Clinical Study of Venetoclax Combined With CACAG Regimen in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

A Prospective,Randomized,and Comparative Study on the Efficacy of Venetoclax Combined With CACAG Regimen and BAT Regimen in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

The purpose of this study is to compare the efficacy and safety of venetoclax combined with CACAG regimen with BAT regimen in the treatment of relapsed/refractory acute myeloid leukemia.

Study Overview

• Status: Recruiting
• Conditions: Relapsed/Refractory Acute Myeloid Leukemia
• Intervention / Treatment: Drug: Azacytidine;Cytarabine;Aclacinomycin;Chidamide;Venetoclax;Granulocyte colony-stimulating factor; Drug: Best-Available Therapy(BAT) Regimen

Detailed Description

Despite advances in therapies for acute myeloid leukemia (AML) in the past decades, some patients still suffer from relapsed/refractory (R/R) disease, resulting in poor outcomes. With a median overall survival (OS) of 4-7 months under classic chemotherapy approaches, it is imperative to explore new treatment options.Accumulating research has demonstrated the importance of epigenetic modification in the pathogenesis of chemoresistance. Recent studies have shown that combining venetoclax with hypomethylating agents (HMAs) such as azacitidine, or low-dose cytarabine (LDAC) improves the response and survival rates in R/R AML patients. To enhance the response rate, we designed a regimen that combines chidamide, azacitidine, cytarabine, aclarubicin, and G-CSF with venetoclax (CACAG+VEN regimen) for the treatment of patients with R/R AML. In this study, we intend to compare the efficacy and safety of venetoclax combined with the CACAG regimen with Best-Available Therapy(BAT) regimen in the treatment of relapsed/refractory acute myeloid leukemia.

• Study Type: Interventional
• Enrollment (Estimated): 200
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Daihong Liu, doctor; Phone Number: +8613681171597; Email: daihongrm@163.com
• Study Contact Backup: Name: Liping Dou, Doctor; Phone Number: +8613681207138; Email: lipingruirui@163.com

Study Locations

• China
  • Beijing
    • Beijing, Beijing, China, 100853
      • Recruiting
      • Chinese PLA General Hospital
      • Contact: Daihong Liu, Doctor; Phone Number: 86-13681171597; Email: daihongrm@163.com
      • Contact: Liping Dou, Doctor; Phone Number: 86-13681207138; Email: lipingruirui@163.com
      • Principal Investigator: Daihong Liu, Doctor

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients who are able to understand and willing to sign the informed consent form (ICF).
• All patients should aged 14 to 75 years,no gender limitation.
• Patients with R/R AML, diagnosed in accordance with the 2021 edition of the CMA criteria
• Liver function: ALT and AST≤2.5 times the upper limit of normal ,bilirubin≤2 times the upper limit of normal;
• Renal function: creatinine ≤the upper limit of normal;
• Patients without any uncontrolled infections , without organ dysfunction or without severe mental illness;
• The score of Eastern Cooperative Oncology Group (ECOG) is 0-3,and the predicted survival ≥ 4 months.
• Patients without severe allergic constitution.

Exclusion Criteria:

• Patients with allergy or contraindication to the study drug;
• Female patients who are pregnant or breast-feeding.
• Patients with a known history of alcohol or drug addiction on the basis that there could be a higher risk of non-compliance to study treatment;
• Patients with mental illness or other states unable to comply with the protocol;
• Less than 6 weeks after surgical operation of important organs.
• Liver function: ALT and AST>2.5 times the upper limit of normal ,bilirubin>2 times the upper limit of normal;Renal function: creatinine >the upper limit of normal;
• The patient is not suitable for this clinical trial (poor compliance, substance abuse, etc.)

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: Venetoclax Combined With CACAG Regimen; Venetoclax combined with CACAG regimen for relapsed/refractory AML. Recipients were randomized and those entering the experimental group received azacytidine,cytarabine,aclacinomycin,chidamide,venetoclax and granulocyte colony-stimulating factor. Azacytidine was used as 75 mg/m2/day from day 1 to day 7.Cytarabine was used as 75-100 mg/m2 bid from day 1 to day 5. Aclacinomycin was used as 20 mg/day on days 1,3,5. Chidamide was used as 30 mg/day on days 1,4,8,11. Venetoclax was used as 400 mg/day from day 1 to day 14.Granulocyte colony-stimulating factor was used as 300 ug/day from day 0 until agranulocytosi recovery.	Drug: Azacytidine;Cytarabine;Aclacinomycin;Chidamide;Venetoclax;Granulocyte colony-stimulating factor; Azacytidine (75mg/m2/day, days 1 to 7).; Cytarabine (75-100mg/m2 q12h, days 1 to 5).; Aclacinomycin(20mg/day, days 1,3,5).; Chidamide(30mg/day , days 1,4,8,11).; Venetoclax (100mg on day 1,200mg on day 2,400mg on days 3-14).; Granulocyte colony stimulating factor (300 μg/day, day 0 until agranulocytosis recovery); Other Names: CACAG+VEN
Active Comparator: Best-Available Therapy(BAT) Regimen; BAT regimen for relapsed/refractory AML.Recipients were randomized and those entering this group received FLAG/CLAG/MAE/DCAG/HAA/HAD regimen.	Drug: Best-Available Therapy(BAT) Regimen; FLAG regimen:Fludarabine(30mg/m2,days 1-5)+Cytarabine (1-2g/m2 applied 4h after fludarabine, days 1 to 5)+Granulocyte colony-stimulating factor(300ug/day,days 0 to 5); CLAG regimen:Cladribine(5mg/2,days 1-5)+Cytarabine (1-2g/m2 applied 4h after fludarabine, days 1 to 5)+Granulocyte colony-stimulating factor(300ug/day,days 0 to 5); MAE regimen:Mitox(10mg/m2,days 1 to 5)+VP-16(100mg/m2,days 1 to 5)+Cytarabine (100-150mg/m2,days 1 to 7); DCAG regimen:Decitabine(20mg/m2,days 1 to 5)+Aclacinomycin(20mg/day on days 1,3,5)+Cytarabine (100mg q12h,days 1 to 5)+Granulocyte colony-stimulating factor(300 ug/day,day 0 until agranulocytosi recovery); HAA regimen:HHT(2mg/m2,days 1 to 7)+Aclacinomycin(20mg/day,days 1 to 7) and Cytarabine (100-200 mg/m2, days 1 to 5);; HAD regimen:HHT(2mg/m2,days 1 to 7)+Daunorubicin(45mg/m2/day,days 1 to 3)+Cytarabine (100-200 mg/m2,days 1 to 5).; Other Names: FLAG/CLAG/MAE/DCAG/HAA/HAD Regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR) after 1 course of treatment	Defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi), or partial response (PR).Biological characteristics exploratory studies were analyzed by single-cell sequencing and Atac-seq. Further, according to European LeukemiaNet risk group, we analyzed the outcomes of patients by molecular subtype as a sub-group analysis.	1 months after the start of study treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival (OS)	Defined as the time from joining the clinical study to death due to any cause.	180 days after study treatment
Complete Remission (CR) Rate after 1 course of treatment	Defined in accordance with the IWG Response Criteria in AML. Bone marrow blasts<5 percent; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions.	2 months after study treatment
Event-free survival	Defined as the time interval from treatment initiation to the occurrence of induction failure,relapse,or death,whichever came first.	180 days after study treatment
Treatment-related adverse events	Defined as adverse events that occurred from the first dose of study treatment to 30 days after the discontinuation of treatment.	From the first dose of study treatment to 30 days after the discontinuation of treatment
Early death	Defined as death within 30 days of chemotherapy.	Within 30 days of the start of the first course of treatment
Disease-free survival	Defined as the time interval from disease remission to the occurrence of relapse or death,whichever came first.	180 days after study treatment
Complete Remission (CR) Rate after 2 courses of treatment	Defined in accordance with the IWG Response Criteria in AML. Bone marrow blasts<5 percent; absence of blasts with Auer rods; absence of extramedullary disease; absolute neutrophil count >1.0 x 109/L (1000/µL); platelet count >100 x 109/L (100,000/µL); independence of red cell transfusions.	After two courses of chemotherapy (each course is 28 days)
Overall Response Rate (ORR) after 2 course of treatment	Defined as the percentage of participants achieving a best overall response of complete response (CR), CR with incomplete blood count recovery (CRi), or partial response (PR).Biological characteristics exploratory studies were analyzed by single-cell sequencing and Atac-seq. Further, according to European LeukemiaNet risk group, we analyzed the outcomes of patients by molecular subtype as a sub-group analysis.	After two courses of chemotherapy (each course is 28 days)
Rate of Minimal Residual Disease (MRD)-Negative Response	Percentage of participants who achieved MRD-negative response, defined as < 1 leukemia cell per 10,000 leukocytes as assessed by flow cytometry.	After two courses of chemotherapy (each course is 28 days)

Collaborators and Investigators

• Sponsor: Chinese PLA General Hospital
• Collaborators: The General Hospital of Western Theater Command; First Hospital of China Medical University; Yantai Yuhuangding Hospital; The General Hospital of Northern Theater Command; Air Force Medical Center; The 940th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army; The 960th Hospital of Joint Logistics Support Force of Chinese People's Liberation Army; People's Liberation Army (PLA) Strategic Support Force Characteristic Medical Center
• Investigators: Study Chair: Daihong Liu, doctor, Chinese PLA General Hospital

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): January 31, 2026
• Study Completion (Estimated): January 31, 2026

Study Registration Dates

• First Submitted: October 10, 2023
• First Submitted That Met QC Criteria: October 10, 2023
• First Posted (Actual): October 16, 2023

Study Record Updates

• Last Update Posted (Actual): October 16, 2023
• Last Update Submitted That Met QC Criteria: October 10, 2023
• Last Verified: February 1, 2023

More Information

Terms related to this study

• Keywords: Relapsed/Refractory Acute Myeloid Leukemia
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Leukemia; Leukemia, Myeloid; Leukemia, Myeloid, Acute; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Antiviral Agents; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Adjuvants, Immunologic; Antibiotics, Antineoplastic; Venetoclax; Lenograstim; Azacitidine; Cytarabine; Aclacinomycins
• Other Study ID Numbers: S2023-413-01

Drug and device information, study documents

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