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).
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
230
Cycle 1: 80 mg once daily orally on days 1-28. Cycle 2 - 12: 80mg once daily orally on days 1-28. Cycle 13 - 24: gilteritinib 120 mg once daily orally on days 1-28. Following HSCT, maintenance with gilteritinib (120 mg once daily orally on days 1-28) will be offered for up to 36 cycles and started between day 30 and 90 after hematopoietic stem-cell transplantation (HSCT).
Cycle 1: ramp-up from 100mg on day 1, 200 mg on day 2 and 400 mg on days 3 - 28. Cycle 2 - 12: venetoclax 400 mg once daily orally days 1-7.
Cycle 1: 75 mg/m² once daily subcutaneously on days 1-7. Cycle 2 -12: 75 mg/m² once daily subcutaneously on days 1-5. Cycle 13 - 24: 75 mg/m² once daily subcutaneously on days 1-5.
Phase II: Achievement of CR/CRi documented within 6 months from randomization, occurring prior to allografting and before initiation of any post-protocol treatments.
The European LeukemiaNet (ELN) 2022 criteria will be used to evaluate CR/CRi.
Time frame: Within 6 months from randomization
Phase III: Overall survival
Time frame: From baseline through study completion, an average of 7 years
Achievement of CR/CRi documented within 6 months from randomization, occurring prior to allografting and before initiation of any post-protocol treatments (for the phase III component of the trial only)
Time frame: Within 6 months from randomization
Overall survival (for the phase II component of the trial only)
Time frame: From baseline through study completion, an average of 7 years
Event-free survival
Event-free survival defined as the time between the date of randomization and the date of relapse, treatment failure or death, whichever occurs first
Time frame: From baseline through study completion, an average of 7 years
Incidence of adverse events
Time frame: From baseline through study completion, an average of 7 years
Deterioration from baseline by ≥10 points in global health status measured by EORTC QLQ-C30
Time frame: Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization
Deterioration from baseline by ≥10 points in physical functioning measured by EORTC QLQ-C30
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Local SOC is "7+3" + Midostaurin (100 mg) or Quizartinib (35.4 mg)
Time frame: Weeks 1, 2, 3, 4, 10 and month 6, 12 and 30 from randomization
Deterioration from baseline by ≥10 points in role functioning measured by EORTC QLQ-C30
Time frame: Weeks 1, 2, 3, 4, 10 and month 6, 12 and 30 from randomization
Deterioration from baseline by ≥10 points in fatigue measured by EORTC QLQ-C30
Time frame: Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization
Deterioration from baseline by ≥10 points in pain measured by EORTC QLQ-C30
Time frame: Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization
High burden of treatment ("Quite a bit" / "Very much") measured by item Q168 from IL471
Time frame: Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization
High burden of illness ("Quite a bit" / "Very much") measured by item Q46 from IL471
Time frame: Weeks 1, 2, 3, 4, 10, and month 6, 12, and 30 from randomization