AML Patients Bearing FLT3 Mutations Based on Peripheral Blast Clearance (AMELIORATE)

Gruppo Italiano Malattie EMatologiche dell'Adulto

Status and phase: Enrolling; Phase 3

Conditions: Acute Myeloid Leukemia With FLT3/ITD Mutation

Treatments: Drug: Cytarabine HD; Drug: Daunorubicin; Drug: Midostaurin; Drug: Cytarabine

Study type: Interventional

Funder types: Other

Identifiers

NCT04174612

AML1919

Details and patient eligibility

About

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

Enrollment: 172 estimated patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

1. Patients with de novo AML, untreated, newly diagnosed, according to WHO 2016 criteria
2. Presence of a mutation of FLT3 gene, either ITD and/or TKD
3. Adequate availability of diagnostic biologic material for full cytological, cytogenetic, genetic and immunophenotypic disease characterization according to ELN criteria.
4. Presence of morphologically identifiable blasts on peripheral blood at diagnosis
5. Presence of a Leukemia-associated aberrant immune-phenotype (LAIP) as assessed by MFC (multiparametric flow cytometry) at diagnosis
6. Age between 18 and 65 years, included
7. ECOG performance status 0-2 or disease-related reversible ECOG 3 score following adequate supportive care.
8. Signed written informed consent according to ICH/EU/GCP and national local laws

Exclusion criteria

1. Diagnosis of acute promyelocytic leukemia
2. 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
3. Patients with LVEF less than 45% (by echocardiogram or MUGA)
4. 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.
5. Uncontrolled bacterial or fungal infections
6. QTc >470 msec on screening ECG (Fridericia's formula)
7. A history of cancer that is not in remission phase following surgery and/or chemotherapy and/or radiotherapy with life expectancy < 1 year.
8. 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.

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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172 participants in 2 patient groups

Standard clinical treatment

Active Comparator group

Description:

Patients will complete "3+7" + Midostaurin induction course.

Treatment:

Drug: Midostaurin

Drug: Cytarabine

Drug: Daunorubicin

Experimental treatment

Experimental group

Description:

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

Treatment:

Drug: Cytarabine HD

Drug: Midostaurin

Drug: Daunorubicin