randomization to progression or death
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)
Nonhematological adverse reactions
Record of adverse events in other organs or systmes during and after VEN+AZA+Chidamide regimen induction (infection and organ injury)

Full Information

First Posted
September 30, 2022
Last Updated
October 3, 2022
Sponsor
The First Affiliated Hospital of Soochow University
Collaborators
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
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1. Study Identification

Unique Protocol Identification Number
NCT05566054
Brief Title
Venetoclax and Azacitidine Combined With Chidamide (VAC) for the Treatment of Newly Diagnosed Acute Monocytic Leukemia
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
Study Type
Interventional

2. Study Status

Record Verification Date
October 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2022 (Actual)
Primary Completion Date
September 30, 2024 (Anticipated)
Study Completion Date
September 30, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
The First Affiliated Hospital of Soochow University
Collaborators
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

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No

5. 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
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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Acute Monocytic Leukemia, Newly Diagnosed
Keywords
Chidamide, Azacitidine, Venetoclax

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
92 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
VAC group
Arm Type
Experimental
Arm Description
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.
Arm Title
VA group
Arm Type
Active Comparator
Arm Description
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.
Intervention Type
Drug
Intervention Name(s)
Chidamide
Intervention Description
Chidamide 10mg orally daily for 7 days (d1-d7)
Intervention Type
Drug
Intervention Name(s)
Azacitidine
Intervention Description
azacytidine 75mg/m2 daily for 7 days (d1-d7)
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Intervention Description
Venetoclax orally once daily (100 mg d1, 200 mg d2, 400 mg d3-28)
Primary Outcome Measure Information:
Title
Composite Complete Remission Rate
Description
The composite complete remission rate(complete remission plus complete remission with incomplete blood cell count recovery)
Time Frame
At the end of Cycle 1 or 2 (each cycle is 28 days)
Title
Overall response rate (ORR)
Description
The overall response (completed remission without minimal residual disease, completed remission with incomplete blood count recovery, morphologic leukemia-free state and partial remission)
Time Frame
At the end of Cycle 1 or 2 (each cycle is 28 days)
Secondary Outcome Measure Information:
Title
Duration of Response (DOR)
Description
It is measured the time from initial response to subsequent disease progression or relapse
Time Frame
1 year
Title
Overall Survival (OS)
Description
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
Time Frame
1 year
Title
Progression-Free Survival (PFS)
Description
It is measured from the time from randomization to progression or death
Time Frame
1 year
Title
Adverse reactions in hematology
Description
Record of adverse events in hematological system during and after VEN+AZA+Chidamide regimen induction (agranulocytosis days, PLT/RBC transfusion units)
Time Frame
At the end of Cycle 1 (each cycle is 28 days)
Title
Nonhematological adverse reactions
Description
Record of adverse events in other organs or systmes during and after VEN+AZA+Chidamide regimen induction (infection and organ injury)
Time Frame
At the end of Cycle 1 (each cycle is 28 days)

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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: >= 60 years of age >=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). Must meet the laboratory requirements per the protocol. 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. 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. Did not receive radiotherapy, chemotherapy, targeted therapy or hematopoietic stem cell transplantation within 4 weeks before enrollment; Other comorbidities that are not suitable for intensive chemotherapy; The patient refused to receive intensive chemotherapy; Ability to understand and willing to sign the informed consent for this trial. Exclusion Criteria: Patients who are allergic to the study drug or drugs with similar chemical structures Pregnant or lactating women, and women of childbearing age who do not want to practice effective methods of contraception Active infection Active bleeding Patients with new thrombosis, embolism, cerebral hemorrhage, or other diseases or a medical history within one year before enrollment 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 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) 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 Urgery on the main organs within the past six weeks Drug abuse or long-term alcohol abuse that would affect the evaluation results Patients who have received organ transplants (excepting bone marrow transplantation) Patients not suitable for the study according to the investigator's assessment
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Sheng-Li Xue, M. D.
Phone
008651267781139
Email
slxue@suda.edu.cn
Facility Information:
Facility Name
The First Affliated Hospital of Soochow University
City
Suzhou
State/Province
Jiangsu
ZIP/Postal Code
215006
Country
China
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sheng-Li Xue, M.D.
Phone
+86 512 6778 1139
Email
slxue@suda.edu.cn

12. IPD Sharing Statement

Plan to Share IPD
No

Learn more about this trial

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

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