Evaluation of Low-Intensity Therapy with Gilteritinib, Venetoclax, and Glasdegib Versus High-Intensity Therapy in Relapsed/Refractory Acute Myeloid Leukemia

The primary objective of the IMPACT-AML trial is to evaluate the clinical benefit of low intensity therapy in patients with **relapse or refractory acute myeloid leukemia** (R/R AML) by assessing event-free survival compared to high intensity therapy. This is clinically relevant as it aims to determine if a less aggressive treatment approach can provide similar or improved outcomes, potentially reducing treatment-related morbidity and improving patient quality of life.

Secondary objectives include:

• Determining if low intensity therapy improves overall survival.
• Assessing if low intensity therapy enhances the overall response, including complete remission (CR), complete remission with incomplete hematologic recovery (CRh/CRi), and morphologic leukemia-free state (MLFS).
• Evaluating improvements in patient-reported quality of life with low intensity therapy.
• Comparing the safety profile of low intensity therapies to high intensity therapies.

The clinical trial involves participants diagnosed with **acute myeloid leukemia** (AML), specifically those experiencing a first or second relapse or refractory AML as defined by the European LeukemiaNet (ELN) 2022 criteria. The study population includes both male and female subjects aged over 18 years, with an Eastern Cooperative Oncology Group (ECOG) performance status of less than 4, indicating they are ambulatory and capable of self-care. Participants are required to be clinically eligible for both low intensity therapy and high dose chemotherapy, with no specific treatment protocol deemed superior for their condition. The trial does not include a vulnerable population. Participants must not be pregnant or breastfeeding, and those of childbearing potential must adhere to strict birth control measures. The total number of participants is not provided by the sponsor. Selection criteria ensure that participants are willing and able to provide informed consent, and that both treatment options are available and feasible according to local practice. Lifestyle factors such as diet and physical activity are not specified in the trial data.

The clinical trial is designed to evaluate the clinical benefit of low-intensity therapy compared to high-dose chemotherapy in patients with **acute myeloid leukemia** (AML) who are experiencing relapse or refractory conditions. This trial is structured as a randomized, pragmatic, low-intervention clinical trial, adhering to the guidelines of the Clinical Trial Regulation Reg.536/2014. The trial will employ a double-blind, controlled methodology to ensure unbiased results. The estimated duration of the trial is from January 2025 to January 2028, with the recruitment phase beginning in January 2025.

Participants will undergo a series of study visits, starting with an inclusion (screening) visit to assess eligibility based on criteria such as age, performance status, and medical history. The primary inclusion criteria include a diagnosis of non-APL AML, being in the first or second relapse or refractory stage, and being a candidate for both low-intensity therapy and high-dose chemotherapy. Follow-up visits will be scheduled to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing the primary endpoint of event-free survival and secondary endpoints such as overall survival and response rates.

The expected length of participant involvement is approximately three years, aligning with the overall trial duration. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any medical condition that contraindicates continued participation. The trial will utilize a range of antineoplastic agents, including **cytarabine**, **amsacrine**, and **gemtuzumab ozogamicin**, administered through various routes such as intravenous infusion and oral intake, depending on the specific treatment arm. The trial aims to provide valuable insights into the efficacy and safety of these therapeutic approaches in managing AML.

The clinical trial involves the administration of several **antineoplastic** agents, each with specific dosing regimens and administration routes. **Cytarabine** is administered as an injection with a maximum daily dose of 6 g and a total dose of 18 g over a treatment period of 10 days. The pharmaceutical form is PHF00230MIG, and it is not a pediatric formulation. **Amsacrine** is delivered via intravenous infusion, with a maximum daily dose of 125 mg/m² and a total dose of 750 mg/m² over 7 days. The pharmaceutical form is PHF00230MIG.

**Gemtuzumab ozogamicin** is administered through intravenous infusion, with a maximum daily dose of 3 mg/m² and a total dose of 5 mg over 2 days. It is designated as an orphan drug and is not a pediatric formulation. **Mitoxantrone hydrochloride** is given via intravenous infusion, with a maximum daily and total dose of 12 mg/m² over 6 days. The pharmaceutical form is PHF00230MIG.

**Daunorubicin hydrochloride** is administered through intravenous infusion, with a maximum daily and total dose of 90 mg/m² over 3 days. The pharmaceutical form is PHF00231MIG. **Gilteritinib** is taken orally, with a maximum daily and total dose of 200 mg over a 12-week period. It is designated as an orphan drug and is not a pediatric formulation.

**Venetoclax** is administered orally, with a maximum daily and total dose of 400 mg over 12 weeks. The pharmaceutical form is PHF00082MIG. **Glasdegib** is also taken orally, with a maximum daily and total dose of 100 mg over 12 weeks. It is designated as an orphan drug and is not a pediatric formulation.

**Decitabine** is administered intravenously, with a maximum daily and total dose of 20 mg/m² over 10 days. It is designated as an orphan drug and is not a pediatric formulation. **Idarubicin hydrochloride** is given via intravenous infusion, with a maximum daily and total dose of 14 mg/m² over 3 days. The pharmaceutical form is PHF00016MIG.

**Fludarabine phosphate** is administered through intravenous infusion, with a maximum daily and total dose of 30 mg/m² over 5 days. The pharmaceutical form is PHF00082MIG. **Azacitidine** can be administered either intravenously or subcutaneously, with a maximum daily and total dose of 75 mg/m² over 7 days. The pharmaceutical form is PHF00243MIG.

**Etoposide** is given via intravenous infusion, with a maximum daily and total dose of 100 mg/m² over 6 days. The pharmaceutical form is PHF675. **Cladribine** is administered as an injection, with a maximum daily and total dose of 5 mg/m² over 5 days. The pharmaceutical form is PHF00230MIG.

**Ivosidenib** is taken orally, with a maximum daily and total dose of 500 mg over 12 weeks. It is designated as an orphan drug and is not a pediatric formulation. The pharmaceutical form is PHF00082MIG. Each medication's administration and dosing are monitored for compliance throughout the trial.

The efficacy of the clinical trial for **Acute Myeloid Leukemia (AML)** will be assessed using several primary and secondary endpoints. The primary endpoint is event-free survival, defined as the time from randomization to treatment failure, hematologic relapse from complete remission (CR), complete remission with partial hematologic recovery (CRh), complete remission with incomplete hematologic recovery (CRi), or death from any cause, whichever occurs first. Secondary endpoints include overall survival, defined as the time from randomization to the date of death from any cause, and overall response rate, which encompasses CR, CRh, CRi, and morphologic leukemia-free state (MLFS) as the best assessment of response during the study treatment and the overall study cohort. Additionally, changes in the Hematologic Malignancy–Patient-Reported Outcome (HM-PRO) A-total, as defined by the HM-PRO questionnaire, will be evaluated between screening and end-of-treatment assessment. The proportion of patients experiencing adverse events will also be monitored.

The efficacy parameters will be measured and collected at various timepoints throughout the trial, including at screening, during treatment, and at the end of treatment. The HM-PRO questionnaire will be utilized to assess patient-reported outcomes related to hematologic malignancy. Data analysis will focus on comparing the efficacy of low-intensity therapy versus high-dose chemotherapy in patients with relapse or refractory AML, with the aim of determining the clinical benefit in terms of event-free survival. The trial is designed as a low intervention clinical trial, with all drugs used having market authorization in Europe and their use being evidence-based. The trial will adhere to clinical practice standards, with additional procedures limited to quality of life assessments and sample biobanking, ensuring minimal additional risk or burden to participants.