Phase I/II Study of Venetoclax, Cytarabine, and Mitoxantrone in Relapsed or Refractory Acute Myeloid Leukemia Eligible for Intensive Salvage Therapy

The primary objective of this Phase I/II clinical trial is to evaluate the **safety**, tolerability, maximum tolerated dose, and recommended Phase II dose of **venetoclax** when combined with increasing doses of **cytarabine** and a fixed dose of **mitoxantrone** in patients with relapsed or refractory acute myeloid leukemia (AML) who are deemed fit for intensive salvage therapy. This study is clinically relevant as it aims to optimize treatment regimens for AML patients who have limited options due to relapse or resistance to standard therapies, potentially improving outcomes in this challenging patient population.

The clinical trial involves **adult patients** aged 18 to 75 years, both male and female, diagnosed with **acute myeloid leukemia (AML)** at first or second relapse following intensive chemotherapy, including allogeneic stem cell transplantation, or those who are primary refractory to standard induction chemotherapy and eligible for intensive salvage treatment. The sponsor has not provided the total number of participants. The study population was selected based on their fitness for intensive chemotherapy, defined by an ECOG performance status of 0-2, a life expectancy greater than three months, and adequate hepatic and renal function. Participants must be afebrile and hemodynamically stable for at least 72 hours before the initiation of study medication. Relevant lifestyle considerations include the requirement for male subjects to refrain from unprotected sex and sperm donation, and for women of childbearing potential to use effective contraception methods. The trial does not include a vulnerable population.

The clinical trial is designed to evaluate the **safety**, tolerability, maximum tolerated dose, and recommended phase II dose of **venetoclax** in combination with increasing doses of **cytarabine** and a fixed dose of **mitoxantrone** in subjects with relapsed or refractory acute myeloid leukemia (AML) who are considered fit for intensive salvage therapy. This trial follows a **randomized**, **double-blind**, and controlled design, ensuring that neither the participants nor the researchers know which treatment the participants are receiving, thus minimizing bias. The trial is expected to run until September 30, 2025, with recruitment having started on April 6, 2020.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to assess eligibility based on criteria such as age, health status, and previous treatment history. The inclusion criteria require participants to be between 18 and 75 years old, have a confirmed diagnosis of AML according to WHO criteria, and be fit for intensive chemotherapy. Following the screening, participants will attend regular follow-up visits to monitor their response to the treatment and any adverse effects. The end-of-study visit will conclude the participant's involvement, where final assessments will be conducted to evaluate the primary and secondary endpoints of the trial.

The expected length of participant involvement in the trial is determined by the individual response to the treatment and the overall trial timeline. Conditions that may lead to early termination from the study include significant adverse reactions, withdrawal of consent, or any medical condition that, in the opinion of the investigator, would make continued participation detrimental to the participant's health. The primary endpoints of the trial include determining the maximum tolerated dose of cytarabine in combination with venetoclax and mitoxantrone, while secondary endpoints focus on the complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) rate.

The clinical trial involves the administration of **Venetoclax**, an orally bioavailable, small-molecule B-cell lymphoma-2 (Bcl-2) family inhibitor. Venetoclax is provided in the form of a film-coated tablet and is administered orally. The dosing schedule for Venetoclax is determined based on the trial phase and participant response, with the aim to establish the maximum tolerated dose and recommended phase II dose. Participant compliance with the dosing regimen is monitored throughout the study to ensure adherence to the protocol.

In addition to Venetoclax, the trial includes the administration of **Mitoxantrone Hydrochloride**, an antineoplastic agent classified under anthracyclines and related substances. Mitoxantrone is administered via intravenous infusion. The dosing of Mitoxantrone is fixed, and it is used in combination with increasing doses of Cytarabine to evaluate the safety and tolerability of the treatment regimen. The administration schedule is designed to optimize therapeutic outcomes while minimizing potential adverse effects.

**Cytarabine**, a cytostatic agent, is also utilized in this trial. It is administered through intravenous infusion, with the dose being escalated to determine the optimal combination with Venetoclax and Mitoxantrone. The trial aims to assess the safety profile and efficacy of this combination in patients with relapsed or refractory acute myeloid leukemia (AML) who are considered fit for intensive salvage therapy. The administration of Cytarabine is carefully monitored to ensure patient safety and to evaluate the pharmacodynamic interactions with the other agents in the study.

The efficacy of the clinical trial will be assessed using specific primary endpoints tailored to each phase of the study. In Phase I, the primary endpoint is the determination of the maximum tolerated dose of **cytarabine** when combined with **venetoclax** and **mitoxantrone** within a 3+3 dose-escalation design. This phase focuses on evaluating the safety and tolerability of the drug combination to establish a recommended dose for subsequent phases.

In Phase II, the primary endpoint is the rate of complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) in patients with relapsed or refractory acute myeloid leukemia (AML). This endpoint is crucial for assessing the therapeutic efficacy of the drug regimen in achieving disease remission. The trial will collect and analyze data on these endpoints to determine the effectiveness of the treatment protocol.