AML Patients Bearing FLT3 Mutations Based on Peripheral Blast Clearance

Study Overview
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Brief Summary
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Prospective, multi-center, interventional, randomized, open clinical trial for the treatment of acute myeloid leukemia with FLT3 mutations customized upon the prognostic parameter PBC

Official Title
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A Phase 3, Prospective, Randomized Multi-center Intervention Trial of Early Intensification in AML Patients Bearing FLT3 Mutations Based on Peripheral Blast Clearance: A MYNERVA-GIMEMA Study

Conditions
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Acute Myeloid Leukemia With FLT3/ITD Mutation

Intervention / Treatment
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* Drug: Cytarabine
* Drug: Daunorubicin
* Drug: Midostaurin
* Drug: Cytarabine HD


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with de novo AML, untreated, newly diagnosed, according to WHO 2016 criteria Presence of a mutation of FLT3 gene, either ITD and/or TKD Adequate availability of diagnostic biologic material for full cytological, cytogenetic, genetic and immunophenotypic disease characterization according to ELN criteria. Presence of morphologically identifiable blasts on peripheral blood at diagnosis Presence of a Leukemia-associated aberrant immune-phenotype (LAIP) as assessed by MFC (multiparametric flow cytometry) at diagnosis Age between 18 and 65 years, included ECOG performance status 0-2 or disease-related reversible ECOG 3 score following adequate supportive care. Signed written informed consent according to ICH/EU/GCP and national local laws Exclusion Criteria: Diagnosis of acute promyelocytic leukemia Diagnosis of AML with t(8;21)(q22:q22)/RUNX1-RUNX1T1 and t(16;16)(p13:q22) or inversion of chromosome 16 (16)(p13q22)/CBFB-MYH11; in case of suspicion of CBF-related AML due to morphological and/or immunophenotypic features, specific FISH or molecular testing is strongly recommended in accordance with WHO criteria3,157 Patients with LVEF less than 45% (by echocardiogram or MUGA) Pre-existing, uncontrolled pathology such as heart failure (congestive/ischaemic, acute myocardial infarction within the post 3 months, untreatable arrhythmias, NYHA classes III and IV), sever liver disease with total bilirubin ≥2,5 x ULN and/or ALT>3 ULN (unless attributable to AML), acute or chronic pancreatitis, kidney function impairment with serum creatinine ≥2,5 (unless attributable to AML) and severe neuropsychiatric disorder that impairs the patient's ability to understand and sign the informed consent or to cope with the intended treatment plan. For altered liver, pancreas and kidney function tests, eligibility criteria can be reassessed at 24-96 hours, following the institution of adequate supportive measures. Uncontrolled bacterial or fungal infections QTc >470 msec on screening ECG (Fridericia's formula) A history of cancer that is not in remission phase following surgery and/or chemotherapy and/or radiotherapy with life expectancy < 1 year. Pregnancy declared by the patient herself. A pregnancy test is performed at diagnosis and, if applicable, before allogeneic HSCT . Female and male patients who are fertile must agree to use an effective form of contraception with their sexual partners from enrollment through 4 months after the end of treatment.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Standard clinical treatment<br>Patients will complete 3+7 + Midostaurin induction course. | Drug: Cytarabine<br>* 100 mg/m2/bid day 1-3 100 mg/m2/die day 4-7<br>Drug: Daunorubicin<br>* 60 mg/m2/die day 1-3<br>Drug: Midostaurin<br>* 50 mg/bid day 8-21<br>|
| Experimental: Experimental treatment<br>The experimental arm will provide 2 main modifications compared to standard: i) immediate switch to intensified induction with high-doses Cytarabine (on days 5, 6 and 7 of induction) ii) early allocation to high-risk disease category to be refined according to ELN stratification and post induction MRD status | Drug: Daunorubicin<br>* 60 mg/m2/die day 1-3<br>Drug: Midostaurin<br>* 50 mg/bid day 8-21<br>Drug: Cytarabine HD<br>* 100 mg/m2/bid day 1-3 100 mg/m2/die day 4 1.500 mg bid day 5-7<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event Free Survival | Improvement of outcome measured as event-free survival (EFS) in patients with FLT3+ acute myeloid leukemia who are predicted to have low chemosensitivity, as defined upon the biomarker peripheral blast clearance (PBC), following the application of an early intensification of overall treatment, both in induction (high-doses delivery) and in consolidation (allocation to allogeneic transplant) phase, compared with standard regimens | 2,5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events rate | Adverse events rate according to CTCAE criteria | 2,5 years | 
| Rate of death in aplasia | rate of death in aplasia | 2 months | 
| Neutrophil recovery | Median number of days for neutrophil recovery | 2 months | 
| platelet recovery | Median number of days for platelet recovery | 2 months | 
| CR rate | Complete remission rate after induction | 6 months | 
| DFS | Disease-free survival | 2 years | 
| OS | Overall survival | 2 years | 
| CIR | Cumulative incidence of relapse | 2 years | 
| MRD assessment | MRD negativity rate at the end of induction and consolidation | 6 months |