Evaluation of Hydroxycarbamide Addition to Cytarabine and Daunorubicin Regimen in Newly Diagnosed Adult Acute Myeloid Leukemia

The primary objective of the HEAT-AML study is to evaluate the **safety** and tolerability of hydroxyurea (HU) at three different dose levels when added to standard acute myeloid leukaemia (AML) therapy, which includes cytarabine (ara-C) and daunorubicin. This involves assessing the frequency and severity of toxicities and determining the appropriate dose. Additionally, the study aims to assess the effect of HU on the rate of negative minimal residual disease (MRD-negativity) after the second standard chemotherapy cycle. These objectives are clinically relevant as they aim to enhance the therapeutic efficacy and safety profile of AML treatment, potentially leading to improved patient outcomes.

Secondary objectives include: - Assessing the time to haematopoietic recovery after each chemotherapy treatment cycle. - Evaluating the effect of HU on ara-CTP accumulation in peripheral blasts. - Determining the impact of HU on remission rates (CR/CRi/MLFS). - Assessing the effect of HU on event-free survival (EFS) and relapse-free survival (RFS) two years post-diagnosis. - Evaluating the impact of HU on overall survival (OS) two years after diagnosis. - Investigating the role of SAMHD1 protein expression in relation to the aforementioned secondary objectives.

The clinical trial involves participants who are newly diagnosed with **acute myeloid leukemia (AML)** and are aged 18 years or older. The study population includes both male and female subjects, with no specific upper age limit mentioned. Participants are required to have adequate renal and hepatic functions unless these are clearly related to the disease. The trial does not specify the total number of participants, as the sponsor has not provided this information. The selection of the trial population is based on the diagnosis of AML and related myeloid precursor neoplasia according to the WHO 2008 classification, excluding acute promyelocytic leukemia. Lifestyle considerations such as diet and physical activity are not detailed in the available data. The trial includes a vulnerable population, and male participants are required to use effective contraceptive methods during and after the study. Written informed consent is mandatory for participation.

The clinical trial is designed to evaluate the **safety** and **efficacy** of adding **hydroxycarbamide** to standard treatment regimens for adults with newly diagnosed acute myeloid leukaemia (AML). This study is a phase I/II, multi-center, randomized, double-blind, controlled trial. The trial aims to assess the tolerability of hydroxycarbamide at three different dose levels when combined with standard AML therapy, which includes **cytarabine** and **daunorubicin**. The primary endpoint is the achievement of minimal residual disease (MRD) negativity after the second chemotherapy cycle. Secondary endpoints include the safety profile, time to hematopoietic recovery, and overall efficacy measures such as response rate, event-free survival, relapse-free survival, and overall survival.

The trial is expected to run until December 31, 2027, with recruitment having commenced on September 2, 2019. Participants will be involved in the study for the duration of their treatment cycles, with the possibility of early termination if they experience unacceptable toxicity levels or if they withdraw consent. The study visits are structured as follows: an initial screening visit to confirm eligibility based on inclusion criteria such as age, diagnosis, and organ function, followed by regular follow-up visits to monitor treatment response and adverse events. The end-of-study visit will assess the final outcomes and any long-term effects of the treatment.

Participants are required to meet specific inclusion criteria, including a confirmed diagnosis of AML according to the WHO 2008 classification, adequate renal and hepatic function, and the ability to provide informed consent. Male participants must agree to use effective contraception during the study and for six months following treatment. The trial excludes individuals with conditions that could interfere with the study outcomes or those unable to comply with the study protocol. The study's design ensures rigorous monitoring of safety and efficacy, with data collected at each visit to inform ongoing assessments and potential adjustments to the treatment regimen.

The clinical trial involves the administration of **Hydroxycarbamide medac 500 mg capsule, hard** as an experimental medication. This pharmaceutical form is a hard capsule containing the active substance **hydroxycarbamide**. The route of administration is oral, and the dosing schedule involves three different dose levels to be determined during the trial. The primary objective is to assess the safety and tolerability of hydroxycarbamide when added to standard therapy for acute myeloid leukemia (AML). Participant compliance will be monitored through regular assessments and documentation of dosing adherence.

In addition to hydroxycarbamide, the study includes the administration of **Cytarabine STADA 20 mg/ml solution for injection**. This medication contains the active substance **cytarabine** and is administered intravenously. Cytarabine is part of the standard-of-care therapy for AML and will be used in conjunction with hydroxycarbamide and daunorubicin. The frequency and dosage of cytarabine will follow established protocols for AML treatment, ensuring consistency with standard therapeutic regimens.

The third component of the treatment regimen is **Cerubidin 20 mg solution for infusion**, which contains the active substance **daunorubicin**. This medication is also administered intravenously and is a standard component of AML therapy. The dosing schedule for daunorubicin will align with standard treatment protocols, and its administration will be closely monitored to ensure participant safety and adherence to the trial protocol.

Throughout the trial, participant compliance with the medication regimen will be monitored through regular follow-ups and documentation. The trial aims to evaluate the combined effect of hydroxycarbamide with standard AML therapy, focusing on the rate of negative minimal residual disease (MRD-negativity) after the second standard chemotherapy cycle. The study will adhere to rigorous safety and efficacy assessments to ensure the reliability of the trial outcomes.

The efficacy of the clinical trial titled "HEAT-AML (Hydroxyurea-Enhanced Ara-C Treatment of Adult Acute Myeloid Leukaemia)" will be assessed primarily through the evaluation of **minimal residual disease (MRD) negativity** after the second standard chemotherapy cycle. MRD-negativity is defined as the absence of malignant blasts as a percentage of total bone marrow cells and as a percentage of the whole white blood cell compartment. These percentages are calculated based on the frequency of cells with an aberrant phenotype.

Secondary endpoints for efficacy assessment include the response rate, which encompasses complete remission (CR), complete remission with incomplete hematologic recovery (CRi), and morphologic leukemia-free state (MLFS). Additionally, event-free survival (EFS), relapse-free survival (RFS), and overall survival (OS) will be evaluated. The time to hematopoietic recovery, defined as the time from the start of each chemotherapy cycle until recovery of absolute neutrophil count (ANC) to 0.5 and 1.0 x 10⁹/L and platelets to 50 x 10⁹/L, will also be measured. These parameters will be collected and analyzed at specified timepoints throughout the trial to determine the efficacy of the treatment regimen.