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

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ClinicalTrials.gov Identifier: NCT04174612
Recruitment Status : Recruiting
First Posted : November 22, 2019
Last Update Posted : September 18, 2020
Sponsor:
Information provided by (Responsible Party):
Gruppo Italiano Malattie EMatologiche dell'Adulto

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

Condition or disease Intervention/treatment Phase
Acute Myeloid Leukemia With FLT3/ITD Mutation Drug: Cytarabine Drug: Daunorubicin Drug: Midostaurin Drug: Cytarabine HD Phase 3

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 172 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Actual Study Start Date : April 24, 2020
Estimated Primary Completion Date : February 1, 2022
Estimated Study Completion Date : August 1, 2025


Arm Intervention/treatment
Active Comparator: Standard clinical treatment
Patients will complete "3+7" + Midostaurin induction course.
Drug: Cytarabine
100 mg/m2/bid day 1-3 100 mg/m2/die day 4-7

Drug: Daunorubicin
60 mg/m2/die day 1-3

Drug: Midostaurin
50 mg/bid day 8-21

Experimental: Experimental treatment

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
60 mg/m2/die day 1-3

Drug: Midostaurin
50 mg/bid day 8-21

Drug: Cytarabine HD
100 mg/m2/bid day 1-3 100 mg/m2/die day 4 1.500 mg bid day 5-7




Primary Outcome Measures :
  1. Event Free Survival [ Time Frame: 2,5 years ]
    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


Secondary Outcome Measures :
  1. Adverse events rate [ Time Frame: 2,5 years ]
    Adverse events rate according to CTCAE criteria

  2. Rate of death in aplasia [ Time Frame: 2 months ]
    rate of death in aplasia

  3. Neutrophil recovery [ Time Frame: 2 months ]
    Median number of days for neutrophil recovery

  4. platelet recovery [ Time Frame: 2 months ]
    Median number of days for platelet recovery

  5. CR rate [ Time Frame: 6 months ]
    Complete remission rate after induction

  6. DFS [ Time Frame: 2 years ]
    Disease-free survival

  7. OS [ Time Frame: 2 years ]
    Overall survival

  8. CIR [ Time Frame: 2 years ]
    Cumulative incidence of relapse

  9. MRD assessment [ Time Frame: 6 months ]
    MRD negativity rate at the end of induction and consolidation



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Ages Eligible for Study:   18 Years to 65 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04174612


Contacts
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Contact: Paola Fazi 0670390528 p.fazi@gimema.it
Contact: Enrico Crea 0670390514 e.crea@gimema.it

Locations
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Italy
Aou Careggi- Sod Ematologia Recruiting
Firenze, Italy
Contact: Vannucchi         
Principal Investigator: Alessandro Vannucchi         
Sponsors and Collaborators
Gruppo Italiano Malattie EMatologiche dell'Adulto
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Responsible Party: Gruppo Italiano Malattie EMatologiche dell'Adulto
ClinicalTrials.gov Identifier: NCT04174612    
Other Study ID Numbers: AML1919
First Posted: November 22, 2019    Key Record Dates
Last Update Posted: September 18, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Cytarabine
Daunorubicin
Midostaurin
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antibiotics, Antineoplastic
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Protein Kinase Inhibitors