The Efficacy of Triple Regimen in Newly Diagnosed AML Patients With FLT3 Mutation (FLT3AML-2024)

The Efficacy of a Triple Regimen Including Gilteritinib, Venetoclax, and Azacitidine in Newly Diagnosed Fit AML Patients With FLT3 Mutation

The FMS tyrosine kinase 3 (FLT3) gene mutation occurs in 30% of newly diagnosed AML patients, leading to a higher relapse rate and mortality rate. In the past, multi-drug combination chemotherapy regimens had limited efficacy in newly diagnosed AML patients with FLT3 mutations, especially in those with FLT3-ITD. However, the FLT3 inhibitors greatly improved the survival of AML patients with FLT3 mutations. Although several studies have focused on the effectiveness of FLT3 inhibitor combination therapy for FLT3-mutated AML, further studies are needed to determine the optimal regimen and dosage. A triple regimen consisting of Gilteritinib, Venetoclax, and Azacitidine had shown good efficacy in unfit newly diagnosed FLT3-mutated AML patients. This clinical trial aims to determine the optimal triple regimen and investigate its efficacy in newly diagnosed fit FLT3-mutated AML patients.

Study Overview

• Status: Recruiting
• Conditions: AML; FLT3 Gene Mutation
• Intervention / Treatment: Drug: Cytarabine; Drug: Venetoclax; Drug: Gilteritinib; Drug: Azacitadine (AZA)

Detailed Description

This stuay intends to conduct a clinical study to explore the efficacy and safety of the triple induction regimen consisting of Gilteritinib, Venetoclax, and Azacitidine in newly diagnosed FLT3 mutated AML patients who are suitable for intensive chemotherapy. Patients will receive 2 courses of triple regimen therapy for induction and those who achieved complete remission will receive 3 courses of intermediate-dose cytarabine for consolidation. After consolidation therapy, dose-adjusted triple regimen therapy will be applied for 6 courses as maintenance treatment. Bone marrow morphology and minimal residual disease detected by flow cytometry and next-generation sequencing will be monitored during the treatment to provide evidence for treatment decisions. Response and survival of patients will be recorded to evaluate the efficacy of the triple regimen.

• Study Type: Interventional
• Enrollment (Estimated): 66
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Hui Wei, Doctor; Phone Number: 13132507161; Email: weihui@ihcams.ac.cn

Study Locations

• China
  • Tianjin Municipality
    • Tianjin, Tianjin Municipality, China, 300020
      • Recruiting
      • Blood Diseases Hospital
      • Contact: hui wei, MD; Phone Number: 86-13132507161; Email: weihui@ihcams.ac.cn

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. MDS/AML patients WHO meet AML and ICC definitions according to WHO (2022) or ICC standards (10%-20% of bone marrow naive cells) and have FLT3-TKD or ITD mutations detected by PCR or second-generation sequencing.
2. Age ≥15 years old, male or female.
3. The physical status assessment (ECOG-PS) of the Eastern Oncology Collaboration group was 0-2 points.
4. Pass the requirements of the following laboratory tests (performed within 7 days before treatment) :

1) Total bilirubin ≤ 1.5 times the upper limit of normal value (same age); 2) AST and ALT≤ 2.5 times the upper limit of normal value (same age); 3) Blood creatinine < 2 times the upper limit of normal (same age); 4) Myocardial enzymes < 2 times the upper limit of normal (same age); 5) Echocardiography (ECHO) was performed to determine the ejection fraction of the heart within the normal range.

Exclusion Criteria:

1. Acute promyelocytic leukemia with PML-RARA fusion gene
2. Acute myeloid leukemia with RUNX1-RUNX1T1 or CBFB-MYH11 fusion gene
3. Acute myeloid leukemia with BCR-ABL fusion gene
4. Have treated patients (those who have previously received induction chemotherapy but can receive hydroxyurea down-cell therapy).
5. Concurrent malignant tumors of other organs (those requiring treatment).
6. Active heart disease, defined as one or more of the following:

1) A history of uncontrolled or symptomatic angina; 2) Myocardial infarction less than 6 months after enrollment; 3) Have a history of arrhythmia requiring drug treatment or severe clinical symptoms; 4) Uncontrolled or symptomatic congestive heart failure (> NYHA level 2); 5) The ejection fraction is lower than the lower limit of the normal range. 7. Serious infectious diseases (uncured tuberculosis, pulmonary aspergillosis). 8. Those who were not considered suitable for inclusion by the researchers.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Triple Regimen Induction of Arm1; Patients will receive induction with a triple regimen therapy: Azacitidine 75mg/m2/d d1-7; Gilteritinib: 120mg d1-14; Venetoclax: 100mg d1, 200mg d2, 400mg d3-14	Drug: Cytarabine; Consolidation therapy (3 courses): intermediate-dose cytarabine regimen :2g/m2 q12h d1-3, age < 60 years;1g/m2 q12h d1-3, age ≥60 years. If NGS detected FLT3 mutation before consolidation chemotherapy, gilteritinib will be added during the consolidation course at d4-17.; Other Names: Gilteritinib; Drug: Venetoclax; Venetoclax dose and schedule determined by arms and treatment phases; Drug: Gilteritinib; Gilteritinib 120mg schedule determined by arms or treatment phases; Drug: Azacitadine (AZA); Azacitidine 75mg/m2/d schedule determined by treatment phases
Experimental: Triple Regimen Induction of Arm2; Patients will receive induction with a triple regimen therapy: Azacitidine 75mg/m2/d d1-7; Gilteritinib: 120mg d1-14; Venetoclax: 100mg d1, 200mg d2, 400mg d3-7	Drug: Cytarabine; Consolidation therapy (3 courses): intermediate-dose cytarabine regimen :2g/m2 q12h d1-3, age < 60 years;1g/m2 q12h d1-3, age ≥60 years. If NGS detected FLT3 mutation before consolidation chemotherapy, gilteritinib will be added during the consolidation course at d4-17.; Other Names: Gilteritinib; Drug: Venetoclax; Venetoclax dose and schedule determined by arms and treatment phases; Drug: Gilteritinib; Gilteritinib 120mg schedule determined by arms or treatment phases; Drug: Azacitadine (AZA); Azacitidine 75mg/m2/d schedule determined by treatment phases
Experimental: Triple Regimen Induction of Arm3; Patients will receive induction with a triple regimen therapy: Azacitidine 75mg/m2/d d1-7; Gilteritinib: 120mg d1-7; Venetoclax: 100mg d1, 200mg d2, 400mg d3-7	Drug: Cytarabine; Consolidation therapy (3 courses): intermediate-dose cytarabine regimen :2g/m2 q12h d1-3, age < 60 years;1g/m2 q12h d1-3, age ≥60 years. If NGS detected FLT3 mutation before consolidation chemotherapy, gilteritinib will be added during the consolidation course at d4-17.; Other Names: Gilteritinib; Drug: Venetoclax; Venetoclax dose and schedule determined by arms and treatment phases; Drug: Gilteritinib; Gilteritinib 120mg schedule determined by arms or treatment phases; Drug: Azacitadine (AZA); Azacitidine 75mg/m2/d schedule determined by treatment phases

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Event-free survival (EFS)	The interval from the date of enrollment to the date of failed to achieve complete remission, the date of relapse, or the date of death, whichever occurred first.	up to 2 years after the date of the last enrolled participants
Composite Complete remission (CRc) rate	The ratio of patients achieved CRc（CR/CRh/CRi) after induction therapy	up to 3 months after the date of the last enrolled participants
Composite Complete remission (CRc) with negative MRD detected by flow cytometry.	The ratio of CRc with negative MRD detected by flow cytometry after induction, consolidation, and maintenance therapy.	up to 1 years after the date of the last enrolled participants
To determine the tolerated dose of triple regimens	The dose of gilteritinib and venetoclax that can be safely combined with azacitidine	up to 3 months after enrollment of the first participants

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
overall survival	The interval from the date of enrollment to the date of death or the date of last follow-up, , whichever occurred first.	up to 2 years after the date of the last enrolled participants
Relapse free survival	The interval from CR to the date of relapse, or the date of death, or the date of last follow-up, whichever occurred first. This outcome analyzes patients achieved CR in two courses of induction therapy.	up to 2 years after the date of the last enrolled participants
30-day mortality	Percentage of patients who died within 30 days from enrollment	Within 30 days of the date of the last enrolled participants
60-day mortality	Percentage of patients who died within 60 days from enrollment	Within 60 days of the date of the last enrolled participants
CRc with negative MRD detected by NGS (next-generation sequencing)	The ratio of CRc with negative MRD detected by NGS after induction,consolidation, and maintenance therapy	up to 1 years after the date of the last enrolled participants

Collaborators and Investigators

• Sponsor: Institute of Hematology & Blood Diseases Hospital, China
• Investigators: Principal Investigator: Hui Wei, doctor, Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College

Publications and helpful links

General Publications

• Wang ES, Goldberg AD, Tallman M, Walter RB, Karanes C, Sandhu K, Vigil CE, Collins R, Jain V, Stone RM. Crenolanib and Intensive Chemotherapy in Adults With Newly Diagnosed FLT3-Mutated AML. J Clin Oncol. 2024 May 20;42(15):1776-1787. doi: 10.1200/JCO.23.01061. Epub 2024 Feb 7.
• Department of Error. Lancet. 2023 Oct 14;402(10410):1328. doi: 10.1016/S0140-6736(23)02235-3. No abstract available.
• Knight TE, Edwards H, Meshinchi S, Taub JW, Ge Y. "FLipping" the Story: FLT3-Mutated Acute Myeloid Leukemia and the Evolving Role of FLT3 Inhibitors. Cancers (Basel). 2022 Jul 13;14(14):3398. doi: 10.3390/cancers14143398.

Study record dates

Study Major Dates

• Study Start (Actual): October 8, 2024
• Primary Completion (Estimated): September 1, 2026
• Study Completion (Estimated): August 31, 2027

Study Registration Dates

• First Submitted: August 8, 2024
• First Submitted That Met QC Criteria: August 15, 2024
• First Posted (Actual): August 20, 2024

Study Record Updates

• Last Update Posted (Actual): May 13, 2026
• Last Update Submitted That Met QC Criteria: May 10, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Nucleic Acids, Nucleotides, and Nucleosides; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Nucleosides; Arabinonucleosides; Cytarabine; venetoclax; gilteritinib
• Other Study ID Numbers: IIT2024055

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
• product manufactured in and exported from the U.S.: No