AML, Adult
Conditions
Brief summary
This is a multicenter, randomized, controlled, open-label phase III trial evaluating the efficacy and safety of the VAG regimen (azacitidine, venetoclax, and gilteritinib) compared with standard 3+7 chemotherapy (cytarabine plus daunorubicin or idarubicin) combined with gilteritinib in newly diagnosed, fit patients with FLT3-mutated acute myeloid leukemia (AML). A total of 300 patients aged ≥14 to \<75 years with FLT3-ITD or FLT3-TKD mutations will be enrolled and randomized 1:1 to the experimental or control arm, stratified by age (≤60 vs. \>60 years). The primary endpoint is event-free survival (EFS). Secondary endpoints include composite complete remission (CRc) rate, minimal residual disease (MRD) negativity rate by flow cytometry and NGS, overall survival (OS), relapse-free survival (RFS), and 30-day and 60-day mortality.
Detailed description
This study is designed to investigate whether the triplet combination of azacitidine (a hypomethylating agent), venetoclax (a BCL-2 inhibitor), and gilteritinib (a FLT3 inhibitor) as induction therapy improves outcomes compared to standard intensive chemotherapy plus gilteritinib in patients with newly diagnosed FLT3-mutated AML who are fit for intensive chemotherapy.
Interventions
DRUGGilteritinib + Azacitidine + Venetoclax
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.
DRUGCytarabine + Daunorubicin (or Idarubicin) + Gilteritinib
Patients randomized to this arm receive the standard "3+7" intensive chemotherapy plus gilteritinib as the control regimen.
DRUGRe-induction Therapy
Cytarabine 100 mg/m²/d continuous IV d1-7 or d1-5; Daunorubicin 60 mg/m²/d (or Idarubicin 12 mg/m²/d) IV d1-3 or d1-2; Gilteritinib 120mg d8-21 or d6-19.
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.
DRUGMaintenance Therapy
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.
Sponsors
Institute of Hematology & Blood Diseases Hospital, China
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
14 Years to 75 Years
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Event-Free Survival (EFS) | From randomization until treatment failure, relapse after CRc, death from any cause, or last follow-up, assessed up to 3 years |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Composite Complete Remission Rate | After induction therapy (approximately 4-8 weeks) | — |
| Measurable residual disease-negative CRc rate by flow cytometry | At the time of achieving CRc | Measurable residual disease-negative CRc rate by flow cytometry after every courses therapy |
| Measurable residual disease-negative CRc rate by NGS for FLT3-ITD | At the time of achieving CRc | Measurable residual disease-negative CRc rate by NGS for FLT3-ITD after every courses therapy |
| Relapse-Free Survival (RFS) | From achievement of CRc until relapse, death, or last follow-up, assessed up to 3 years | — |
| 30-day and 60-day mortality | 30 and 60 days after start of induction therapy | — |
| Overall Survival (OS) | From randomization until death from any cause, assessed up to 3 years | — |
Contacts
CONTACTHui Wei, MD
Outcome results
None listed