A single arm, open-label Phase 3b study to describe the safety and tolerability of ivosidenib in combination with azacitidine in adult patients newly diagnosed with IDH1m acute myeloid leukemia (AML) ineligible for intensive induction chemotherapy ALIDHE

The primary objective of this study is to evaluate the **safety** and tolerability of the combination treatment with ivosidenib and azacitidine in adult patients newly diagnosed with isocitrate dehydrogenase 1 mutation-positive (IDH1m) acute myeloid leukemia (AML) who are ineligible for intensive induction chemotherapy. This is clinically relevant as it aims to provide a therapeutic option for a patient population with limited treatment alternatives, potentially improving patient outcomes and expanding treatment strategies for IDH1m AML.

Secondary objectives include:

• Assessing the efficacy of ivosidenib combined with azacitidine according to local clinical practice, which is crucial for understanding the real-world applicability and effectiveness of the treatment regimen.
• Evaluating the impact of the treatment on health-related quality of life (QoL), which is important for understanding the broader implications of the treatment on patient well-being beyond clinical outcomes.
• Assessing the impact of treatment on healthcare resource utilization (HCRU) and costs, which provides insights into the economic implications and potential cost-effectiveness of the treatment.
• Evaluating the IDH1m diagnostic pathway, which is essential for optimizing diagnostic strategies and ensuring appropriate patient selection for the treatment.

The clinical trial involves a total of **25 participants** diagnosed with **Isocitrate dehydrogenase1 mutation-positive (IDH1m) acute myeloid leukemia (AML)**. The study population includes both male and female subjects, aged 18 years and older, with a focus on those who are ineligible for intensive chemotherapy due to age (≥75 years) or other health conditions. Participants were selected based on specific inclusion criteria, such as having previously untreated AML and documented R132 IDH1m. The trial also considers individuals with adequate hepatic and renal function, as well as those with an Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. The study population includes a vulnerable group, indicating that special considerations are in place to ensure their safety and well-being throughout the trial. Lifestyle factors such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the **safety** and tolerability of a combination therapy involving **ivosidenib** and **azacitidine** in adult patients newly diagnosed with **IDH1m acute myeloid leukemia (AML)** who are ineligible for intensive induction chemotherapy. This is a Phase 3b, single-arm, open-label study. The trial is expected to commence recruitment on March 13, 2023, and conclude by December 17, 2026. Participants will be involved in the study for a maximum treatment period of 112 weeks, depending on their response and tolerance to the treatment regimen.

The trial will include several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. The screening visit will determine eligibility based on criteria such as age, comorbidities, and documented R132 IDH1m status. Follow-up visits will monitor the participants' response to treatment, assess any adverse events, and adjust dosages if necessary. The end-of-study visit will evaluate the overall outcomes and any long-term effects of the treatment.

Participants may be withdrawn from the study early if they experience severe adverse events, fail to comply with the study protocol, or if the investigator deems it necessary for their safety. The primary endpoints include the incidence of adverse events, serious adverse events, and clinical laboratory anomalies. Secondary endpoints focus on event-free survival, complete remission rates, and overall survival, among others. The study aims to provide comprehensive data on the efficacy and safety of the treatment combination in this specific patient population.

The clinical trial involves the administration of **azacitidine**, marketed under the name Vidaza, which is provided as a **powder for suspension for injection**. The pharmaceutical form is a suspension for injection, and it is administered via the injection route. The dosage is specified as 75 mg/m², with a maximum total dose amounting to 27,300 mg/m² over a treatment period of up to 48 weeks. The active substance, azacitidine, is of chemical origin and is produced by Bristol-Myers Squibb Pharma EEIG. The administration schedule and participant compliance are monitored to ensure adherence to the dosing regimen.

The study also includes the administration of **ivosidenib**, provided as a 250 mg film-coated tablet, known by the sponsor product code AG-120/S95031. This medication is administered orally, with a maximum daily dose of 500 mg and a total dose of up to 392,000 mg over a treatment period of 112 weeks. Ivosidenib is also of chemical origin and is manufactured by the Institut de Recherches Internationales Servier (I.R.I.S). The trial monitors participant compliance with the oral dosing schedule to ensure accurate data collection and assessment of the treatment's safety and tolerability.

Efficacy in this clinical trial will be assessed using a range of primary and secondary endpoints. The primary endpoints include the evaluation of adverse events (AEs), serious adverse events (SAEs), adverse events of special interest (AESIs), and clinical laboratory anomalies assessed as AEs. Additionally, the trial will monitor the number of patients requiring transfusion, the number of units transfused, and the rate of infections. These parameters will provide a comprehensive overview of the safety and tolerability of the treatment regimen.

Secondary endpoints will focus on various efficacy measures, including **event-free survival (EFS)**, complete remission (CR), CR with partial hematologic recovery (CRh), and CR with incomplete hematologic recovery (CRi). The duration of response (DOR), time to response (TTR), and overall survival (OS) will also be evaluated. Patient-reported outcomes will be collected using the Hematologic Malignancy-Patient-Reported Outcome (HM-PRO) and Family Reported Outcome Measure (FROM-16) for caregivers and family. Additional assessments will include the 5-level EuroQol 5-dimensions (EQ-5D-5L), length of hospital stay (LOS), outpatient visits, emergency room (ER) visits, and the proportion of days at home. Molecular profiling methods will be employed to analyze time to results, allele subtypes, and co-mutation profiles.