Phase 2/3 Randomized Double-Blind Study of Liposomal Annamycin and Cytarabine vs. Placebo and Cytarabine in Refractory/Relapsed Acute Myeloid Leukemia

The primary objective of this study is to identify the optimal dosage regimen of **L-Annamycin** for Injection (190 versus 230 mg/m²/day) in combination with **Cytarabine** Injection (2.0 g/m²/day) as a second-line therapy for remission induction in adult subjects with refractory/relapsed **Acute Myeloid Leukemia** (AML). This is measured by the rate of complete remission (CR) after one treatment cycle. The clinical relevance of this objective lies in its potential to improve treatment outcomes for patients with refractory/relapsed AML, a condition with limited therapeutic options and poor prognosis.

Secondary objectives include:

• Identifying the optimal dosage regimen of L-Annamycin for Injection in combination with Cytarabine Injection as measured by safety and tolerability.
• Comparing the pharmacokinetics of annamycin, annamycinol (a metabolite of annamycin), and cytarabine when administered in combination with L-Annamycin or placebo.
• Comparing the efficacy of two dose levels of L-Annamycin in combination with Cytarabine versus placebo, as measured by duration of response (DoR), overall survival (OS), and rate of subsequent transplantation for subjects achieving CR or complete remission with partial hematological recovery (CRh) after one treatment cycle.
• Confirming the superior efficacy of the optimal dosage regimen of L-Annamycin in combination with Cytarabine versus placebo, as measured by DoR, OS, and rate of subsequent transplantation for subjects achieving CR or CRh.
• Further evaluating the pharmacokinetics of annamycin and annamycinol in additional subjects administered the optimal dosage regimen.

The clinical trial involves a total of **135 participants** diagnosed with **Acute Myeloid Leukemia** (AML), specifically targeting adult subjects with refractory or relapsed AML. The study population includes both male and female participants, aged between **18 and 80 years**. Participants were selected based on their confirmed diagnosis of AML according to the 2022 International Consensus Classification and the European LeukemiaNet recommendations. The trial excludes individuals who have undergone chemotherapy, radiation, or major surgery within two weeks prior to the study, except for those who have recovered from any toxic side effects. Participants are required to have an Eastern Cooperative Oncology Group performance status of 0 to 2 and a life expectancy of more than six weeks. The trial does not include a vulnerable population, and all participants must have adequate laboratory results at screening. Lifestyle considerations such as diet and physical activity are not specified, but participants must not have received any investigational therapy within four weeks prior to the study. The trial aims to evaluate the efficacy of L-Annamycin in combination with Cytarabine as a second-line therapy for remission induction in this specific patient group.

The clinical trial is designed as a **randomized**, **double-blind**, placebo-controlled study with an adaptive design, aimed at evaluating the efficacy of Liposomal Annamycin in combination with **cytarabine** versus placebo in combination with cytarabine for the treatment of adult subjects with refractory or relapsed **acute myeloid leukemia** (AML). The trial is divided into two parts: Part A focuses on identifying the optimal dosage regimen of Liposomal Annamycin (190 mg/m²/day versus 230 mg/m²/day) in combination with cytarabine (2.0 g/m²/day), while Part B aims to confirm the superior efficacy of the optimal dosage regimen determined in Part A. The primary endpoint is the rate of complete remission (CR) after one treatment cycle, with secondary endpoints including duration of response (DoR), overall survival (OS), rate of subsequent transplantation, pharmacokinetics, safety, and tolerability.

The trial is expected to commence recruitment on April 1, 2025, and conclude by March 28, 2029. Participants will be involved in the study for a maximum treatment period of 6 cycles, with each cycle lasting 35 days ± 14 days. The study includes several key visits: an initial screening visit to confirm eligibility based on criteria such as age, diagnosis, and prior treatment history; regular follow-up visits to monitor treatment response and safety; and an end-of-study visit to assess final outcomes. Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it necessary for their safety.

Inclusion criteria require participants to have a confirmed diagnosis of AML, be between 18 and 80 years of age, and have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Exclusion criteria are not explicitly detailed in the provided data. The trial's adaptive design allows for modifications based on interim results, ensuring the most effective treatment regimen is identified and confirmed. The study's rigorous methodology and comprehensive design aim to provide valuable insights into the treatment of refractory or relapsed AML, potentially improving therapeutic outcomes for this challenging condition.

The clinical trial involves the administration of **Liposomal Annamycin**, a solution for infusion, as an experimental treatment. Liposomal Annamycin is formulated for infusion and is administered at a dosage of 190 to 230 mg/m² per day. The maximum total dose is 1380 mg/m², with a treatment period not exceeding 6 days. The active substance, **Annamycin**, is a chemical compound classified under the ATC code L01DB, which pertains to anthracyclines and related substances. The administration route is via infusion, and the formulation is not pediatric-specific. Compliance with the dosing schedule is monitored throughout the trial.

**Cytarabine** is used as a comparator treatment in the study. It is available in two pharmaceutical forms: a solution for infusion and a solution for injection. The active substance, **Cytarabine**, is administered at a dosage of 2.0 g/m² per day, with a maximum total dose of 20 g/m² over a 10-day treatment period. The administration routes include infusion and intravenous infusion. Cytarabine is a chemical compound, and its use in the trial is not specific to pediatric formulations. Participant adherence to the dosing regimen is closely monitored.

The trial also includes the use of a **0.9% Sodium Chloride Injection, USP/Ph. Eur./BP/JP** as a placebo. This product serves as a non-experimental treatment and is used to maintain the double-blind nature of the study. The pharmaceutical form and administration details are not specified, and it is not a pediatric formulation. The placebo is used to ensure the integrity of the study's control group, and participant compliance is tracked to ensure accurate trial results.

Efficacy in this clinical trial will be assessed primarily by the **rate of complete remission (CR)** after one treatment cycle, which is defined as 35 days ± 14 days following the initiation of randomized treatment. This endpoint is crucial for evaluating the effectiveness of the treatment regimen in inducing remission in adult subjects with refractory or relapsed acute myeloid leukemia (AML).

Secondary efficacy endpoints include the duration of remission (DoR), overall survival (OS), and the rate of subsequent transplantation, such as allogeneic or autologous hematopoietic stem cell transplantation (alloHSCT/autoHSCT), for subjects who achieve CR or complete remission with partial hematologic recovery (CRh) at the specified timepoint. Additionally, pharmacokinetics of annamycin, annamycinol, and cytarabine will be evaluated in both Part A and Part B of the study. Safety and tolerability are also considered secondary endpoints, providing a comprehensive assessment of the treatment's efficacy and safety profile.