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

Official title

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

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 triple regimen and investigate its efficacy in newly diagnosed fit FLT3-mutated AML patients.

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.

Interventions

• Drug Venetoclax
  Venetoclax dose and schedule determined by arms and treatment phases
• 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.
• Drug Gilteritinib
  Gilteritinib 120mg schedule determined by arms or treatment phases
• Drug Azacitadine (AZA)
  Azacitidine 75mg/m2/d schedule determined by treatment phases

Primary outcome measures

• Composite Complete remission (CRc) rate [Time frame: up to 3 months after the date of the last enrolled participants]
• Composite Complete remission (CRc) with negative MRD detected by flow cytometry. [Time frame: up to 1 years after the date of the last enrolled participants]
• To determine the tolerated dose of triple regimens [Time frame: up to 3 months after enrollment of the first participants]
• Event-free survival (EFS) [Time frame: up to 2 years after the date of the last enrolled participants]

Secondary outcome measures (5)

• CRc with negative MRD detected by NGS (next-generation sequencing) [Time frame: up to 1 years after the date of the last enrolled participants]
• overall survival [Time frame: up to 2 years after the date of the last enrolled participants]
• Relapse free survival [Time frame: up to 2 years after the date of the last enrolled participants]
• 30-day mortality [Time frame: Within 30 days of the date of the last enrolled participants]
• 60-day mortality [Time frame: Within 60 days of the date of the last enrolled participants]

Eligibility criteria

Inclusion criteria

• 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.
• Age ≥15 years old, male or female.
• The physical status assessment (ECOG-PS) of the Eastern Oncology Collaboration group was 0-2 points.
• 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

• Acute promyelocytic leukemia with PML-RARA fusion gene
• Acute myeloid leukemia with RUNX1-RUNX1T1 or CBFB-MYH11 fusion gene
• Acute myeloid leukemia with BCR-ABL fusion gene
• Have treated patients (those who have previously received induction chemotherapy but can receive hydroxyurea down-cell therapy).
• Concurrent malignant tumors of other organs (those requiring treatment).
• 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.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

China · 1 center

• Blood Diseases Hospital — Tianjin

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. PMID 38324741
• Department of Error. Lancet. 2023 Oct 14;402(10410):1328. doi: 10.1016/S0140-6736(23)02235-3. No abstract available. PMID 37838437
• 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. PMID 35884458

Identifiers

NCT: NCT06561880 · IIT2024055

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗