Phase III Randomized Trial of Decitabine, Venetoclax, and Tretinoin in Acute Myeloid Leukemia Patients Ineligible for Induction Chemotherapy

The primary objective of this study is to evaluate the **efficacy** of all-trans retinoic acid (ATRA) compared to placebo as an adjunct to the standard treatment regimen of decitabine (DAC) and venetoclax (VEN) in patients with newly diagnosed acute myeloid leukemia (AML) who are ineligible for induction chemotherapy. The primary endpoint is overall survival (OS), which is a critical measure of treatment effectiveness in this patient population, as it directly correlates with the potential to extend life expectancy.

Secondary objectives include:

• Comparing ATRA versus placebo in terms of objective best response, which encompasses complete remission (CR) with or without full hematopoietic regeneration (CRi), morphologic leukemia-free state (MLFS), or partial remission (PR).
• Assessing CR with negative measurable residual disease (CRMRD-).
• Evaluating the probability of survival associated with the objective best response.
• Investigating the impact on quality of life and safety.

The clinical trial involves participants diagnosed with **newly diagnosed acute myeloid leukemia (AML)**. The study population includes both male and female subjects aged 18 years and older. Participants are required to have a previously untreated AML diagnosis as per WHO 2016 criteria, with an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less. The trial does not include a vulnerable population. Participants must have a white blood cell count of less than 25×10⁹/L, with allowances for hydroxyurea or Ara-C to meet this criterion. The trial targets individuals for whom standard induction chemotherapy is not feasible or beneficial, including those aged 75 years or older, with an ECOG of 1 or higher, a Hematopoietic Cell Transplantation Comorbidity Index (HCT-CI) of 3 or more, adverse genetics, or those who decline standard aggressive chemotherapy. A projected life expectancy of at least 8 weeks is required, along with the ability to understand and comply with trial procedures. Written informed consent is mandatory. The sponsor has not provided information regarding the total number of participants in the trial.

The clinical trial is a **randomized**, double-blind, controlled study designed to evaluate the efficacy of all-trans retinoic acid (ATRA) versus **placebo** as an adjunct to the standard treatment regimen of decitabine and venetoclax in patients with newly diagnosed **acute myeloid leukemia** (AML) who are ineligible for induction chemotherapy. The trial is a phase III study, with an estimated duration from October 2022 to September 2027. Participants will be randomly assigned to receive either ATRA or placebo, both administered orally in encapsulated form to ensure blinding. The primary endpoint is overall survival, while secondary endpoints include objective best response, quality of life assessments, and other clinical measures.

The trial will commence with a screening visit to confirm eligibility based on criteria such as age, untreated AML status, and specific health parameters. Following successful screening, participants will be enrolled and begin the treatment phase, which spans a maximum of 60 days. During this period, regular follow-up visits will be scheduled to monitor the participants' health status, treatment adherence, and any adverse events. These visits are crucial for assessing the efficacy and safety of the treatment regimen. The end-of-study visit will occur after the treatment phase, where final assessments will be conducted to evaluate the primary and secondary endpoints.

Participant involvement is expected to last for the duration of the treatment phase, approximately 60 days, with additional time allocated for follow-up assessments. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any medical condition that contraindicates continued participation. The study is conducted under strict ethical guidelines, ensuring that all participants provide informed consent and are fully aware of the trial's nature and procedures.

The clinical trial involves the administration of **Tretinoin**, marketed under the name Vesanoid 10 mg Kapseln, which is provided in the form of a soft capsule. The active substance, Tretinoin, is of chemical origin and is encapsulated in hard gelatin capsules to maintain blinding. The dosage is calculated based on body surface area, with a maximum daily dose of 45 mg/m² and a total maximum dose of 1035 mg/m² over the treatment period. The route of administration is oral, and the treatment duration is set for a maximum of 60 days. Participant compliance will be monitored through regular assessments to ensure adherence to the dosing schedule.

The trial also includes a **Placebo** control, supplied as P-Tabletten weiß 7 mm Lichtenstein, which is manufactured to be optically identical to the encapsulated Tretinoin capsules. The placebo is provided in tablet form and is also administered orally. The placebo tablets contain no active pharmaceutical ingredients and are used to maintain the study's double-blind design. The placebo treatment is administered with the same frequency and duration as the Tretinoin treatment, ensuring consistency across the study arms. Compliance with the placebo regimen will be monitored similarly to the active treatment group.

The efficacy of the treatment in the clinical trial will be assessed primarily through the measurement of **Overall Survival (OS)** time. This parameter serves as the primary endpoint to evaluate the effectiveness of all-trans retinoic acid (ATRA) compared to placebo when added to the backbone treatment of decitabine and venetoclax in patients with acute myeloid leukemia who are ineligible for induction chemotherapy.

Secondary endpoints include the assessment of objective best response, which encompasses complete remission (CR), complete remission with incomplete hematologic recovery (CRi), morphologic leukemia-free state (MLFS), or partial remission (PR). Additionally, the trial will evaluate CR with negative minimal residual disease (CRMRD-), OS time with objective best response, and quality of life using the EORTC QLQ-C30, with a particular focus on fatigue, as well as the FACIT Fatigue Scale.