Prospective evaluation of response to treatment by analysis of measurable residual disease in younger adult patients (18-60 years) with acute myeloid leukemia (AML). The Backbone InterGroup (BIG)-2 umbrella trial from the Acute Leukemia French Intergroup (ALFA, FILO) - BIG2

Trial details

Who runs it

Centre Hospitalier Universitaire De Toulouse

Trial code

EU 2026-525759-96-00

Record updated

2026. október 23.

Original description

Primary Objectives: Sub-study 1 (FLT3-ITD+ without CBF, comparative): To determine whether the addition of quizartinib to induction chemotherapy (7+3) results in a significant improvement in MRD response after one cycle, as assessed by PCR-NGS, compared to midostaurin added to 7+3 in patients 18-60 years of age with newly diagnosed FLT3-ITD AML without CBF AML.Read full original descriptionShow less

Prospective evaluation of response to treatment by analysis of measurable residual disease in younger adult patients (18-60 years) with acute myeloid leukemia (AML). The Backbone InterGroup (BIG)-2 umbrella trial from the Acute Leukemia French Intergroup (ALFA, FILO) - BIG-2

Primary Objectives: Sub-study 1 (FLT3-ITD+ without CBF, comparative): To determine whether the addition of quizartinib to induction chemotherapy (7+3) results in a significant improvement in MRD response after one cycle, as assessed by PCR-NGS, compared to midostaurin added to 7+3 in patients 18-60 years of age with newly diagnosed FLT3-ITD AML without CBF AML.

Sub-study 2 (FLT3-ITD- salvage, comparative): To determine whether the addition of venetoclax to high-dose cytarabine (HDAC) results in a significant improvement in MRD response after one cycle, as assessed by multiparameter flow cytometry, compared to HDAC alone in patients 18 60 years of age with newly diagnosed FLT3 ITD negative AML (including CBF AML patients with FLT3 ITD) and with a suboptimal response to 7+3 induction (i.e., no response or CR/CRh/CRi with positive MFC MRD after one cycle of 7+3 induction).

Sub-study 3 (FLT3-ITD- responders, exploratory): To describe the effect of an MRD-guided program on overall survival (OS) in patients 18-60 years of age with newly diagnosed FLT3 ITD negative AML (including CBF AML patients with FLT3 ITD) and who achieved CR/CRh/CRi without MFC MRD after one cycle of 7+3 induction.

Main secondary objective: Sub-study 1 (FLT3-ITD+ without CBF, comparative): To determine whether the addition of Quizartinib to induction chemotherapy (7+3) and to consolidation chemotherapy (IDAC) results in a significant improvement in MRD response after two cycles (combined induction and consolidation), as assessed by FLT3 ITD PCR NGS, compared to the addition of Midostaurin in patients 18 60 years of age with newly diagnosed FLT3 ITD AML without CBF AML.

Inclusion: Age ≥ 18 years and < 61 years; Health insurance coverage; Sub-study 1 : Presence of FLT3-ITD activating mutation in bone marrow (allelic ratio ≥ 0.03); Sub-study 1 : Receiving standard 7+3 induction chemotherapy regimen as specified in the protocol; Sub-study 1: Serum electrolytes within the institution’s normal limits: potassium, calcium (total calcium, calcium corrected for serum albumin in case of hypoalbuminemia, or ionized calcium), and magnesium; Sub-study 2: Refractory (no response) or CR/CRh/CRi with positive MRD by MFC in bone marrow (≥ 0.1%) after one cycle of 7+3 induction; Sub-study 2: Eligible for a second cycle of intensive chemotherapy; Sub-study 3: CR/CRh/CRi without MRD by MFC in bone marrow (< 0.1% OR < LOD) after one cycle of 7+3 induction; Signed written informed consent; Newly diagnosed de novo AML, or secondary AML arising from a previously known myelodysplastic syndrome (MDS), or post cytotoxic therapy-related AML (AML-pCT), according to the 2022 WHO classification; No prior treatment for AML (with the exception of hydroxyurea) or for MDS (with the exception of hematopoietic growth factors); ECOG performance status ≤ 3; Eligible to induction chemotherapy; No contraindication to anthracyclines: decompensated or uncontrolled heart failure, recent myocardial infarction, current signs of cardiac impairment, uncontrolled arrhythmias, or left ventricular ejection fraction (LVEF) < 50%; Total bilirubin ≤ 2 x upper limit of normal (UNL), ASAT (SGOT) and ALAT (SGPT) ≤ 2.5 X UNL, creatinine < 150 µmol/l, unless AML-related values; Women of childbearing potential should use appropriate methods of contraception.

Exclusion: Patients with secondary AML arising from a previously known myeloproliferative neoplasm (MPN) according to the 2022 WHO classification; Sub-study 1: Prior treatment with quizartinib or other FLT3 inhibitors; Sub-study 1: Treatment with any strong or moderate CYP3A inducers within 2 weeks or 5 half-lives of randomization whichever is longer; Sub-study 2: Prior venetoclax exposure; Patients with t(9;22)(q34.1;q11.2)/BCR::ABL1 or previous Ph1+ disorder (chronic myelogenous leukemia); Sub-study 2: Uncontrolled infection such as sepsis, or multiple organ dysfunction syndrome, uncontrolled fever; Sub-study 2: Documented uncontrolled fungal infection (positive blood test and cultures); Severe psychiatric or organic disorder, supposed to be independent from AML, that would contraindicate treatment, including allogeneic HSCT; Prior cancer, if not stable for at least two years, except in-situ carcinoma and skin carcinoma; Uncontrolled severe infection at study entry; Patients with uncontroled HIV-1 and -2 infection, or active hepatitis virus B or C infection; Sub-study 1: Uncontrolled or significant cardiovascular disease, including any of the following: • Bradycardia < 50 beats per minute • QTcF interval >450 msec • Diagnosis of or suspicion of long QT syndrome (including family history of long QT syndrome) • Systolic blood pressure ≥180 mm Hg or diastolic blood pressure ≥110 mm Hg • History of clinically relevant ventricular arrhythmias (e.g., ventricular tachycardia, ventricular fibrillation, or torsade de pointes) • History of second (Mobitz II) or third-degree heart block (patients with pacemakers were eligible if they had no history of fainting or clinically relevant arrhythmias while using the pacemaker) • History of uncontrolled angina pectoris or myocardial infarction within 6 months before screening • History of New York Heart Association class 3 or 4 heart failure • Left ventricular ejection fraction ≤45% or less than the institutional lower limit of normal per multigated acquisition scan or echocardiogram done within 30 days before randomization • Complete left bundle branch block; Pregnant or lactating women; Sub-study 1: Patients with CBF-AML; Sub-study 1: Uncorrected Grade 3 or 4 hypokalemia, hypomagnesemia or hypocalcemia. Subjects with Grade 1 or 2 electrolyte abnormalities can be enrolled while electrolytes are being corrected; Sub-study 2: Patients with AML with FLT3-ITD mutation without CBF; Legal incapacity (patients under tutorship, curatorship or judicial protection); Sub-study 3: Patients with AML with FLT3-ITD mutation without CBF; Patients with acute promyelocytic leukemia (APL), as confirmed either by t(15;17) or by the presence of PML::RARA fusion transcripts; Any psychological, familial, social, or geographic reason that would compromise clinical follow up.

EU CTIS 2026-525759-96-00