Phase III Clinical Trial for CPX-351 in Myeloid Leukemia in Children with Down Syndrome 2018

The primary objective of this Phase III clinical trial is to evaluate the **event-free survival (EFS)** in children with **Myeloid Leukemia** associated with **Down Syndrome**, ensuring it is not inferior to the results of the ML-DS 2006 trial, which reported a 5-year EFS of 87±3%. This objective is clinically relevant as it aims to confirm the efficacy of CPX-351, a formulation containing **cytarabine** and **daunorubicin**, in maintaining or improving survival outcomes in this specific pediatric population.

Secondary objectives include:

• Reduction of toxicity by assessing severe adverse events of grade III or higher according to CTCAE v4.0.
• Identification of prognostic factors, such as trisomy 8, that may influence the risk of relapse, toxicity, and poor outcomes.
• Evaluation of the role of different methods in determining minimal residual disease measurement.
• Assessment of the response rate to the treatment.

The clinical trial involves a total of **18 participants** diagnosed with **Myeloid Leukemia in Children with Down Syndrome**. The study population includes both male and female subjects, specifically children aged over 6 months and up to 6 years. Participants are required to have a **Lansky performance score** or **Karnofsky performance status** of at least 50, indicating a certain level of general health status. The trial population was selected based on specific criteria, including the presence of **Trisomy 21** (Down syndrome or mosaic) and certain morphological or immunophenotyping characteristics such as FAB M0, M6, or M7. Participants must be able to adhere to the study visit schedule and other protocol requirements, and they must accept that vaccination with live vaccines is not possible during the trial. The trial includes a vulnerable population, as it involves children with a serious health condition. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed to evaluate the efficacy and safety of **Vyxeos Liposomal** in treating **Myeloid Leukemia in Children with Down Syndrome**. This is a Phase III, randomized, double-blind, controlled trial. The primary objective is to achieve an event-free survival (EFS) that is not inferior to the ML-DS 2006 trial, with a 5-year EFS rate of 87±3%. The trial is expected to run from January 1, 2021, to January 1, 2028, with a maximum treatment period of 112 days for each participant.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, **Down syndrome** status, and specific leukemia characteristics. Following the screening, participants will be randomized to receive the investigational product or control. The trial includes multiple follow-up visits to monitor treatment response, adverse events, and overall health status. The end-of-study visit will assess the final outcomes, including EFS, overall survival, and secondary endpoints such as disease-free survival and treatment-related mortality.

Participant involvement is expected to last for the duration of the treatment period, with additional follow-up visits as required by the protocol. Conditions that may lead to early termination from the study include failure to adhere to the study protocol, withdrawal of consent, or the occurrence of significant adverse events. The trial will utilize **intravenous infusion** as the route of administration for the investigational product, with a maximum daily dose of 100 units and a total dose not exceeding 500 units. The study will adhere to ethical guidelines, ensuring informed consent is obtained from the legal representatives of the participants.

The clinical trial involves the administration of **Vyxeos Liposomal**, a pharmaceutical product formulated as a **powder for concentrate for solution for infusion**. This experimental medication contains the active substances **cytarabine** and **daunorubicin**, both of which are of chemical origin. The product is manufactured by Jazz Pharmaceuticals Ireland Ltd. Vyxeos Liposomal is administered via **intravenous infusion**. The maximum daily dose is 100 units, with a total maximum dose of 500 units over the course of the treatment. The treatment period is limited to a maximum of 112 days. The product is specifically labeled for the study, and it is not a pediatric formulation.

In this trial, no non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatments are utilized. The study focuses solely on the administration of Vyxeos Liposomal. Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to achieve an event-free survival (EFS) rate that is not inferior to the ML-DS 2006 trial, with a target 5-year EFS of 87±3% in children with Down syndrome affected by myeloid leukemia.

Efficacy in the clinical trial for CPX-351 in children with Down Syndrome and **Myeloid Leukemia** will be assessed using several primary and secondary endpoints. The primary endpoint is **Event-Free Survival (EFS)**, defined as the time from diagnosis to the first event or last follow-up, with events including death from any cause, failure to achieve remission, relapse, and secondary malignancy. Failure to achieve remission is considered an event on day 0.

Secondary endpoints include **Overall Survival (OS)**, defined as the time from diagnosis to death from any cause or last follow-up, **Disease-Free Survival (DFS)**, and **Early Response Rate** (CR, CRp, CRi) after induction. Additional secondary endpoints are **Treatment-Related Mortality (TRM)**, **Minimal Residual Disease** assessed by FACS and NGS, **Adverse Events** according to NCI CTCAE v4.0, and the **Duration of Myelosuppression**, specifically when neutrophil counts are less than 0.5 Gpt/L.