The Efficacy of Triple Regimen in Newly Diagnosed AML Patients With FLT3 Mutation

Phase 2RecruitingNCT06561880

Institute of Hematology & Blood Diseases Hospital, China36 enrolled

Overview

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 dosage of the triple regimen and investigate its efficacy in newly diagnosed fit FLT3-mutated AML patients. Besides, this trial will provide evidence for treatment decisions based on measurable residual disease in patients with the triple regimen.

This stuay intends to conduct a multi-center, single-arm clinical study to explore the efficacy of the triple induction regimen consisting of Gilteritinib, Venetoclax, and Azacitidine in newly diagnosed FLT3 mutated AML patients who are suitable for intensive chemotherapy. The maximum dose of Gilteritinib that can be safely combined with Azacitidine and Venetoclax will be determined. Patients will receive 2 courses of a 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

Allocation

Purpose

TREATMENT

Masking

Interventions

GilteritinibDRUG

Induction therapy regimen(2 courses): triple regimen therapy: Azacitidine 75mg/m2/d d1-7; Venetoclax 100mg d1,200mg d2,400mg d3-28; Gilteritinib (as required at admission: 80 or 120mg) d1-28. dose-adjusted triple regimen therapy: Azacitidine 75mg/m2/d d1-5; Venetoclax 400mg d1-7; Gilteritinib (as required at admission: 80 or 120mg) d1-28. Patients with no remission after the first induction course will receive another course with triple regimen therapy; Patients with complete remission after the first induction course will receive another course of dose-adjusted triple regimen therapy.

CytarabineDRUG

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.

GilteritinibDRUG

Maintenance treatment (6 courses): dose-adjusted triple regimen therapy:Azacitidine 75mg/m2/d d1-5; Venetoclax 400mg d1-7; Gilteritinib (as required at admission: 80 or 120mg) d1-28.

Eligibility

Sex: ALLMin age: 14 Years

Medical Language ↔ Plain English

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.

Outcomes

Primary Outcomes

To determine the maximum tolerated dose of gilteritinib

The maximum dose of gilteritinib that can be safely combined with azacitidine and venetoclax

Time frame: up to 3 months after enrollment of the first participants

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.

Time frame: up to 2 years after the date of the last enrolled participants

Complete remission (CR)/CR with partial hematologic recovery (CRh)/CR with incomplete hematologic recovery (CRi) with negative MRD detected by flow cytometry.

The ratio of CR/CRh/CRi with negative MRD detected by flow cytometry after induction, consolidation, and maintenance therapy.

Time frame: up to 1 years after the date of the last enrolled participants

CR/CRh/CRi with negative MRD detected by NGS (next-generation sequencing)

The ratio of CR/CRh/CRi with negative MRD detected by NGS after induction,consolidation, and maintenance therapy.

Time frame: up to 1 years after the date of the last enrolled participants

Secondary Outcomes

CR/CRh/CRi rate

The ratio of patients achieved CR/CRh/CRi after two course of induction therapy

Time frame: up to 3 months after the date of the last enrolled participants

overall survival

The interval from the date of enrollment to the date of death or the date of last follow-up, , whichever occurred first.

Time frame: 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.

Time frame: 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

Time frame: Within 30 days of the date of the last enrolled participants

60-day mortality

Percentage of patients who died within 60 days from enrollment

Time frame: Within 60 days of the date of the last enrolled participants

The Efficacy of Triple Regimen in Newly Diagnosed AML Patients With FLT3 Mutation

Overview

Conditions

Interventions

Eligibility

Locations (1)

Outcomes

Primary Outcomes

Secondary Outcomes

Central Contacts