An open-label, single-arm, pilot study of Venetoclax in combination with 5 days Azacitidine in treatment-naïve subjects with acute myelogenous leukemia who are ≥18 years of age and not eligible for standard induction therapy (VENAZA-5S PILOT TRIAL)

The primary objective of this study is to generate initial data on the **efficacy** of the combination of Venetoclax and 5-day courses of Azacitidine in treatment-naïve subjects with acute myeloid leukemia who are 18 years of age or older and not eligible for standard induction therapy. This objective is clinically relevant as it aims to provide insights into the potential benefits of this combination regimen for a patient population with limited treatment options.

Secondary objectives include:

• Describing the depth and duration of response with the combination regimen.
• Describing survival outcomes with the combination regimen.
• Evaluating the safety and toxicity profile of the combination regimen.
• Assessing potential treatment interruptions and discontinuations.
• Monitoring potential hospitalizations.
• Evaluating Quality of Life (QoL) using the EORTC QLQ-C30 questionnaire.
• Describing minimal residual disease (MRD) levels during study treatment.

The clinical trial involves participants diagnosed with **acute myeloid leukemia** (AML), specifically those who are ineligible for standard cytarabine and anthracycline induction regimens due to age or comorbidities. The study population includes both male and female subjects aged 18 years and older, with a projected life expectancy of at least 12 weeks. Participants are required to have adequate renal and liver function. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants or specific lifestyle considerations such as diet or physical activity. The selection criteria ensure that the study population is representative of individuals with AML who meet the specified health and eligibility requirements.

The clinical trial is designed as an **open-label**, single-arm, pilot study to evaluate the efficacy of a combination therapy involving **venetoclax** and **azacitidine** in treatment-naïve subjects with **acute myeloid leukemia** (AML) who are 18 years or older and not eligible for standard induction therapy. The trial aims to generate initial data on the efficacy of this combination in a descriptive manner. The study is expected to last until December 2024, with recruitment having commenced in March 2023. Participants will be involved in the study for a maximum of six cycles of therapy, with each cycle lasting approximately one month.

The trial includes several key visits: an initial screening visit, regular follow-up visits, and an end-of-study visit. During the screening visit, eligibility criteria such as a confirmed diagnosis of AML, age, life expectancy, and adequate renal and liver function will be assessed. Follow-up visits will occur regularly to monitor the participants' response to the treatment, assess any adverse effects, and ensure compliance with the study protocol. The end-of-study visit will evaluate the overall outcomes and gather final data on the participants' health status.

Participants are expected to remain in the study for the full duration unless specific conditions necessitate early termination. These conditions include significant adverse reactions, withdrawal of consent, or any medical reasons that would make continued participation unsafe. The primary endpoint of the study is the response rate, defined as the rate of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) after up to six cycles of therapy. Secondary endpoints include the rate of CR or CRi by the initiation of Cycle 2, overall survival, event-free survival, and quality of life assessments.

The clinical trial involves the administration of **Venclyxto** (venetoclax) as part of the experimental treatment regimen. Venclyxto is provided in the form of 100 mg **film-coated tablets**. The active substance, venetoclax, is of chemical origin. The medication is administered **orally** with a maximum daily dose of 400 mg and a cumulative maximum dose of 72,000 mg over the treatment period. The treatment duration is set for a maximum of six months. Participant compliance with the dosing schedule will be monitored throughout the trial to ensure adherence to the prescribed regimen.

In addition to Venclyxto, the trial includes the administration of **Vidaza** (azacitidine) as a non-experimental treatment. Vidaza is supplied as a 25 mg/ml **powder for suspension for injection**. The active substance, azacitidine, is also of chemical origin. The administration route for Vidaza is via **subcutaneous injection**. The maximum daily dose is 75 mg/m², with a total maximum dose of 2,250 mg/m² over the course of the treatment. The treatment period for Vidaza is similarly capped at six months. Compliance with the administration schedule will be closely monitored to ensure accurate dosing and adherence to the trial protocol.

Efficacy in this clinical trial will be assessed primarily through the **response rate**, defined as the rate of complete remission (CR) or complete remission with incomplete blood count recovery (CRi) after up to six cycles of therapy. Secondary endpoints include the rate of CR or CRi by the initiation of Cycle 2, the rate of CR with partial hematologic recovery (CRh) after up to six cycles, and the time from initiation of treatment until achievement of CR or CRi. Additional secondary endpoints encompass the objective response rate, event-free survival (EFS), overall survival (OS), and a descriptive assessment of minimal residual disease (MRD) levels during study treatment.

Further secondary measures include the time to treatment discontinuation, the rate of patients experiencing at least one treatment interruption, and the delay of subsequent cycles, dose reductions, or interruptions in study drug administration. The duration of patient hospitalization and quality of life (QoL) will also be evaluated, with QoL being measured through the EORTC QLQ-C30 instrument. These efficacy parameters will be collected and analyzed at specified timepoints throughout the trial to provide a comprehensive assessment of the treatment's impact on patients with acute myelogenous leukemia who are not eligible for standard induction therapy.