Sequential Administration of Gilteritinib, Venetoclax, and Azacitidine in Newly Diagnosed FLT3-Mutated Acute Myeloid Leukemia Ineligible for Intensive Therapy

The primary objective of this study is to explore the optimal **tolerable** and efficacious dose of **gilteritinib** when combined with standard treatment using **venetoclax** and **azacitidine** in patients with newly diagnosed **acute myeloid leukemia** (AML) with **FLT3 mutations** who are ineligible for intensive treatment. The primary endpoint is the ratio of dose delivered to dose planned, as this measure reflects both treatment efficacy and tolerability/safety. This is clinically relevant as it aims to optimize treatment regimens for a vulnerable patient population, potentially improving outcomes and minimizing adverse effects.

Secondary objectives include evaluating the following: - Ratio of dose delivered/dose planned after cycle 2 - Rate of remission, duration of response, relapse-free survival, overall survival, and cumulative incidence of relapse - Depth of response by assessment of measurable residual disease - Tolerability - Duration of cytopenias and transfusion dependence

The clinical trial involves participants diagnosed with **acute myeloid leukemia** (AML) who possess FLT3 mutations and are ineligible for intensive treatment. The study population includes both male and female subjects aged 18 years and older. Participants are selected based on their diagnosis of AML according to WHO 2022 or ICC 2022 criteria, with a minimum bone marrow blast count of 20%, and must not have acute promyelocytic leukemia. The trial includes individuals who are either 75 years or older or those aged 18 to 74 with specific comorbidities that preclude standard induction therapy. These comorbidities include an ECOG Performance Status of 2 or 3, certain cardiac and pulmonary conditions, moderate hepatic impairment, or other physician-assessed conditions incompatible with intensive chemotherapy. Participants must have undergone pre-treatment with a combination of venetoclax and azacitidine and have available bone marrow assessment results. The trial population is considered vulnerable, and both genders are included. However, the sponsor has not provided the total number of participants involved in the study.

The clinical trial is designed to evaluate the optimal dose of **gilteritinib** when combined with standard treatment using **venetoclax** and **azacitidine** in patients with newly diagnosed **acute myeloid leukemia** (AML) who have FLT3 mutations and are ineligible for intensive treatment. This is a Phase II, randomized, double-blind, controlled trial with an estimated duration of 12 months for each participant. The trial will commence recruitment on November 1, 2024, and is expected to conclude by October 31, 2028.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis of AML, presence of FLT3 mutations, and ineligibility for standard induction therapy. Following the screening, participants will receive a pre-treatment cycle of venetoclax and azacitidine, with a bone marrow assessment on day 21. Subsequent visits will occur at regular intervals to monitor treatment efficacy and safety, including the primary endpoint of the ratio of dose delivered to dose planned over the 12-month treatment period. Secondary endpoints include complete remission rates, depth of response by minimal residual disease, and tolerability as measured by adverse events.

The end-of-study visit will evaluate the overall outcomes and safety of the treatment regimen. Participants are expected to be involved in the trial for the full 12-month period unless conditions arise that necessitate early termination, such as significant adverse events or withdrawal of consent. The trial's design ensures rigorous monitoring and assessment to determine the most effective and tolerable dosing strategy for this patient population.

The clinical trial involves the administration of **Azacitidine**, a **hypomethylating agent** used in the treatment of patients with newly diagnosed **acute myeloid leukemia** (AML) with **FLT3 mutations** who are ineligible for intensive treatment. Azacitidine is provided in the form of a **powder for suspension for injection** and is administered via the **subcutaneous** route. The maximum daily dose is 75 mg/m², with a total maximum dose of 6300 mg/m² over a treatment period of up to 12 months. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

**Venetoclax**, marketed as Venclyxto, is a **cytostatic** agent included in the trial as an auxiliary treatment. It is available as **film-coated tablets** and is administered **orally**. The maximum daily dose of Venetoclax is 400 mg, with a total maximum dose of 67200 mg over a 12-month period. The tablets are manufactured by ABBVIE DEUTSCHLAND GMBH & CO. KG. Compliance with the oral dosing schedule is monitored throughout the trial to ensure proper administration.

**Gilteritinib**, marketed as Xospata, is a **tyrosine kinase inhibitor** used in this trial as a test treatment. It is also provided in the form of **film-coated tablets** and administered **orally**. The maximum daily dose is 80 mg, with a total maximum dose of 26880 mg over a 12-month period. The tablets are produced by ASTELLAS PHARMA EUROPE B.V. Gilteritinib is designated as an orphan drug for this indication, and participant adherence to the dosing schedule is closely monitored to ensure efficacy and safety.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is the ratio of dose delivered to dose planned over the 12-month treatment period, evaluated at the end of the study (EOS). This measure reflects both treatment efficacy, as patients live longer event-free, and safety, with fewer dose reductions and omitted doses. Secondary endpoints include the ratio of dose delivered to dose planned after cycle 2, complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), duration of response (DOR), relapse-free survival (RFS), overall survival (OS), cumulative incidence of relapse (CIR), depth of response by minimal residual disease (MRD), tolerability assessed through adverse events, and duration of cytopenias and transfusion dependence.