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

Официальное название

A Multicenter, Randomized, Controlled Trial of a Triple-Drug Regimen (Venetoclax, Azacitidine, Gilteritinib) Followed by Intensive Chemotherapy, Versus Standard Chemotherapy Plus Gilteritinib, in Fit Adults With Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia.

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат Gilteritinib + 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.
• Препарат Cytarabine + Daunorubicin (or Idarubicin) + Gilteritinib
  Patients randomized to this arm receive the standard "3+7" intensive chemotherapy plus gilteritinib as the control regimen.
• Препарат Re-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.
• Препарат Consolidation Therapy
  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 m
• Препарат Maintenance 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.

Первичные конечные точки

• Event-Free Survival (EFS) [Срок оценки: From randomization until treatment failure, relapse after CRc, death from any cause, or last follow-up, assessed up to 3 years]

Вторичные конечные точки (6)

• Composite Complete Remission Rate [Срок оценки: After induction therapy (approximately 4-8 weeks)]
• Measurable residual disease-negative CRc rate by flow cytometry [Срок оценки: At the time of achieving CRc]
• Measurable residual disease-negative CRc rate by NGS for FLT3-ITD [Срок оценки: At the time of achieving CRc]
• Relapse-Free Survival (RFS) [Срок оценки: From achievement of CRc until relapse, death, or last follow-up, assessed up to 3 years]
• 30-day and 60-day mortality [Срок оценки: 30 and 60 days after start of induction therapy]
• Overall Survival (OS) [Срок оценки: From randomization until death from any cause, assessed up to 3 years]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Список центров уточняется — проверьте первичный протокол.

Идентификаторы

NCT: NCT07407140 · IIT2026012

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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