Study to identify the most appropriate therapy for patients with Acute Myeloid Leukemia carrying FLT3 mutation, using the PBC biomarker to customize therapy.

Phase 3

Recruiting

Conditions: Acute Myeloid Leukemia (LMA) with FLT3 mutation

Registration Number: 2023-505901-17-00

Lead Sponsor: Fondazione Gimema Franco Mandelli Onlus, Fondazione Gimema Franco Mandelli Onlus

Brief Summary: The primary objective of the trial is the improvement of outcome measured as eventfree survival (EFS) in patients with FLT3+ acute myeloid leukemia who are predicted to have low chemosensitivity, by the measurement of “peripheral blast clearance (PBC)”, following the application of an early intensification of treatment, both in induction (high-doses delivery) and in consolidation (allocation to allogeneic transplant) phase, compared with standard regimens.

Detailed Description: Not available

Recruitment & Eligibility

Status: Ongoing, recruiting

Sex: Not specified

Target Recruitment: 172

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 TK

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.

Pre-existing HIV positive serology (i.e. already known before enrolment). The participation to the study will require serology testing for HIV positivity at baseline: in case of HIV positivity or refusal to perform HIV testing, the patient will be considered not eligible.

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.

Study & Design

Study Type: Not specified

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
The primary endpoint is to evaluate the event-free survival (EFS) at 2 years of an experimental intensified PBC-driven arm in comparison to a standard therapeutic regimen in patients with FLT3+ AML and low peripheral blood clearance (PBC) measured at day 4.		The primary endpoint is to evaluate the event-free survival (EFS) at 2 years of an experimental intensified PBC-driven arm in comparison to a standard therapeutic regimen in patients with FLT3+ AML and low peripheral blood clearance (PBC) measured at day 4.

Secondary Outcome Measures

Name	Time	Method
Feasibility and safety of PBC-driven treatment: 1. Adverse events rate according to CTCAE criteria according to PBC and treatment arm 2. Rate of deaths in aplasia as per ELN 2017 definition according to PBC and treatment arm 3. Days to neutrophils recovery after induction and consolidation cycles according to PBC and treatment arm 4. Days to platelets recovery after induction and consolidation cycles according to PBC and treatment arm		Feasibility and safety of PBC-driven treatment: 1. Adverse events rate according to CTCAE criteria according to PBC and treatment arm 2. Rate of deaths in aplasia as per ELN 2017 definition according to PBC and treatment arm 3. Days to neutrophils recovery after induction and consolidation cycles according to PBC and treatment arm 4. Days to platelets recovery after induction and consolidation cycles according to PBC and treatment arm
Efficacy, in lowPBC-patients, of PBC-driven treatmentaccording to treatment arm:1.CR rate as perELN2017after1st induction cycle 2.CR rate as perELN2017after2cycles 3.Disease-free surv. as per ELN2017 4.Overall surv. as per ELN2017 5.Cumulative incidence of relapse and Treatment-related mortality 6.MRD at pre-def. time-points as per ELN2017according to PBC and treatment arm 7.Actual rate of patients receiving allogeneic transplant in first CR and with active disease according to PBC and tx arm		Efficacy, in lowPBC-patients, of PBC-driven treatmentaccording to treatment arm:1.CR rate as perELN2017after1st induction cycle 2.CR rate as perELN2017after2cycles 3.Disease-free surv. as per ELN2017 4.Overall surv. as per ELN2017 5.Cumulative incidence of relapse and Treatment-related mortality 6.MRD at pre-def. time-points as per ELN2017according to PBC and treatment arm 7.Actual rate of patients receiving allogeneic transplant in first CR and with active disease according to PBC and tx arm
Evaluation of outcome for PBC-high patients treated per protocol (standard) and in comparison, with PBC-low treated as per randomization (standard vs experimental), and according to PBC and treatment arm: 1.CRrate as perELN2017after 1°induction cycle 2.CRrate as perELN2017after2cycles 3.DFS as per ELN2017 4.OS as per ELN2017 5.CIR and TRM 6. MRD at defined TPs as per ELN2017 7. actual rate of pz receiving allo HSCT in 1° CR and with active disease		Evaluation of outcome for PBC-high patients treated per protocol (standard) and in comparison, with PBC-low treated as per randomization (standard vs experimental), and according to PBC and treatment arm: 1.CRrate as perELN2017after 1°induction cycle 2.CRrate as perELN2017after2cycles 3.DFS as per ELN2017 4.OS as per ELN2017 5.CIR and TRM 6. MRD at defined TPs as per ELN2017 7. actual rate of pz receiving allo HSCT in 1° CR and with active disease

Trial Locations

Locations (38): Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
🇮🇹
Palermo, Italy
Azienda Ospedaliera Universitaria Citta' Della Salute E Della Scienza Di Torino
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Turin, Italy
Azienda USL IRCCS Di Reggio Emilia
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Reggio Emilia, Italy
Fondazione IRCCS Policlinico San Matteo
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Pavia, Italy
Azienda Ospedale-Universita Padova
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Padova, Italy
Careggi University Hospital
🇮🇹
Florence, Italy
Fondazione Policlinico Universitario Agostino Gemelli IRCCS
🇮🇹
Rome, Italy
IRCCS CROB
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Rionero in Vulture(PZ), Italy
Istituto Tumori Bari Giovanni Paolo II
🇮🇹
Bari, Italy
Grande Ospedale Metropolitano Bianchi Melacrino Morelli
🇮🇹
Reggio Calabria, Italy
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Azienda Ospedaliera Ospedali Riuniti Villa Sofia Cervello
🇮🇹Palermo, Italy
Antonino Mulè
Site contact
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segreteriadirezionegenerale@ospedaliriunitipalermo.it