A phase 1/2 multicenter open-label study to investigate treatment of hydroxyurea (HU) in combination with valproic acid (VPA) or 6- mercaptopurine (6-MP) in combination with VPA in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) considered unfit for standard chemotherapy

The primary objective of this study is to determine the **safety** and tolerability of the treatment combinations of hydroxyurea with valproic acid, and 6-mercaptopurine with valproic acid, administered at established clinical doses in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) who are considered unfit for standard chemotherapy. Additionally, the study aims to establish the preliminary efficacy of these treatment combinations, as defined by the protocol, and to evaluate changes in patients' performance status from baseline throughout the study period. These objectives are clinically relevant as they address the need for alternative therapeutic options for patients who cannot undergo standard chemotherapy, potentially improving patient outcomes and quality of life.

Secondary objectives include:

• Survival analyses to assess the impact of the treatment on patient longevity.
• Evaluation of changes in reported Quality of Life (QoL) compared to baseline, providing insights into the treatment's impact on patients' daily living and well-being.
• Exploratory analyses to examine baseline and longitudinal potential biomarker expression that may predict pharmacologic activity and outcome, offering a deeper understanding of the treatment's biological effects.
• Analysis of longitudinal biomarker expression in relation to treatment response, which could inform future therapeutic strategies.
• Exploratory assessment of serum concentrations of valproic acid in relation to treatment response, if feasible, to optimize dosing strategies.

The clinical trial involves participants diagnosed with **Acute Myeloid Leukemia (AML)**, including those with relapsed or refractory AML, secondary AML (sAML), high-risk myelodysplastic syndromes (MDS), or acute promyelocytic leukemia not eligible for standard therapy. The study population comprises both male and female adults aged 18 years or older. Participants are required to have adequate renal and hepatic function, as well as an **ECOG performance status** of 0, 1, or 2. The trial does not include a vulnerable population. The sponsor has not provided information regarding the total number of participants. Selection criteria include individuals not eligible for standard therapy, either due to a high HCT-CI score or personal choice, and those with adequate organ function as defined by specific laboratory values. Participants must provide written informed consent and adhere to contraception requirements if of reproductive potential. The trial does not impose specific lifestyle considerations such as diet or physical activity.

The clinical trial is designed as a **phase 1/2 multicenter open-label study** to evaluate the treatment of **hydroxyurea** in combination with **valproic acid** or **6-mercaptopurine** in combination with valproic acid in patients diagnosed with **acute myeloid leukemia (AML)** or high-risk myelodysplastic syndrome (HR-MDS) who are considered unfit for standard chemotherapy. The primary objectives are to determine the safety and tolerability of these treatment combinations and to establish their preliminary efficacy. The trial is expected to run until September 2032, with recruitment having commenced in February 2023.

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 renal and hepatic function. Following the screening, participants will be enrolled in the study and will attend regular follow-up visits to monitor safety, tolerability, and clinical benefit. These visits will include physical examinations, laboratory tests, and assessments of performance status using the Eastern Cooperative Oncology Group (ECOG) scale. The end-of-study visit will conclude the participant's involvement, during which final assessments will be conducted.

The expected length of participant involvement will vary depending on individual response to treatment and the occurrence of any adverse events. Conditions that may lead to early termination from the study include the development of unacceptable toxicity, withdrawal of consent, or any other medical condition that, in the opinion of the investigator, warrants discontinuation. The trial will employ established clinical doses of the study drugs, which are administered orally, and will utilize health-related quality of life questionnaires to assess the impact of treatment on participants' well-being.

The clinical trial involves the administration of **VALPROIC ACID**, also known as **SODIUM VALPROATE** or Sodium Dipropylacetate, which is an antiepileptic medication. The pharmaceutical form of this medication is coded as PHF00211MIG. It is administered orally, and the dosing schedule is determined based on established clinical doses. The medication is not a pediatric formulation and is not classified as an orphan drug. Participant compliance with the dosing regimen will be monitored throughout the study.

**HYDROXYCARBAMIDE**, also referred to as **HYDROXYUREA**, is another experimental medication used in this trial. It is a cytostatic agent with the pharmaceutical form coded as PHF00082MIG. This medication is also administered orally at established clinical doses. Similar to VALPROIC ACID, HYDROXYCARBAMIDE is not a pediatric formulation and is not designated as an orphan drug. The trial will ensure adherence to the dosing schedule through regular monitoring.

The third experimental medication is **MERCAPTOPURINE**, known by synonyms such as 3,7-DIHYDROPURINE-6-THIONE and 6-MERCAPTOPURINE. It is a cytostatic agent with the pharmaceutical form coded as PHF00245MIG. Administration is oral, and dosing follows established clinical guidelines. This medication is not formulated for pediatric use and does not have orphan drug status. Compliance with the treatment regimen will be assessed throughout the trial period.

In this study, the experimental medications are used in combination to evaluate their safety, tolerability, and preliminary efficacy in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) who are considered unfit for standard chemotherapy. The trial does not include any non-experimental treatments such as placebo or comparator treatments. The focus is on the combination of these medications to assess their potential clinical benefits.

Efficacy in this clinical trial will be assessed through a combination of primary and secondary endpoints. The primary endpoints include determining the clinical benefit in patients receiving **hydroxyurea** in combination with **valproic acid** and in those receiving **6-mercaptopurine** in combination with **valproic acid**. Additionally, the baseline and longitudinal Eastern Cooperative Oncology Group (ECOG) performance status of the patients will be evaluated. Secondary endpoints will focus on the percentage of patients with clinical benefit after 3 and 6 cycles in each treatment arm, overall response rate (ORR) as defined by the European LeukemiaNet (ELN) response criteria 2022, duration of clinical benefit, time to progression, and overall survival (OS).

Health-related quality of life will be assessed using validated questionnaires such as EQ-5D-5L, SF-36, QLQ-C30, and NCI-PRO-CTCAE. The trial will also monitor the number of hospital admissions and blood or platelet transfusions during and after the study compared to baseline. These assessments will be conducted at specified intervals throughout the study period to ensure comprehensive data collection and analysis. The trial aims to establish the preliminary efficacy of the treatment combinations at established clinical doses in patients with acute myeloid leukemia (AML) or high-risk myelodysplastic syndrome (HR-MDS) who are considered unfit for standard chemotherapy.