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

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione Gimema Franco Mandelli Onlus

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Hemic and Lymphatic Diseases [C15]

Trial duration

24 Apr 2020 → ongoing

Decision date (initial)

2024-01-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Fondazione GIMEMA Franco Mandelli onlus · AIRC Associazione Italiana per la Ricerca sul Cancro - MYNERVA program

External identifiers

EU CT number

2023-505901-17-00

EudraCT number

2019-003936-21

ClinicalTrials.gov

NCT04174612

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Therapy

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.

Secondary objectives 3

1. Feasibility and safety of PBC-driven treatment, as assessed by: 1-adverse events rate according to CTCAE criteria, - rate of death in aplasia - days to neutrophil recovery and - days to platelet recovery after induction and consolidation cycles, according to treatment arm
2. Efficacy, in low PBC-patients, of PBC-driven treatment as assessed by: 1-CR rate after first induction cycle, 2-CR rate after two cycles, 3-DFS, 4-OS, 5-CIR and TRM, 6-MRD status, 7- Allogeneic transplant rate in first CR and with active disease
3. Evaluation of outcome for PBC-high patients treated per protocol (standard) and in comparison, with PBC-low treated as per randomization (standard vs experimental), as assessed by: 1-CR rate after first induction cycle, 2-CR rate after two cycles, 3-DFS, 4-OS, 5-Cumulative incidence of relapse (CIR) and Treatment-related mortality (TRM), 6-MRD status, 7- Allogeneic transplant rate in first CR and with active disease

Conditions and MedDRA coding

Acute Myeloid Leukemia (LMA) with FLT3 mutation

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 8

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 TK
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 9

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. 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.
6. Uncontrolled bacterial or fungal infections
7. QTc >470 msec on screening ECG (Fridericia’s formula)
8. A history of cancer that is not in remission phase following surgery and/or chemotherapy and/or radiotherapy with life expectancy < 1 year.
9. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. 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 endpoints 3

1. 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
2. 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
3. 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

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione Gimema Franco Mandelli Onlus

Sponsor organisation

Fondazione Gimema Franco Mandelli Onlus

Address

Via Casilina 5

City

Rome

Postcode

00182

Country

Italy

Scientific contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

GIMEMA Centro Dati

Public contact point

Organisation

Fondazione Gimema Franco Mandelli Onlus

Contact name

GIMEMA Centro Dati

Third parties 4

Locations

1 EU/EEA country · 37 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 3 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

2 submissions — initial application plus substantial / non-substantial modifications