Phase II Multicenter Study on Gilteritinib with Fludarabine, Cytarabine, and Idarubicin in Newly Diagnosed FLT3-Positive Acute Myeloid Leukemia

Trial ID: 2024-518617-25-00
Sponsor: Fondazione Gimema Franco Mandelli Onlus

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Diseases & Conditions

Acute myeloid leukaemia

Objectives

The primary objective of this study is to determine the **efficacy** and tolerability of Gilteritinib when combined with chemotherapy, specifically fludarabine, cytarabine, and idarubicin (FLAI), in achieving Complete Remission (CR + CRi + CRp) in patients with newly diagnosed, non-M3, FLT3-positive acute myeloid leukemia (AML). This is clinically relevant as achieving complete remission is a critical goal in the treatment of AML, potentially leading to improved patient outcomes and survival rates.

Secondary objectives include:

Describing the duration of MRD-negative CR.
Describing survival outcomes.
Describing the feasibility of hematopoietic stem cell transplantation (HSCT).
Describing safety.
Evaluating whole gene FLT3 mutations.
Analyzing minimal residual disease (MRD) with next-generation sequencing (NGS) technologies.
Describing quality of life.

These objectives aim to provide a comprehensive understanding of the treatment's impact on various clinical parameters, which are essential for optimizing therapeutic strategies in AML management.

Participants

The clinical trial involves participants diagnosed with **newly diagnosed non-M3 FLT3-positive acute myeloid leukemia**. The study population includes both male and female subjects aged between 18 and 65 years. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance score of 0 to 2, indicating they are in relatively good health with adequate baseline organ function, including cardiac, renal, and hepatic function. The trial does not include a vulnerable population. Participants must have a positive diagnosis for the FLT3 activating mutation in bone marrow or whole blood and must not have received prior treatment for acute myeloid leukemia. Women of childbearing potential are required to have a negative pregnancy test before the study and agree to use two acceptable contraceptive methods during and after the study. The total number of participants is not provided as the sponsor did not give this information. Participants were selected based on their ability to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment. Lifestyle considerations such as diet and physical activity are not specified in the available data.

Plans and Procedures

The clinical trial is designed as a **Phase II, open-label, multicenter study** to evaluate the tolerability and efficacy of **gilteritinib** in combination with fludarabine, cytarabine, and idarubicin as induction therapy for patients with newly diagnosed non-M3 FLT3-positive **acute myeloid leukemia** (AML). The primary objective is to determine the efficacy and tolerability of gilteritinib in achieving complete remission (CR, CRi, CRp) in this patient population. The trial is expected to commence recruitment on September 30, 2025, and conclude by September 30, 2030.

Participants will be involved in the study for a maximum treatment period of 15 days, with the possibility of early termination if they do not meet the inclusion criteria or if adverse events occur. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess the final outcomes. The inclusion criteria specify that participants must be between 18 and 65 years old, have an ECOG performance score of 0 to 2, and demonstrate adequate baseline organ function. Additionally, participants must test positive for the FLT3 activating mutation and have untreated AML according to WHO 2016 criteria.

The primary endpoint is the rate of complete remission after the first or second course of treatment. Secondary endpoints include the percentage of minimal residual disease (MRD) negative CR, progression-free survival (PFS), overall survival (OS), and the incidence of adverse events (AEs). The study will also analyze the incidence and type of FLT3 mutations and the overlap between conventional MRD and next-generation sequencing (NGS) technologies. Participants are required to adhere to the study visit schedule and protocol requirements, including follow-up for survival assessment. The trial is not classified as low intervention and is categorized under Phase II studies.

Treatment

The clinical trial involves the administration of **Gilteritinib**, marketed under the name Xospata, as the experimental medication. Xospata is provided in the form of 40 mg **film-coated tablets**. The active substance, Gilteritinib, is a chemical compound also known by the synonym ASP2215. The medication is administered orally, with a maximum daily dose of 120 mg. The total maximum dose over the treatment period is 12.6 grams. The treatment duration is limited to a maximum of 15 days. The pharmaceutical product is manufactured by Astellas Pharma Europe B.V. and is not formulated for pediatric use.

In addition to the experimental treatment, the study includes a combination of standard chemotherapy agents: **fludarabine**, **cytarabine**, and **idarubicin**. These agents are used as part of the induction therapy for newly diagnosed non-M3 FLT3-positive acute myeloid leukemia. The combination aims to evaluate the efficacy and tolerability of Gilteritinib when added to this chemotherapy regimen. The study does not utilize a placebo or comparator treatment, focusing instead on the combination therapy's potential to achieve complete remission, including complete remission with incomplete hematologic recovery (CRi) and complete remission with partial hematologic recovery (CRp).

Efficacy

The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the rate of Complete Remission (CR), which includes CR with incomplete hematologic recovery (CRi) and CR with partial hematologic recovery (CRp), after the administration of either the first or second course of treatment. This will be measured to determine the effectiveness of the treatment regimen in achieving remission in patients with newly diagnosed, non-M3, FLT3-positive acute myeloid leukemia (AML).

Secondary endpoints will provide additional insights into the efficacy of the treatment. These include the percentage of patients achieving minimal residual disease (MRD) negative CR, assessed through flow cytometry after each treatment cycle, consolidation, end of treatment, and during follow-up. The duration of MRD negative CR will be described as the time from achieving MRD negative CR to the occurrence of an MRD positive test, relapse, or death from any cause. Progression-free survival (PFS) and overall survival (OS) will also be evaluated, measuring the time from the first day of treatment administration to progression or death, respectively. The proportion of patients proceeding to hematopoietic stem cell transplantation (HSCT) in MRD negative CR will be documented, along with the incidence of adverse events (AEs) and the analysis of whole gene **FLT3** mutations.

Additional analyses will include the overlap between conventional MRD and MRD assessed with next-generation sequencing (NGS) technologies for correlative purposes, adherence to treatment, and quality of life assessments. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to provide a comprehensive evaluation of the treatment's impact on the patient population.

Inclusion and Exclusion Criteria

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Inclusion Criteria

The patient is ≥ 18 and ≤65 years old.
The patient has an Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0 to 2.
The patient has adequate baseline organ function, including cardiac, renal, and hepatic function:a. Left ventricular ejection fraction (LVEF) ≥institutional lower limit of normal as measured by multigated acquisition (MUGA) scan or 2-dimensional (2-D) echocardiography (ECHO) within 21 days before start of therapy and no clinically significant abnormalities on a 12-lead electrocardiogram (ECG). b. ECG: QTcF≤450 male ≤480 female c. Serum creatinine ≤ 1.5 x ULN or an estimated glomerular filtration rate of > 50 mL/min as calculated by the Modification of Diet in Renal Disease equation. d. Bilirubin ≤3 times the upper limit of normal ULN mg/dL except for Gilbert’s condition e. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 times the upper limit of normal (ULN)., except if due to leukemic involvement.
Patient is positive at diagnosis for FLT3 activating mutation in bone marrow or whole blood.
Diagnosis of untreated AML according to WHO 2016, non-APL.
If the patient is a woman of childbearing potential (WOCBP), she must have a negative serum or urine pregnancy test at screening within 1 week before treatment.
The patient (male and female) agrees to use two acceptable contraceptive methods for the duration of time on the study and continue to use acceptable contraceptive methods for 6 months after the end of treatment
The patient has signed informed consent before initiation of any study-specific procedures or treatment.
The patient is able to adhere to the study visit schedule and other protocol requirements, including follow-up for survival assessment.

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Exclusion Criteria

Patient was diagnosed as acute promyelocytic leukemia.
Patient has BCR-ABL-positive leukemia or chronic myelogenous leukemia in blast crisis.
Patient has clinically active central nervous system leukemia.
Patient has been diagnosed with another malignancy, unless disease-free for at least 3 years. Subjects with treated nonmelanoma skin cancer, in situ carcinoma or cervical intraepithelial neoplasia, papillary thyroid carcinoma, regardless of the disease-free duration, are eligible for this study if definitive treatment for the condition has been completed. Subjects with organconfined prostate cancer with no evidence of recurrent or progressive disease are eligible if hormonal therapy has been initiated or the malignancy has been surgically removed or treated with definitive radiotherapy.
Patient has had major surgery within 4 weeks prior to the first study dose.
Patient has radiation therapy within 4 weeks prior to the first study dose.
Patient has congestive heart failure New York Heart Association (NYHA) class 3 or 4 or patient with a history of congestive heart failure NYHA class 3 or 4 in the past, unless a screening echocardiogram performed within 1 month prior to study entry results in a left ventricular ejection fraction that is ≥ 45%.
Patient has an active uncontrolled infection.
Patient has active human immunodeficiency virus infection.
Patient has active hepatitis B or C or other active hepatic disorder. Chronic conditions previously cured or in active prophylaxis are allowed in the study
Patient has infections, comorbidities or any disease, condition or alteration that per judgment of the investigator may be jeopardized by therapy
Patients receiving any other investigational or commercial agents or therapies administered with the intention to treat their malignancy with the exception of Hydroxyurea (HU) or 6- Mercaptopurine (6MP) in patients who need to continue this agent to maintain WBC count ≤10,000/mm3. HU and 6MP must be discontinued at the time of initiation of study medications.