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)

Study Overview
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Brief Summary
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The purpose of this study was to confirm the preliminary evidence from early clinical trials that midostaurin may provide clinical benefit not only to AML patients with the FLT3-mutations but also in FLT3-MN (SR<0.05) AML (FLT3 mutant to wild type signal ratio below the 0.05 clinical cut-off). This study evaluated the efficacy and safety of midostaurin in combination with daunorubicin or idarubicin and cytarabine for induction and intermediate-dose cytarabine for consolidation, and midostaurin single agent post-consolidation therapy in newly diagnosed patients with FLT3-MN (SR<0.05) AML.

Detailed Description
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This was a multi-center, multinational, randomized, double-blind Phase III study using a group sequential design. Subjects were stratified according to age (<60 vs. ≥ 60 years). Subjects within each stratum were randomized in a 1:1 ratio into one of two treatment arms: Midostaurin + chemotherapy 'or' Placebo + chemotherapy. The study consisted of the following phases: Screening/randomization phase: Subjects had to sign informed consent form before screening for enrollment. Subjects started chemotherapy at day 1 and were randomized at day 8. Induction phase: All subjects received at least one cycle (28 days) of induction therapy with continuous infusion cytarabine (D1 - D7) and daunorubicin or idarubicin (D1 - D3) (induction 1). Subjects who did not achieve CR or CRi with adequate blood count recovery after Induction 1 received a second cycle with intermediate-dose cytarabine (D1 - D3) and daunorubicin or idarubicin (D1 - D3) (induction 2). Subjects who did not achieve CR or CRi with adequate blood recovery after induction 2 discontinued study treatment and were followed for survival. Consolidation phase: Subjects who achieved CR or CRi with adequate blood count recovery after induction with one or two cycles of induction proceeded to consolidation therapy with either 3 or 4 cycles respectively of intermediate-dose cytarabine (D1 - D3), or to Hematopoietic Stem Cells Transplantation (HSCT) with or without preceding consolidation cycles. Post-consolidation phase: Subjects who maintained CR or CRi with adequate blood count recovery at the end of the consolidation phase received 12 cycles (28 days/cycle) of continuous therapy with midostaurin or placebo twice daily at 50 mg. Subjects who underwent HSCT after achieving CR or CRi with adequate blood count recovery received midostaurin or placebo twice daily 50 mg post-transplant therapy, continuously, for up to 12 cycles (28 days/cycle). Post HSCT post-consolidation therapy began >30 days but not later than 100 days following HSCT. Follow-up phase: All enrolled subjects were followed through the treatment period and until relapse/treatment failure, thereafter for start of new line of therapy and survival.

Official Title
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A Phase III, Randomized, Double-blind Study of Chemotherapy With Daunorubicin or Idarubicin and Cytarabine for Induction and Intermediate Dose Cytarabine for Consolidation Plus Midostaurin (PKC412) or Chemotherapy Plus Placebo in Newly Diagnosed Patients With FLT-3 Mutation Negative Acute Myeloid Leukemia (AML)

Conditions
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Acute Myeloid Leukemia (AML)

Intervention / Treatment
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* Drug: Midostaurin
* Drug: Placebo
* Drug: Chemotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of AML (≥20% blasts in the bone marrow based on WHO 2016 classification). Patients with APL with PML-RARA are not eligible. Suitability for intensive induction chemotherapy in the judgment of the investigator Documented absence of an ITD and TKD activating mutation at codons D835 and I836 in the FLT3 gene, as determined by analysis in a Novartis designated laboratory using a validated clinical trial assay with clinical cutoff of 0.05 mutant to wild type signal ratio Age ≥18 years Laboratory values that indicate adequate organ function assessed locally at the screening visit Exclusion Criteria: Central nervous system (CNS) leukemia Therapy-related secondary AML Isolated extramedullary leukemia Prior therapy for leukemia or myelodysplasia AML after antecedent myelodysplasia (MDS) with prior cytotoxic treatment (e.g., azacytidine or decitabine) Prior treatment with a FLT3 inhibitor (e.g., midostaurin, quizartinib, sorafenib)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Midostaurin + chemotherapy<br>Participants received Midostaurin in Induction 50mg twice daily on Day 8 until 48 hrs before start of next cycle. During Induction 2 and consolidation 50mg twice daily on Day 4 until 48 hrs before start of next cycle. During post-consolidation 50mg twice daily for 28 consecutive days of each 28-day treatment cycle up to 12 cycles. For participants who could not tolerate the protocol-specified dosing schedule, dose interruptions and/or reductions were either recommended or mandated allowing participants to continue the study treatment. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation. | Drug: Midostaurin<br>* Midostaurin was provided as 25 mg capsules 8PC, was supplied as double-blind in blister packs and taken orally.<br>* Other names: PKC412;Drug: Chemotherapy<br>* Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v.<br>|
| Placebo Comparator: Placebo + chemotherapy<br>Participants received matching placebo to midostaurin with same dose, plus chemotherapy. Chemotherapy consisted of daunorubicin or idarubicin and cytarabine for induction and intermediate dose cytarabine for consolidation | Drug: Placebo<br>* Placebo was provided as 25 mg soft gelatin capsules 8PC, was supplied as double-blind in blister packs and taken orally.<br>Drug: Chemotherapy<br>* Along with the study drug/placebo, chemotherapy was given as well: either Daunorubicin or Idarubicin and Cytarabine - all taken by i.v.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival (EFS) | 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. | From date of Randomization up to approx. 30 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | 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). | 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. | 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. | 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. | 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 | 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. | 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. | 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 | 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 | 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. | 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. | 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 | 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 | 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 | 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 | 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. | 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. | From date of Randomization up to approx. 18 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Newly diagnosed FLT3-mutation negative, PKC412, midostaurin, cytarabine, daunorubicin, idarubicin, acute myeloid leukemia, AML, FLT3-MN (SR<0.05), combination treatment, induction failure, event free survival, EFS, minimal residual disease