Phase 2 Evaluation of Gemtuzumab Ozogamicin and Gilteritinib in FLT3-ITD Relapsed/Refractory Acute Myeloid Leukemia in Adults

The primary objective of the AGORA-1/ALFA 2100 study is to evaluate the **safety** and **efficacy** of combining gilteritinib with the GO-cytarabine AGORA platform in adult patients with FLT3-ITD mutated relapsed or refractory acute myeloid leukemia (AML). In the first stage, the focus is on assessing the safety through the occurrence of dose-limiting toxicity (DLT). The second stage aims to determine the efficacy by measuring event-free survival (EFS). These objectives are clinically relevant as they address the need for effective treatment options in a population with limited therapeutic alternatives.

The secondary objectives include evaluating response rates to the study treatment, early mortality rates at day-30, and the incidence of subsequent allogeneic hematopoietic stem cell transplantation (HSCT), both overall and in responding patients. Additionally, the study will assess the duration of response (DOR), relapse-free survival (RFS), and overall survival (OS). Subgroup analyses will be conducted based on patient, disease, and treatment-related factors. Safety will be monitored through adverse events (AEs), serious adverse events (SAEs), treatment-emergent adverse events (TEAEs), and the incidence of sinusoidal obstruction syndrome (SOS). Patient-reported outcomes (PROs) and sensitivity analyses will also be evaluated. These secondary objectives provide a comprehensive understanding of the treatment's impact on various clinical outcomes and patient experiences.

The clinical trial focuses on patients diagnosed with **Acute Myeloid Leukemia** (AML), specifically those with FLT3-ITD mutated relapsed or refractory AML (R/R AML). The study population includes both male and female participants aged 18 years and older. Participants are required to have a confirmed diagnosis of R/R AML positive for CD33 antigen, with specific criteria regarding previous treatments and mutations. The trial does not include a vulnerable population. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, and meet specific liver function and renal function criteria. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet, physical activity, or habits are not specified in the available data.

The clinical trial is designed to evaluate the safety and efficacy of combining **gilteritinib** with the GO-cytarabine AGORA platform in patients with FLT3-ITD mutated relapsed or refractory **Acute Myeloid Leukemia** (AML). This is a Phase 2, randomized, double-blind, controlled study. The trial is expected to commence recruitment on June 3, 2023, and conclude by June 3, 2028. The study is divided into two stages: the first stage focuses on assessing the safety of the combination therapy through the identification of dose-limiting toxicities, while the second stage evaluates the efficacy in terms of event-free survival.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, diagnosis, and specific genetic mutations. Follow-up visits will be scheduled to monitor safety, response rates, and any adverse events. The end-of-study visit will conclude the participant's involvement, assessing overall survival and treatment outcomes. The expected duration of participant involvement is contingent upon individual response and tolerance to the treatment, with early termination possible in cases of severe adverse events or disease progression.

Key elements of the research methodology include the use of **MYLOTARG** 5 mg powder for concentrate for solution for infusion and **Xospata** 40 mg film-coated tablets, administered intravenously and orally, respectively. The trial will also monitor secondary endpoints such as response rates, early mortality rates, and the incidence of subsequent allogeneic hematopoietic stem cell transplantation. Subgroup analyses will be conducted based on factors like age, cytogenetics, and mutation profiles. The trial is not classified as a low-intervention study, given the investigational nature of the drug combination and the need for rigorous safety monitoring.

The clinical trial involves the administration of **MYLOTARG**, which is a **5 mg powder for concentrate for solution for infusion**. The active substance in MYLOTARG is **gemtuzumab ozogamicin**, a protein-based compound. The pharmaceutical form is a solution for infusion, and the route of administration is **intravenous**. The frequency and specific dosing schedule are determined based on the trial protocol, with careful monitoring of participant compliance to ensure accurate data collection and safety. MYLOTARG is manufactured by Pfizer Europe MA EEIG and is authorized for use in the European Union under the marketing authorization number EU/1/18/1277/001.

Another experimental medication used in the trial is **Xospata**, which consists of **40 mg film-coated tablets**. The active substance in Xospata is **gilteritinib**, a chemical compound. The pharmaceutical form is a film-coated tablet, and the route of administration is **oral use**. The dosing schedule is outlined in the trial protocol, with adherence monitored to ensure participant compliance. Xospata is produced by Astellas Pharma Europe B.V. and holds the marketing authorization number EU/1/19/1399/001 in the European Union.

Both MYLOTARG and Xospata are utilized in combination as part of the AGORA treatment platform in this Phase 2 study, which aims to evaluate the safety and efficacy of the combination in adults with FLT3-ITD relapse/refractory acute myeloid leukemia (AML). The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment. The study's primary objectives focus on assessing dose-limiting toxicity and event-free survival, with all treatments administered according to the specified protocol to ensure the integrity of the trial data.

The efficacy of the combination treatment involving **gemtuzumab ozogamicin** and gilteritinib in patients with FLT3-ITD mutated relapsed/refractory acute myeloid leukemia (R/R AML) will be assessed primarily through event-free survival (EFS). EFS is defined in the context of the study to accommodate real-life settings, considering factors such as suboptimal tolerance, minimal residual disease (MRD) monitoring, and the availability of new treatment options. The primary endpoint for the second stage of the trial is the evaluation of EFS, which will provide insights into the efficacy of the treatment combination.

Secondary efficacy endpoints include the overall response rate (ORR), which encompasses complete remission (CR), CR with incomplete hematologic recovery (CRi), and CR with partial hematologic recovery (CRh). Additional secondary endpoints are early mortality rates at day 30, incidence of subsequent allogeneic hematopoietic stem cell transplantation (HSCT), duration of response (DOR), relapse-free survival (RFS), and overall survival (OS). Subgroup analyses will be conducted based on patient-related factors such as age, disease-related factors including cytogenetics and mutation profiles, and treatment-related factors like the performance of subsequent allogeneic HSCT. Safety will also be monitored through the occurrence of adverse events (AEs), serious adverse events (SAEs), and treatment-emergent adverse events (TEAEs), alongside patient-reported outcomes.