FLT3-ITD Targeted Therapy in Fit AML Patients

Gilteritinib in Combination With Azacitidine and Venetoclax Compared to Induction Chemotherapy "7+3" in Combination With a FLT3-inhibitor in Fit, Newly Diagnosed, FLT3-ITD Mutated Adult AML Patients: a Randomized Trial of the EORTC Leukemia Group and GIMEMA.

This international, multicenter, randomized (1:1), open-label phase II/III trial will evaluate the efficacy and safety of gilteritinib combined with azacitidine and venetoclax (experimental arm) versus standard "7+3" induction plus a FLT3inhibitor (quizartinib or midostaurin) (control arm) in newly diagnosed FLT3-ITD mutated AML patients eligible for intensive chemotherapy.

Newly diagnosed AML patients deemed fit by the investigator to receive intensive chemotherapy will be screened for FLT3-ITD mutation. Eligible patients will be randomized in a 1:1 ratio between experimental and control arms, stratified by age and WBC at diagnosis:

• Participants assigned to the experimental arm will receive a triplet regimen consisting of VEN, AZA, and gilteritinib, administered for up to 12 cycles. This will be followed by up to 12 additional cycles of AZA in combination with gilteritinib, and subsequently up to 12 cycles of gilteritinib monotherapy
• Participants in the control arm will be treated following the local standard of care, consisting of induction with '7+3', consolidation with high-dose cytarabine, and maintenance with a FLT3 inhibitor (midostaurin, quizartinib, or sorafenib) as per local practice.

Participants in the experimental arm with an available donor should proceed to HSCT based on the local investigator's judgement, but this should not occur prior to the end of cycle 2. For participants in the control group, HSCT is as per the local investigator's judgement, but recommended in first CR/CRi.

For patients with no available donor and not proceeding to HSCT, treatment in the experimental arm is recommended to continue for a minimum of 6 cycles before transitioning to maintenance treatment with AZA and gilteritinib.

Following HSCT, patients in the experimental arm will receive gilteritinib maintenance for up to 36 cycles and in the control arm, FLT3-inhibitor as per local standard of care (i.e., midostaurin, quizartinib or sorafenib).

Inclusion Criteria:

• Newly diagnosed AML cytopathologically confirmed according to the 5th WHO classification
• Age between 18 and 75 years
• FLT3-ITD mutation as per local IVDR-compliant testing. Positivity is defined as a FLT3-ITD / FLT3-wild type (WT) ratio of ≥ 0.05 (5%))
• Eligibility for standard induction chemotherapy
• ECOG PS ≤ 2
• WBC ≤25 x 10^9/L (hydroxyurea, leukapheresis or cytarabine in specific clinical circumstances, are allowed to meet this criterion. Please refer to Section 4.1.1 - Inclusion Criteria).
• Adequate hepatic function (as indicated by total serum bilirubin level ≤2.5 x the institutional upper limit of normal range (UNL), unless due to Gilbert's syndrome, hemolysis or the underlying leukemia approved by the investigator; aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels ≤3 x UNL)
• Adequate renal function as defined by an eGFR ≥ 30 mL/min according to the 2021 CKD-EPI equation

Main Exclusion Criteria:

• Acute promyelocytic leukemia (APL)
• BCR-ABL positive leukemia or Ph1-positive chronic myeloid leukemia
• History of myeloproliferative neoplasm (MPN), including myelofibrosis, essential thrombocythemia, polycythemia vera
• Active central nervous system involvement by AML
• Active, uncontrolled infection (viral, bacterial or fungal): an infection controlled with an approved or closely monitored antibiotic/antifungal treatment is allowed.
• HIV, HBV or HCV active infection
• Grade >3 CTCAE (v. 6) clinically relevant (as per local investigator) adverse events at the time of enrolment
• Prior treatment for myelodysplastic syndrome (MDS) with Venetoclax or hypomethylating agents (decitabine, azacitidine).
• Any prior AML therapies (except for emergency treatment with hydroxyurea or cytarabine for hyperleukocytosis) Note: Subjects who undergo diagnostic workup for APL and treatment with all-trans retinoic acid, but who are found not to have APL, are eligible (treatment with all-trans retinoic acid must be discontinued before starting induction chemotherapy).
• Any prior treatment with a FLT3 inhibitor
• Serious organ dysfunction as left ventricular ejection fraction <40%, FEV1, FVC, DLCO (diffusion capacity) <40% of predicted
• Cardiovascular disability status of New York Heart Association class ≥ 2
• Congenital long QT syndrome or QT Interval Corrected Using Fridericia's Formula (QTcF) >450 msec Note: repeat electrocardiograms after correction of electrolytes or discontinuation of QT prolonging medications are allowed to meet entry criteria. In cases where QTcF >450 msec is considered to be falsely increased due to inaccurate automated reading and not clinically significant (e.g. due to bundle branch block), patients are still eligible if cardiologist reviews and documents that QTcF is ≤ 450 msec when manually measured.
• Participant with a prior or concurrent malignancy or autoimmune disease requiring immunosuppressive therapy.

Note: diseases whose natural history or treatment is not anticipated to interfere with the safety or efficacy assessment of the investigational regimen may be included only after discussion with the 2467 medical monitor and the study coordinator.

• Consumed strong or moderate inducers of Cytochrome P450, family 3, subfamily A (CYP3A) or p-glycoprotein within 14 days of study enrolment or requiring treatment with such a medication during the trial.
• Inability to swallow and/or any gastrointestinal disorders, malabsorption or other abnormalities that would interfere with absorption of the oral study drug.
• Other life-threatening concurrent disease.