VAG Versus Standard Chemotherapy With FLT3 Inhibitor in Adult Patients With FLT3-Mutated AML

Phase 3Not Yet RecruitingNCT07407140

Institute of Hematology & Blood Diseases Hospital, China300 enrolled

Overview

This prospective, multicenter, randomized, open-label, controlled trial compares the efficacy and safety of two induction regimens in adults with newly diagnosed, FLT3-mutated AML who are eligible for intensive chemotherapy. Approximately 300 patients aged ≥14 years will be randomized 1:1 to receive either induction with the VAG regimen (Venetoclax, Azacitidine, and Gilteritinib) or with the standard "3+7" regimen (Cytarabine plus Daunorubicin/Idarubicin) with Gilteritinib. Patients in the experimental arm achieving complete remission will receive one additional cycle of the VAG regimen. Those who do not achieve remission after the first induction cycle will receive one cycle of VAG as re-induction, irrespective of initial assignment. Patients who enter remission will proceed to consolidation with three cycles of intermediate-dose cytarabine. During consolidation, Gilteritinib will be continuously given in the control arm, while in the experimental arm, it will be added only if FLT3 mutation is detected by NGS-based MRD testing prior to consolidation. Subsequently, maintenance therapy will be administered: the experimental arm will receive 6 cycles of VA (Venetoclax and Azacitidine), and the control arm will receive Gilteritinib for up to one year. Allogeneic hematopoietic stem cell transplantation is permitted for eligible intermediate- or high-risk patients in remission. The primary endpoint is Overall Survival (OS).

FLT3 mutations confer poor prognosis in AML, and resistance remains a challenge despite current FLT3 inhibitor-based therapies. Preclinical and early clinical data support the potent efficacy of the triple combination of Venetoclax, Azacitidine, and Gilteritinib (VAG). This study aims to determine if VAG induction is superior to standard "3+7" chemotherapy plus gilteritinib in fit, FLT3-mutated AML patients. The trial includes a VAG salvage strategy for non-responders and a stratified post-remission pathway for all responders.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Interventions

Gilteritinib + Azacitidine + VenetoclaxDRUG

Patients randomized to this arm receive the novel triplet combination as first-line induction therapy. Patients who achieve complete remission (CR) will receive one repeat cycle of the induction therapy.

Cytarabine + Daunorubicin (or Idarubicin) + GilteritinibDRUG

Patients randomized to this arm receive the standard "3+7" intensive chemotherapy plus gilteritinib as the control regimen.

Re-induction TherapyDRUG

Gilteritinib: 80 mg daily, days 1-28. Azacitidine: 75 mg/m²/day, days 1-7. Venetoclax: Ramp-up: 100 mg (day 1), 200 mg (day 2), 400 mg daily (days 3-14). If Day 14 marrow blasts \>5%, Venetoclax continues at 400 mg daily from days 14-21.

Consolidation TherapyDRUG

Applicable to: All patients achieving CRc (CR/CRh/CRi) following two cycles of induction in the experimental arm or one to two cycles in the control arm. Regimen: Intermediate-dose Cytarabine followed by Gilteritinib per group-specific criteria. Cytarabine (Both Arms): Age \<60 years: 2 g/m² IV q12h, Days 1-3. Age ≥60 years: 1 g/m² IV q12h, Days 1-3. Gilteritinib Addition (120 mg oral, Days 4-17): Control Arm: Administered routinely in all patients. Experimental Arm: Added only if an FLT3 mutation is detectable by NGS-based MRD testing prior to the start of each consolidation cycle.

Maintenance TherapyDRUG

Applicable to: All patients who have completed consolidation therapy. Experimental Arm: Adjusted-dose VA regimen for 6 cycles. Azacitidine: 75 mg/m²/day, Days 1-7. Venetoclax: 400 mg daily, Days 1-7. Control Arm: Gilteritinib monotherapy for up to 1 year. Gilteritinib: 120 mg daily, Days 1-365.

Eligibility

Sex: ALLMin age: 14 YearsMax age: 75 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Newly diagnosed AML (excluding CBF-AML and APL) or MDS/AML (with 10%-20% marrow blasts) per WHO 2022 or ICC criteria * Documented FLT3-ITD or FLT3-TKD mutation by PCR or NGS * Age ≥14 and \<75 years * Eligible for intensive chemotherapy * ECOG performance status 0-2 * Adequate organ function (liver, kidney, cardiac) * Written informed consent Exclusion Criteria: * Acute promyelocytic leukemia with PML-RARA * Core-binding factor AML (RUNX1-RUNX1T1 or CBFB-MYH11) * BCR-ABL positive AML * Prior induction chemotherapy for AML (hydroxyurea allowed) * Concurrent active malignancy requiring therapy * Active/symptomatic cardiac disease * Severe uncontrolled infection * Any condition deemed unsuitable by the investigator

Outcomes

Primary Outcomes

Overall Survival (OS)

Time frame: From randomization until death from any cause, assessed up to 3 years

Secondary Outcomes

Composite Complete Remission Rate

Time frame: After induction therapy (approximately 4-8 weeks)

Measurable residual disease-negative CRc rate by flow cytometry

Measurable residual disease-negative CRc rate by flow cytometry after every courses therapy

Time frame: At the time of achieving CRc

Measurable residual disease-negative CRc rate by NGS for FLT3-ITD

Measurable residual disease-negative CRc rate by NGS for FLT3-ITD after every courses therapy

Time frame: At the time of achieving CRc

Event-Free Survival (EFS)

Time frame: From randomization until treatment failure, relapse after CRc, death from any cause, or last follow-up, assessed up to 3 years

Relapse-Free Survival (RFS)

Time frame: From achievement of CRc until relapse, death, or last follow-up, assessed up to 3 years

30-day and 60-day mortality

Time frame: 30 and 60 days after start of induction therapy