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)

Overall Survival (OS) (Key Secondary)

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

Percentage of Participants With Complete Remission (CR) and Complete Remission With Incomplete Hematological Recovery (CRi) But With Adequate Blood Count Recovery Rate.

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

Percentage of Participants With Minimal Residual Disease (MRD) Negative Status

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)

Percentage of Participants With Minimal Residual Disease (MRD) Negative Status During Post-consolidation Phase

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)

Time to Measurable Residual Disease (MRD) Negativity by Flow Cytometry

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

Disease-free Survival (DFS)

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

Cumulative Incidence of Relapse (CIR)

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

Cumulative Incidence of Death (CID)

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

Time to CR or CRi With Adequate Blood Count Recovery

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

Time to Partial and Full Neutrophil Recovery

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

Time to Partial and Full Platelet Recovery

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

Plasma Concentrations for Midostaurin and Its Metabolites: CGP52421 and CGP62221 for Non-poor Metabolizers

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

AUC0-t: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

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

AUClast: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

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

Cmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

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

Time frame: 0 - 12 hrs

Tmax: Pharmacokinetic (PK) Parameter for Midostaurin and Its Metabolites: CGP52421 and CGP62221 at Cycle 1, Day 8

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

Total Score for Each Time Point for the Functional Assessment of Cancer Therapy-Leukemia (FACT-Leu)

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

Scores for Each Time Point for the EQ5D-5L (a Visual Analogue Scale (VAS))

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