Phase III Randomized, Placebo-Controlled Study of Venetoclax with Induction and Consolidation Chemotherapy in Newly Diagnosed AML or MDS-EB2 Patients

The primary objective of this study is to evaluate whether treatment with **venetoclax**, in combination with induction and consolidation therapy, extends event-free survival (EFS) in adult patients with newly diagnosed **acute myeloid leukemia** (AML). This is clinically relevant as prolonging EFS can potentially improve patient outcomes by delaying disease progression and reducing the need for further interventions.

Secondary objectives include:

• Assessing if venetoclax, compared to placebo, prolongs overall survival (OS) in the same patient population.
• Evaluating the impact of venetoclax on complete remission (CR) and complete remission with incomplete hematologic recovery (CRi) rates by the end of induction chemotherapy.
• Determining the effect of venetoclax on CR rates by the end of induction chemotherapy.
• Assessing the rate of CR and CR/CRi without measurable residual disease (CRMRD-, CR/CRiMRD-) by the end of induction chemotherapy.
• Evaluating the impact of venetoclax on relapse-free survival (RFS).
• Assessing the cumulative incidence of relapse (CIR) and death (CID).
• Evaluating the impact of venetoclax on quality of life, using tools such as the EQ-5D-5L visual analogue scale (VAS), EORTC-QLQ-C30 global health status/QoL scale, and PROMIS Cancer Fatigue short form, version 7a.

The clinical trial involves a total of **85 participants** diagnosed with either **acute myeloid leukemia** (AML) or myelodysplastic syndrome with excess blasts-2 (MDS-EB2), as classified by the World Health Organization. The study population includes both male and female adults aged 18 years and older, with no upper age limit specified. Participants are required to have an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The selection criteria ensure that participants have adequate renal and hepatic function, as evidenced by specific laboratory parameters. Individuals with prior chemotherapy for AML, except for hydroxyurea used during the diagnostic phase, are excluded. The trial does not include a vulnerable population, and participants are expected to adhere to specific lifestyle considerations, such as the use of effective contraception methods and abstaining from donating sperm or ova during and after the study period. The trial population was selected based on their eligibility for intensive chemotherapy and the ability to provide informed consent.

The clinical trial is a **randomized**, **placebo-controlled**, Phase III study designed to evaluate the efficacy of **venetoclax** in combination with induction and consolidation chemotherapy in adult patients with newly diagnosed **acute myeloid leukemia** (AML) or **myelodysplastic syndrome with excess blasts-2** (MDS-EB2). The primary objective is to assess whether venetoclax prolongs event-free survival (EFS) compared to placebo. The trial is expected to run until June 2028, with recruitment having commenced in September 2022.

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 organ function. Following randomization, participants will receive either venetoclax or placebo alongside standard chemotherapy. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will conclude the participant's involvement, assessing final outcomes and any long-term effects.

The expected duration of participant involvement varies, with the maximum treatment period for venetoclax being 44 weeks. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or non-compliance with study protocols. The trial's design ensures rigorous monitoring and data collection to evaluate both primary and secondary endpoints, including overall survival, remission rates, and quality of life assessments.

The clinical trial involves the administration of several **experimental medications** and standard treatments to evaluate their efficacy in adult patients with newly diagnosed Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome with excess blasts-2. **Etoposide** is administered as a concentrate for solution for infusion. The maximum daily dose is 100 mg/m², with a total maximum dose of 500 mg/m² over a treatment period of 5 days. The route of administration is **intravenous**. Etoposide is classified under cytostatics and is of chemical origin.

**Venetoclax** is provided in the form of a film-coated tablet, with a maximum daily dose of 400 mg and a total maximum dose of 17,100 mg over a treatment period of 44 days. The administration route is **oral**. Venetoclax is a chemical compound and is used in combination with other treatments in this study.

**Daunorubicin** is administered as a powder for solution for infusion, with a maximum daily dose of 60 mg/m² and a total maximum dose of 360 mg/m² over a treatment period of 6 days. The route of administration is **intravenous**. Daunorubicin is categorized under anthracyclines and related substances, and it is of chemical origin.

**Mitoxantrone** is provided as a concentrate for solution for infusion, with a maximum daily dose of 10 mg/m² and a total maximum dose of 50 mg/m² over a treatment period of 5 days. The administration route is **intravenous**. Mitoxantrone is classified as an antineoplastic agent, specifically under anthracyclines and related substances, and is of chemical origin.

**Cytarabine** is administered as a concentrate for solution for infusion, with a maximum daily dose of 3000 mg/m² and a total maximum dose of 40,400 mg/m² over a treatment period of 22 days. The route of administration is **intravenous**. Cytarabine is classified under cytostatics and is of chemical origin.

In addition to the experimental medications, a **placebo** is used as a comparator treatment in this study. The placebo is administered in a manner consistent with the experimental treatments to ensure blinding and maintain the integrity of the trial. Participant compliance with the dosing schedules is monitored throughout the study to ensure adherence to the treatment protocol.

The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **event-free survival (EFS)** in adult patients with newly diagnosed acute myeloid leukemia (AML). EFS is defined as the time from randomization to treatment failure, death from any cause, relapse after achieving complete remission (CR) or CR with incomplete blood count recovery (CRi), or the start of new (non-study) therapy due to confirmed molecular progression or relapse, whichever occurs first. Treatment failure is defined as not attaining CR or CRi by induction chemotherapy, and the EFS event time for treatment failure is the date of randomization.

Secondary endpoints include overall survival (OS), defined as the time from randomization to death due to any cause, with patients still alive or lost to follow-up being censored at the time they were last known to be alive. The rate of CR or CRi in newly diagnosed AML patients is defined as the proportion of patients achieving CR/CRi by the end of induction chemotherapy. Additionally, the rates of CR and CR/CRi without measurable residual disease (CRMRD-, CR/CRiMRD-) will be evaluated by the end of induction therapy, defined as the proportion of patients achieving CR and CR/CRi with negativity for a genetic marker by RT-qPCR, and/or with negativity by multi-color flow cytometry, if studied pre-treatment.

Other secondary endpoints include relapse-free survival (RFS), cumulative incidence of relapse (CIR), cumulative incidence of death (CID), and quality of life assessments. RFS is defined as the time from achievement of a remission (CR/CRi) following induction therapy to morphologic relapse, start of new (non-study) therapy due to confirmed molecular progression or relapse, or death from any cause. CIR is measured from the date of achievement of a remission (CR/CRi) to the date of relapse or the start of new therapy due to confirmed molecular progression or relapse, with death in remission considered a competing event. CID is measured from the date of achievement of a remission (CR/CRi) to death without prior relapse, with relapse or start of new therapy due to confirmed molecular progression or relapse considered competing events. Quality of life will be assessed using the EQ-5D-5L visual analogue scale (VAS), EORTC-QLQ-C30 global health status/QoL scale and subdomains, and PROMIS Cancer Fatigue short form, version 7a.