Phase 3 Multicenter Open-label Randomized Study of Gilteritinib, Gilteritinib Plus Azacitidine, and Azacitidine in Newly Diagnosed FLT3-Mutated AML

The primary objective of this Phase 3 study is to determine the **efficacy** superiority of ASP2215 (Gilteritinib) plus **azacitidine** compared to azacitidine alone, as measured by overall survival (OS) in patients with newly diagnosed acute myeloid leukemia (AML) with FLT3 mutation who are not eligible for intensive induction chemotherapy. This is clinically relevant as it aims to improve survival outcomes in a patient population with limited treatment options.

Secondary objectives include evaluating the efficacy superiority of ASP2215 plus azacitidine versus azacitidine as measured by event-free survival (EFS). Additional secondary objectives are to assess the safety and efficacy in terms of best response, complete remission (CR) rate, CRc rate, CRh rate, CR/CRh rate, transfusion conversion rate, transfusion maintenance rate, leukemia-free survival (LFS), duration of remission, patient-reported fatigue using the Brief Fatigue Inventory (BFI), adverse events (AEs), clinical laboratory results, physical examinations, vital signs, ECGs, and Eastern Cooperative Oncology Group (ECOG) performance scores.

The clinical trial involves a total of **33 participants** diagnosed with **newly diagnosed acute myeloid leukemia** with an FLT3 mutation, who are not eligible for intensive induction chemotherapy. The study population includes both male and female subjects, with an age range of 18 years and older. Participants were selected based on their diagnosis and ineligibility for intensive chemotherapy, which may be due to age (≥ 65 years) or specific comorbidities such as congestive heart failure, renal impairment, or other significant health conditions. The trial includes a vulnerable population, indicating that some participants may have additional health considerations. Lifestyle factors such as diet and physical activity are not specified, but the inclusion criteria focus on the participants' medical status and treatment history. The selection process ensures that the study population is representative of patients who are unable to undergo intensive chemotherapy, providing valuable insights into the efficacy of the treatment under investigation.

The clinical trial is a **Phase 3**, multicenter, open-label, randomized study designed to evaluate the efficacy of **Gilteritinib** in combination with **Azacitidine** compared to Azacitidine alone in patients with newly diagnosed **Acute Myeloid Leukemia** (AML) with **FLT3 mutation** who are not eligible for intensive induction chemotherapy. The primary objective is to assess the superiority of the combination therapy in terms of overall survival. The trial is expected to run from August 2016 to December 2024, with a maximum treatment period of 101 weeks for participants.

Participants will be randomly assigned to one of the treatment arms. The study involves several key visits, starting with a screening visit to confirm eligibility based on inclusion criteria such as a diagnosis of AML and the presence of the FLT3 mutation. Following randomization, participants will undergo regular follow-up visits to monitor treatment efficacy and safety, including assessments of overall survival, event-free survival, and other secondary endpoints like best response and duration of remission. Safety endpoints will include monitoring adverse events, clinical laboratory results, physical examinations, and vital signs.

The end-of-study visit will occur after the completion of the treatment period or upon early termination. Participants may be withdrawn from the study if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in their best interest. The expected length of participant involvement is up to 101 weeks, contingent upon individual response and tolerability to the treatment regimen. The study is not classified as low intervention, and it adheres to rigorous scientific and ethical standards to ensure the validity and reliability of the results.

The clinical trial involves the administration of **Vidaza**, a **powder for suspension for injection** containing the active substance **azacitidine**. This pharmaceutical form is intended for **intravenous use**. The dosage is calculated based on body surface area, with a maximum daily dose of 75 mg/m². The total maximum dose over the treatment period is 57,619 mg/m². The treatment duration is set for a maximum of 101 days. Vidaza is a product of chemical origin, developed by Bristol-Myers Squibb Pharma EEIG, and is authorized under the marketing authorization number EU/1/08/488/001. Participant compliance with the dosing schedule will be monitored throughout the trial.

**Gilteritinib** is administered in the form of a **film-coated tablet**. The active substance, also of chemical origin, is provided by Astellas Pharma Global Development, Inc. The route of administration is **oral**, with a maximum daily dose of 200 mg. The total maximum dose for the treatment period is 614,600 mg. The treatment period is similarly capped at 101 days. Gilteritinib is identified by the sponsor product code ASP2215 and holds the orphan drug designation number EU/3/17/1961. Compliance with the oral dosing regimen will be closely monitored to ensure adherence to the protocol.

The trial is designed to compare the efficacy of the combination of ASP2215 (Gilteritinib) plus azacitidine against azacitidine alone in patients with newly diagnosed **acute myeloid leukemia** with **FLT3 mutation** who are not eligible for intensive induction chemotherapy. The primary objective is to assess the superiority of the combination therapy in terms of overall survival.

The efficacy of the clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)**. This primary endpoint will determine the efficacy superiority of the combination of ASP2215 (Gilteritinib) plus azacitidine versus azacitidine alone in patients with newly diagnosed Acute Myeloid Leukemia (AML) with FLT3 mutation who are not eligible for intensive induction chemotherapy. The key secondary efficacy endpoint is **Event-free Survival (EFS)**. Additional secondary efficacy endpoints include Best Response, Complete Remission (CR), Complete Remission with incomplete blood count recovery (CRc), Complete Remission with partial hematologic recovery (CRh), Transfusion conversion rate, Transfusion maintenance rate, Leukemia-free survival (LFS), Duration of remission, and Patient-reported fatigue from the Brief Fatigue Inventory (BFI).

The collection and analysis of these efficacy parameters will be conducted at specified timepoints throughout the trial. The trial is designed as a Phase 3, multicenter, open-label, randomized study. The efficacy assessments will be performed using validated scales and laboratory tests, ensuring the reliability and accuracy of the data collected. The trial is expected to conclude by December 31, 2024, with recruitment having started on August 1, 2016. The trial will adhere to rigorous standards to ensure the integrity of the efficacy data collected.