CLAG+VEN vs CLAG in the Treatment of Relapsed/Refractory AML

A Multicenter, Prospective, Randomized Controlled Study Comparing the Efficacy and Safety of CLAG(Cladribine, Cytarabine and G-CSF) Combined With Venetoclax and CLAG in the Treatment of Relapsed/Refractory Acute Myeloid Leukemia

This is a multicenter, prospective, randomized controlled clinical study comparing the efficacy and safety of CLAG+VEN and CLAG regimens in relapsed/refractory(r/r) AML.

Study Overview

• Status: Not yet recruiting
• Conditions: Relapsed/Refractory AML
• Intervention / Treatment: Drug: Cytarabine; Drug: Venetoclax; Drug: Cladribine; Drug: G-CSF

Detailed Description

The efficacy and prognosis of relapsed/refractory(r/r) AML are very poor, and there is no standard chemotherapy regimen were defined for r/r AML. Cladribine, a purine analogue, exerts cytotoxic, proapoptotic, and antiproliferative effects on AML cells. Previous studies have confirmed the efficacy of cladribine in the treatment of r/r AML, with a response rate of 30-45%.Our previous experience has shown that CLAG in combination of venetoclax are effective with tolerable toxicity profiling. However, there is a lack of multicenter, prospective, randomized controlled trials to further confirm the results. Therefore, a clinical study is planned to evaluate the efficacy and safety of CLAG+VEN compared to CLAG in r/r AML who were eligible for intensive therapy.

• Study Type: Interventional
• Enrollment (Estimated): 172
• Phase: Phase 4

Contacts and Locations

• Study Contact: Name: Guopan Yu; Phone Number: +8615876559968; Email: yugpp@163.com
• Study Contact Backup: Name: Guopan Yu

Study Locations

• China
  • Guangdong
    • Guangzhou, Guangdong, China, 510515
      • Department of Hematology,Nanfang Hospital, Southern Medical University
      • Contact: Guopan Yu; Phone Number: +8615876559968; Email: yugpp@163.com

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Diagnosed of AML according to the World Health Organization (WHO) classification.
2. All patients should aged 18 to 65 years.
3. Diagnosed of relapsed and refractory AML, according to The guidelines for diagnosis and treatment of relapse /refractory acute myelogenous leukemia in China（2023）
4. Diagnostic criteria for relapsed AML: Leukemia cells reappear in the peripheral blood or primitive cells in the bone marrow ≥ 5% (excluding other reasons such as bone marrow regeneration after consolidation chemotherapy) after CR, or leukemia cell infiltration appears outside the marrow.
5. Diagnostic criteria for refractory AML: The newly diagnosed patients who failed to respond to two courses of standard treatment; Patients who relapsed within 12 months after consolidation intensive therapy; Patients who relapsed after 12 months and failed to respond to conventional chemotherapy; Patients with two or more recurrences; Patients with persistent extramedullary leukemia.
6. The score of Eastern Cooperative Oncology Group (ECOG) is 0-2.
7. Renal function: creatinine clearance rate ≥ 30ml/min.
8. Liver function: ALT<5 times normal value, bilirubin<3 times normal value.
9. Predicted survival ≥ 3 months.
10. Able to accept oral Venetoclax.
11. Sign an informed consent form and be able to understand and follow the procedures required by this protocol.

Exclusion Criteria:

1. Diagnosed of acute promyelocytic leukemia (AML-M3)
2. Patients with central nervous system (CNS) invasion.
3. Cardiac function < grade 2.
4. Known human immunodeficiency virus (HIV) infection.
5. Other clinically significant uncontrolled conditions, including but not limited to: a. uncontrolled or active systemic infections (viruses, bacteria, or fungi); b. Chronic hepatitis B virus (HBV) or hepatitis C virus (HCV) requiring treatment; c. Secondary tumors requiring active treatment.
6. Allergy to experimental drugs.
7. Pregnant and lactating women.
8. Patients who ineligible 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: CLAGV regimen; CLAG combined with venetoclax for relapsed/refractory AML. Patients were randomized and those entering the experimental group received cladribine, cytarabine, G-CSF and venetoclax. Venetoclax is administered orally at 400mg/d on days 2-8. When combination with P450 3A4 inhibitor, VEN should be reduced to 100-200mg/d and monitoring of VEN blood concentrations is recommended at qualified centers. Cladribine is administered intravenously at a dose of 5 mg/m2/d on days 1-5. Cytarabine is administered intravenously at a dose of 1g/m2/d on days 1-5, starting 2h after cladribine and maintained for more than 3h. The dose of G-CSF was 5ug/kg/d subcutaneously injected on days 0-5. Generally, starting 12 hours before the start of chemotherapy, if the absolute value of white blood cell count is ≥ 20×10^9/L, the use is suspended.For patients with FLT3 mutations, corresponding inhibitors such as sorafenib and gilteritinib can be combined.	Drug: Cytarabine; Given IV; Other Names: Ara-C; Drug: Venetoclax; Given PO; Other Names: Venclexta; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; Drug: G-CSF; Given SC; Other Names: Filgrastim; Granulocyte Colony-stimulating Factor
Active Comparator: CLAG regimen; CLAG regimen for relapsed/refractory AML. Patients were randomized and those entering the experimental group received cladribine, cytarabine, G-CSF. Cladribine is administered intravenously at a dose of 5 mg/m2/d on days 1-5. Cytarabine is administered intravenously at a dose of 1g/m2/d on days 1-5, starting 2h after cladribine and maintained for more than 3h. The dose of G-CSF was 5ug/kg/d subcutaneously injected on days 0-5. Generally, starting 12 hours before the start of chemotherapy, if the absolute value of white blood cell count is ≥ 20×10^9/L, the use is suspended.For patients with FLT3 mutations, corresponding inhibitors such as sorafenib and gilteritinib can be combined.	Drug: Cytarabine; Given IV; Other Names: Ara-C; Drug: Cladribine; Given IV; Other Names: 2-CdA; CdA; Drug: G-CSF; Given SC; Other Names: Filgrastim; Granulocyte Colony-stimulating Factor

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Composite Complete remission (cCR, CR+CRi)	Will compare composite complete remission(CR+CRi: complete response [CR] and complete response with incomplete blood count recovery [CRi]) between CLAGV regimen and CLAG regimen	At the end of Cycle 1 (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response rate (ORR)	Will compare ORR(completed remission[CR], completed remission with incomplete blood count recovery[CRi], and partial remission[PR]) rates between the study arms	At the end of Cycle 1 (each cycle is 28 days)
MRDneg CR rate	Will compare MRD-negative cCR rates between the study arms	At the end of Cycle 1 (each cycle is 28 days)
Overall Survival(OS)	Will compare OS between the study arms	1 year post treatment
Relapse free survival(RFS)	Will compare RFS between the study arms	1 year post treatment
Duration of completed response(DoR)	Will compare DoR between the study arms	1 year post treatment
Relapse rate	Will compare relapse rate between the study arms	1 year post treatment
Incidence of Adverse Events	Will use the CTCAE (National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events) version 5.0 for toxicity and adverse event reporting. Will describe the incidence of infection and treatment-related adverse events.	Duration of treatment, up to 1 year

Collaborators and Investigators

• Sponsor: Nanfang Hospital, Southern Medical University
• Collaborators: Guilin Medical University, China; Guangzhou First People's Hospital; Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University; First People's Hospital of Foshan; Shenzhen Second People's Hospital; Hainan General Hospital; Peking University Shenzhen Hospital; Dongguan People's Hospital; Guangzhou General Hospital of Guangzhou Military Command; Second Affiliated Hospital of Guangzhou Medical University; Southern Medical University, China; Huizhou Municipal Central Hospital; Shantou Central Hospital; Guangdong Second Provincial General Hospital; Zhongshan People's Hospital, Guangdong, China; Yuebei People's Hospital; ZhuHai Hospital; Jiangmen Central Hospital; Guangzhou Panyu Central Hospital; First Affiliated Hospital of Guangxi Medical University; LiuZhou People's Hospital; Shenzhen Hospital of Southern Medical University; Guangzhou No.12 People's Hospital; Central People's Hospital of Zhanjiang; Tungwah Hospital of Sun Yat-Sen University; Maoming People's Hospital; Affiliated Hospital of Guangdong Medical University; Foresea Life Insurance Guangzhou General Hospital
• Investigators: Principal Investigator: Guopan Yu, Nanfang Hospital, Southern Medical University

Study record dates

Study Major Dates

• Study Start (Estimated): February 1, 2025
• Primary Completion (Estimated): June 1, 2025
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: December 30, 2024
• First Submitted That Met QC Criteria: January 7, 2025
• First Posted (Actual): March 25, 2025

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 7, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Anti-Infective Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Antimetabolites, Antineoplastic; Antimetabolites; Antiviral Agents; Adjuvants, Immunologic; Lenograstim; Venetoclax; Cytarabine; Cladribine
• Other Study ID Numbers: NFEC-2024-639

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