Efficacy of Venetoclax and Decitabine in Acute Myeloid Leukemia Secondary to Myeloproliferative Neoplasms Unfit for Intensive Chemotherapy

The primary objective of this Phase 2, multi-center trial is to evaluate the **efficacy** of the VEN-DEC regimen, a combination of **venetoclax** and **decitabine**, in patients with **Acute Myeloid Leukemia** (AML) secondary to myeloproliferative neoplasms who are unfit for intensive chemotherapy. The efficacy is measured by event-free survival (EFS), which is clinically relevant as it provides insight into the duration patients remain free from events such as disease progression or relapse, thus indicating the potential of the treatment to improve patient outcomes.

Secondary objectives include assessing the feasibility and safety of the VEN-DEC regimen through: - Adverse events rate according to CTCAE criteria - Rate of death in aplasia - Days to neutrophil recovery - Days to platelet recovery after the first and second cycle

Additionally, the efficacy of the regimen is further evaluated by: - Rate of Acute Leukemia Response-Complete (ALR-C) at first and second time-points after respective cycles - Overall response rate after each cycle - Disease-free survival (DFS) - Overall survival (OS) - Cumulative incidence of relapse (CIR) - Treatment-related mortality (TRM) - Transfusion need (RBC and platelet) at 3 and 6 months of treatment

The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia** secondary to myeloproliferative neoplasms. The study population includes both male and female subjects, aged 60 years and older, or adult patients deemed unfit for intensive chemotherapy. The trial does not specify the total number of participants, as this information was not provided by the sponsor. Participants were selected based on their diagnosis of untreated, newly diagnosed secondary AML according to WHO 2016 criteria, and an ECOG performance status of 0-2, or a reversible ECOG 3 score following adequate supportive care. The trial includes a vulnerable population, and all participants provided signed written informed consent in accordance with ICH/EU/GCP and national local laws. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is a Phase II, prospective, multi-center intervention study designed to evaluate the efficacy of a combination treatment regimen involving **decitabine** and **venetoclax** in patients with **Acute Myeloid Leukemia** (AML) secondary to myeloproliferative neoplasms who are unfit for intensive chemotherapy. The trial employs a randomized, double-blind, controlled design to ensure the reliability and validity of the results. The primary objective is to assess the event-free survival (EFS) at one year, with secondary endpoints including the feasibility and safety of the regimen, response rates, disease-free survival, overall survival, and treatment-related mortality.

The trial is expected to run from December 2021 to June 2026, with participant involvement lasting up to 168 days, depending on individual response and treatment tolerance. The study begins with an inclusion (screening) visit to confirm eligibility based on criteria such as age, performance status, and disease characterization. Participants will then undergo a series of treatment cycles, with follow-up visits scheduled to monitor response and adverse events. 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 unacceptable toxicity, disease progression, or if they withdraw consent. The trial is conducted in accordance with ICH/EU/GCP guidelines, ensuring ethical standards and participant safety. The study aims to provide valuable insights into the treatment of AML secondary to myeloproliferative neoplasms, potentially offering a new therapeutic option for patients who are not candidates for intensive chemotherapy.

The clinical trial involves the administration of **Venclyxto** (venetoclax) in three different dosages: 100 mg, 50 mg, and 10 mg film-coated tablets. **Venclyxto** is a chemical compound provided by AbbVie Deutschland GmbH & Co. KG. The pharmaceutical form is a film-coated tablet, and the route of administration is oral. The maximum daily dose for the 100 mg tablets is 400 mg, with a total maximum dose of 67.2 g over a treatment period of 168 days. For the 50 mg tablets, the maximum daily dose is 200 mg, with a total maximum dose of 200 mg over a 1-day treatment period. The 10 mg tablets have a maximum daily dose of 100 mg, with a total maximum dose of 100 mg over a 1-day treatment period. Participant compliance is monitored through regular assessments to ensure adherence to the dosing schedule.

**Dacogen** (decitabine) is also utilized in this trial, provided by Janssen-Cilag International NV. It is supplied as a 50 mg powder for concentrate for solution for infusion. The pharmaceutical form is a solution for infusion, and the route of administration is intravenous. The maximum daily dose is 20 mg/m², with a total maximum dose of 600 mg/m² over a treatment period of 30 days. **Dacogen** is designated as an orphan drug for this study. Compliance with the dosing schedule is monitored through infusion records and patient assessments.

The trial does not include any non-experimental treatments such as standard-of-care therapy or placebo. The primary objective is to evaluate the efficacy of the VEN-DEC regimen, which combines **venetoclax** and **decitabine**, in patients with acute myeloid leukemia secondary to myeloproliferative neoplasms who are unfit for intensive chemotherapy. The efficacy is measured as event-free survival (EFS) in the target patient population. All substances used in the trial are of chemical origin, and the study is conducted in accordance with regulatory standards for clinical trials.

The efficacy of the VEN-DEC regimen in the clinical trial will be assessed primarily through the measurement of **event-free survival (EFS)** in patients with acute myeloid leukemia (AML) secondary to myeloproliferative neoplasms (MPN) who are unfit for intensive chemotherapy. EFS is defined as the time from the start of treatment to the occurrence of primary refractory disease, first relapse, or death from any cause, whichever occurs first. The primary endpoint is to evaluate the EFS at one year for patients receiving the experimental VEN-DEC combination.

Secondary efficacy assessments will include several parameters: the response rate categorized as at least Acute Leukemia Response-Complete (ALR-C) at the first time-point after the first cycle (ALR-C-T1), overall response rate at the first time-point after the first cycle categorized as ALR-C-T1 plus ALR-P-T1, response rate categorized as at least ALR-C at the second time-point after the second cycle (ALR-C-T2), and overall response rate after the second cycle categorized as ALR-C-T2 plus ALR-P-T2. Additional secondary endpoints include disease-free survival (DFS), overall survival (OS), cumulative incidence of relapse (CIR), treatment-related mortality (TRM), and transfusion needs, defined as the number of red blood cell (RBC) and platelet units transfused over three and six months of treatment.

The feasibility and safety of the VEN-DEC regimen will also be evaluated by monitoring adverse events as per v5.0 CTCAE criteria, the rate of deaths in aplasia as per ELN 2017 definition, and the days to neutrophil and platelet recovery after the first and second cycles in responding patients. These assessments will provide comprehensive data on the efficacy and safety of the VEN-DEC regimen in the specified patient population.