Phase 3 Randomized Trial of Cytarabine, Midostaurin, and Daunorubicin Hydrochloride in FLT3-Mutated Acute Myeloid Leukemia with Peripheral Blast Clearance

The primary objective of this Phase 3 trial is to improve **event-free survival (EFS)** in patients with **FLT3+ acute myeloid leukemia** who exhibit low chemosensitivity. This is achieved by measuring **peripheral blast clearance (PBC)** and applying early treatment intensification during both the induction phase (with high-dose delivery) and the consolidation phase (with allocation to allogeneic transplant), compared to standard treatment regimens. This objective is clinically relevant as it aims to enhance survival outcomes in a subset of patients with poor prognosis due to low chemosensitivity.

Secondary objectives include:

• Assessing the feasibility and safety of PBC-driven treatment by evaluating 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.
• Evaluating the efficacy of PBC-driven treatment in low PBC patients by measuring complete remission (CR) rates after the first induction cycle and after two cycles, disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR), treatment-related mortality (TRM), minimal residual disease (MRD) status, and allogeneic transplant rate in first CR and with active disease.
• Comparing outcomes for high PBC patients treated per protocol (standard) with low PBC patients treated as per randomization (standard vs experimental) by assessing CR rates after the first induction cycle and after two cycles, DFS, OS, CIR, TRM, MRD status, and allogeneic transplant rate in first CR and with active disease.

The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** (AML) with a FLT3 mutation. The study population includes both male and female subjects, aged between 18 and 65 years, who are newly diagnosed and untreated, as per the WHO 2016 criteria. Participants are required to have a mutation in the FLT3 gene, either ITD and/or TK, and must present with morphologically identifiable blasts in peripheral blood at diagnosis. The trial includes individuals with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-2, or a disease-related reversible ECOG 3 score following adequate supportive care. The trial population is selected based on the availability of adequate diagnostic biologic material for comprehensive disease characterization according to ELN criteria. The sponsor has not provided information regarding the total number of participants. The study considers a vulnerable population, and all participants have provided signed written informed consent in accordance with ICH/EU/GCP and national local laws. Lifestyle factors such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is a **Phase 3**, prospective, randomized, multi-center intervention study designed to evaluate the efficacy of early intensification treatment in patients with **Acute Myeloid Leukemia** (AML) bearing FLT3 mutations. The trial employs a **randomized, controlled** design with a primary objective to improve event-free survival (EFS) by utilizing peripheral blast clearance (PBC) as a biomarker to guide treatment intensification. The study is expected to conclude by October 2025, with recruitment having commenced in April 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, presence of FLT3 mutation, and performance status. Following randomization, participants will receive either the experimental PBC-driven treatment or a standard therapeutic regimen. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and disease progression. The end-of-study visit will assess the primary endpoint of EFS at two years, alongside secondary endpoints such as safety, feasibility, and overall survival.

The expected duration of participant involvement is up to 24 months, contingent upon individual response and disease progression. Conditions that may lead to early termination from the study include withdrawal of consent, significant adverse events, or disease progression that necessitates alternative treatment. The trial will utilize **cytarabine**, **midostaurin**, and **daunorubicin hydrochloride** as part of the treatment regimen, with administration routes including intravenous and oral delivery. The study aims to provide valuable insights into the optimization of treatment strategies for AML patients with FLT3 mutations.

The clinical trial involves the administration of **Cytarabine**, marketed as ARACYTIN 500 mg/10 ml Polvere e Solvente per Soluzione Iniettabile. This experimental medication is provided in the form of a **solution for injection**. The active substance, **cytarabine**, is of chemical origin. The medication is administered intravenously with a maximum daily dose of 3000 mg/m² and a total maximum dose of 9600 mg/m² over a treatment period of up to 6 weeks. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Midostaurin** is used as an auxiliary treatment in the study. It is provided in the form of soft capsules and is administered orally. The active substance, **midostaurin**, is also of chemical origin. The maximum daily dose is 100 mg, with a total maximum dose of 1400 mg over a treatment period of up to 14 days. The administration schedule and participant adherence will be closely monitored to ensure compliance with the study protocol.

Another auxiliary treatment in the trial is **Daunorubicin Hydrochloride**, which is provided as a powder for infusion. The active substance, **daunorubicin hydrochloride**, is of chemical origin. This medication is administered via intravenous infusion, with a maximum daily dose of 60 mg/m² and a total maximum dose of 180 mg/m² over a treatment period of up to 3 weeks. The dosing schedule and participant compliance will be monitored to ensure adherence to the study protocol.

Efficacy in this clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)** at 2 years. This will be evaluated by comparing an experimental intensified peripheral blast clearance (PBC)-driven arm with a standard therapeutic regimen in patients with FLT3+ acute myeloid leukemia (AML) and low peripheral blood clearance, measured at day 4. Secondary endpoints include the feasibility and safety of PBC-driven treatment, assessed by adverse events rate according to CTCAE criteria, rate of deaths in aplasia, and recovery times for neutrophils and platelets after induction and consolidation cycles. Additionally, efficacy in low PBC patients will be evaluated through complete remission (CR) rates after the first and second induction cycles, disease-free survival, overall survival, cumulative incidence of relapse, treatment-related mortality, and minimal residual disease (MRD) at predefined time points, all according to ELN 2017 criteria.