A Global Study of the Efficacy and Safety of Midostaurin + Chemotherapy in Newly Diagnosed Patients With FLT3 Mutation Negative (FLT3-MN) Acute Myeloid Leukemia (AML)

EFS was defined as the time from randomization to failure to obtain a complete remission (CR) or Complete remission with incomplete hematologic recovery (CRi) with adequate blood count recovery in induction, relapse after CR or CRi with adequate blood count recovery or death due to any cause, whichever occurred first as assessed by the investigator.

Time frame: From date of Randomization up to approx. 30 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

The AUC from time zero to a measurable concentration sampling time (t) (mass x time x volume-1). Note: as the last sampling time was at 12 h, AUC0-12h was determined after the first dose, reported at Cycle 1, Day 8

Time frame: 0 - 12 hrs

Population: Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration.

The AUC from time zero to the last measurable concentration sampling time after the first dose reported at Cycle 1, Day 8

Time frame: 0 - 12 hrs

Population: Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration.

The maximum (peak) observed plasma drug concentration after the first dose administration reported at Cycle 1, Day 8

Time frame: 0 - 12 hrs

Population: Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration.

Cumulative Incidence of Death (CID) was defined for all participants achieving CR or CRi with adequate blood count recovery measured from the date of achievement of CR or CRi until the date of death due to any reason. Participants not known to have died were censored on the last contact date. Participants who experienced relapse were counted as a competing cause of failure.

Time frame: From date of CR or CRi with adequate blood count recovery up to approx. 30 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization. CID was only for participants who achieved CR or CRi with adequate blood count recovery.

Cumulative Incidence of Relapse (CIR) was defined for participants with CR or CRi with adequate blood count recovery and was the time from achieving the CR or CRi with adequate blood count recovery until the onset of relapse from CR or CRi with adequate blood recovery. Participants without relapse were censored at the last adequate response assessment. Participants who died without relapse were counted as a competing cause of failure.

Time frame: From date of CR or CRi with adequate blood count recovery up to approx. 30 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization. CIR was only for participants who achieved CR or CRi with adequate blood count recovery.

DFS as measured from the date of first CR or CRi with adequate blood count recovery to relapse or death due to any cause, whichever occurred first. Participants who did not relapse nor die were censored at the last adequate response assessment. Assessment was based on the IWG criteria for AML as per investigator assessment

Time frame: From date of CR or CRi with adequate blood count recovery up to approx. 30 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization. DFW was derived only for participants who reached CR or CRi with adequate blood count recovery in induction (during first 93 days).

OS was defined as the time from randomization to date of death due to any cause. Patients entered the survival follow-up phase once they completed the safety follow up period (30 days after the last dose of midostaurin/placebo) in case of induction failure or if they had relapsed during post-treatment follow-up. Patients were then contacted by telephone every 3 months +/- 2 weeks or had a visit to follow up on their survival status, per Kaplan-Meier estimates.

Time frame: Between randomization to date of death up to approx. 30 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

Assessment was based on the International Working Group (IWG) criteria for AML as per investigator assessment. CR: Bone marrow: \< 5% blasts no blasts with Auer rods; Peripheral blood: neutrophils ≥ 1.0 x 109/L platelets ≥ 100 x 109/L, no blasts; No evidence of extramedullary disease (such as central nervous system (CNS) or soft tissue involvement); Transfusion independent. CRi with adequate blood count recovery is defined as the following: Bone marrow \< 5% blasts no blasts with Auer rods Peripheral blood Neutrophils \>= 1.0 x 109/L and 50 x 109/L \<=platelets \< 100 x 109/L no blasts No evidence of extramedullary disease (such as CNS or soft tissue involvement).

Time frame: At maximum 93 days from induction therapy start

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

MRD- rate was defined as the rate of participants reaching MRD at any timepoint. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP). MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.

Time frame: from start of treatment up to end of post-consolidation (approximately 17 months)

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

MRD- rate was defined as the rate of participants reaching MRD at any timepoint during Post-consolidation phase. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP). MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.

Time frame: from start of post-consolidation to end of post-consolidation phase (up to 12 months)

Population: Full analysis in post-consolidation phase comprised of participants who entered post-consolidation phase

Serial pharmacokinetics (PK) samples were collected in Non-poor metabolizer participants to assess the plasma concentrations of midostaurin, CGP52421 and CGP62221.

Time frame: from Induction (IND) phase 0hr (predose) to Post-consolidation phase (POSTCONS) 12hr

Population: Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration for Non-poor metabolizers. PK samples were not collected in all timepoints of all patients and reported for Non-poor metabolizers only.

The EQ5D-5L questionnaire assesses 5 dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 response options (no problems, slight problems, moderate problems, severe problems and extreme problems) that reflect increasing levels of difficulty. The patient is asked to indicate his/her current health state by selecting the most appropriate level in each of the 5 dimensions. The questionnaire also included a Visual Analogue Scale (VAS), where the patient is asked to rate current health status on a scale of 0 to 100, with 0 being the worst imaginable health state.

Time frame: From date of Randomization up to approx. 18 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

Time to CR or CRi with adequate blood count recovery was defined as the time from randomization to CR or CRi with adequate blood count recovery whichever occurred first

Time frame: At maximum 93 days from induction therapy start

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

Time to MRD- is defined as time from randomization to first occurrence of MRD-. Participants with leukemic blasts below 0.1% were considered as MRD-negative based on leukemia-associated immunophenotype (LAIP). MRD was derived from bone marrow and blood data using cellular and molecular technologies and MRD status was measured using the flow cytometry assessments for LAIP irrespective of the investigator's overall clinical response assessment.

Time frame: From date of Randomization up to approx. 17 months

Population: Analysis set comprised all participants to whom study drug was assigned by randomization.

The time to neutrophil recovery was assessed for the following criteria: Partial neutrophil recovery: Number of days from start of treatment to the first day neutrophils ≥0.5 x 10\^9/L. Full neutrophil recovery: Number of days from start of treatment to the first day neutrophils ≥1.0 x 10\^9/L

Time frame: At maximum 93 days from induction therapy start

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

Time to platelet recovery was assessed for the following criteria: Partial platelet recovery: Number of days from start of treatment to the first day platelets ≥50 x 10\^9/L. Full platelet recovery: Number of days from start of treatment to the first day platelets ≥100 x 10\^9/L.

Time frame: At maximum 93 days from induction therapy start

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug concentration after single dose administration reported at Cycle 1, Day 8

Time frame: 0 - 12 hrs

Population: Pharmacokinetic analysis set-all (PAS-all) included all participants in the safety set who provided at least one evaluable PK concentration.

The total FACT-Leu score consists of 44 items with total scores ranging from 0 to 176. Higher scores indicate better health-related quality of life ( HRQoL). Negative changes from baseline indicate a worsening of HRQoL while positive changes indicate an improvement in HRQoL.

Time frame: From date of Randomization up to approx. 18 months

Population: Full analysis set comprised all participants to whom study drug was assigned by randomization.

On-treatment deaths were collected from start of treatment (FPFT) up to 30 days after study drug discontinuation, for a maximum duration of approx. 18 months. Randomized but not treated deaths were collected after randomization but before treatment with study drug. Post-treatment survival follow-up deaths were collected after the on-treatment period up to approx. 18 months. Participants who did not die during the on-treatment period and had not stopped study participation at the time of data cut-off (when study was terminated) were censored.

Time frame: Start of study treatment up to 30 days post-treatment for approx. 1 year, prior to study treatment up to LPLV, approx. 18 months

Population: Clinical Database Population: all enrolled participants