An ALFA 2101 multicenter randomized phase II study: CPX-351 versus intensive chemotherapy in patients with de novo intermediate or adverse risk AML stratified by genomics

The primary objective of this study is to demonstrate an improvement in the proportion of patients with **Acute Myeloid Leukemia** (AML) achieving deep remission, defined as Complete Remission (CR) or Complete Remission with incomplete hematologic recovery (CRi), with a standardized flow-based Minimal Residual Disease (MRD) threshold of less than 10^-3 in the bone marrow aspirate. This is assessed using the LAIP/Dfn method after the first course of treatment induction in both the experimental arm (induction by CPX-351) and the control arm (induction by 3+7 regimen with idarubicin and cytarabine). Achieving deep remission is clinically relevant as it is associated with improved long-term outcomes and reduced risk of relapse in AML patients.

The secondary objectives include:

• Comparing the proportion of patients achieving CR/CRi with a flow-based MRD threshold of less than 10^-3 in the bone marrow using the LAIP/Dfn method between the experimental and control arms.
• Evaluating the flow-based MRD quantified in the bone marrow and peripheral blood using both the LAIP/DfN and LSC methods at various treatment stages.
• Comparing NGS-based MRD results at different treatment points.
• Assessing clinical outcomes such as overall response rate, CR and CRi rates, cumulative incidence of allogeneic HSCT, early mortality, overall survival, relapse-free survival, event-free survival, and cumulative incidence of relapse.
• Evaluating hematological and non-hematological toxicity profiles and safety using the NCI common toxicity criteria (CTCAE) version 5.0.
• Analyzing changes in the genomic landscape with treatment and the association between somatic mutations and clinical outcomes.
• Assessing quality of life through patient self-assessment.
• Exploring secondary-type mutational profiles, functional flow cytometry assays, and changes in the phenotype of leukemic stem cells and hematopoietic progenitors.

The clinical trial focuses on patients diagnosed with **Acute Myeloid Leukemia** (AML). The study population includes both male and female participants aged 50 years and older. Participants are required to have a performance status of 2 or lower according to the ECOG grading system, indicating they are ambulatory and capable of all self-care but unable to carry out any work activities. The trial does not include vulnerable populations. The selection criteria specify that participants must have de novo AML without MRC-defining cytogenetic lesions, specific chromosomal translocations, or mutations such as NPM1 or FLT3. Additionally, participants should not have received prior treatment for AML, except for a short course of hydroxyurea in cases of high white blood cell count or tumor symptoms. The sponsor has not provided information regarding the total number of participants in the trial. Lifestyle considerations such as diet and physical activity are not specified in the available data.

The clinical trial is designed as a **randomized**, **controlled**, and **double-blind** study to evaluate the efficacy of CPX-351 compared to intensive chemotherapy in patients with de novo intermediate or adverse risk **Acute Myeloid Leukemia** (AML). The trial aims to demonstrate an improvement in the proportion of patients achieving deep remission with a standardized flow-based minimal residual disease (MRD) threshold in the bone marrow aspirate after the first course of treatment induction. The study will involve two arms: the experimental arm with induction by CPX-351 and the control arm with induction by a combination of idarubicin and cytarabine.

The trial is expected to last until June 2027, with recruitment having commenced in June 2022. Participants will be involved in the study for a maximum treatment period of up to 16 weeks, depending on the treatment arm and response to therapy. The study includes several key visits: an initial screening visit to confirm eligibility based on inclusion criteria such as age, performance status, and specific genetic markers, followed by multiple treatment visits for induction and consolidation therapy. Follow-up visits will be scheduled to monitor response and safety, with the end-of-study visit marking the completion of the participant's involvement.

Participants may be withdrawn from the study early if they experience unacceptable toxicity, withdraw consent, or if the investigator deems it in the participant's best interest. The primary endpoint is to compare the proportion of patients achieving a complete remission (CR) or complete remission with incomplete hematologic recovery (CRi) with a flow-based MRD threshold in the bone marrow aspirate. Secondary endpoints include overall response rate, overall survival, and quality of life assessments, among others. The trial will utilize standardized methods for MRD assessment and genomic analysis to evaluate treatment efficacy and safety comprehensively.

The clinical trial involves the administration of **Vyxeos Liposomal**, a combination of **cytarabine** and **daunorubicin**. This experimental medication is provided as a powder for concentrate for solution for infusion, specifically formulated for intravenous administration. The dosage is calculated based on body surface area, with a maximum daily dose of 44 mg/m² and a total maximum dose of 336 mg/m² over a treatment period of up to 9 days. The pharmaceutical form is a solution for infusion, and the product is manufactured by Jazz Pharmaceuticals Ireland Ltd. The active substances, cytarabine and daunorubicin, are of chemical origin and are utilized in the treatment of acute myeloid leukemia (AML).

In the control arm of the study, **cytarabine** is used as a comparator treatment. It is administered as a solution for injection or infusion, also via the intravenous route. The maximum daily dose for cytarabine is 1500 mg/m², with a total maximum dose of 28,400 mg/m² over a treatment period of up to 16 days. This comparator treatment is of chemical origin and is a standard component in the intensive chemotherapy regimen for AML.

Another comparator treatment in the study is **idarubicin**, which is administered as a solution for injection. Like the other treatments, it is given intravenously. The maximum daily dose of idarubicin is 12 mg/m², with a total maximum dose of 36 mg/m² over a treatment period of up to 3 days. Idarubicin is also of chemical origin and is commonly used in combination with cytarabine in the treatment of AML.

Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol. The trial aims to evaluate the efficacy of Vyxeos Liposomal compared to the standard intensive chemotherapy regimen in achieving deep remission in patients with de novo intermediate or adverse risk AML.

Efficacy in this clinical trial will be assessed by evaluating the proportion of patients achieving **Complete Remission (CR)** or **Complete Remission with incomplete hematologic recovery (CRi)** with a flow-based minimal residual disease (MRD) threshold of less than 10^-3 in the bone marrow aspirate. This will be measured using the LAIP/DfN method after the first course of induction therapy. The primary endpoint is to compare this proportion between the experimental arm, which involves induction by CPX-351, and the control arm, which involves induction by the 3+7 regimen with idarubicin and cytarabine. The assessment will occur at Day 1 of, or the day before, the first consolidation cycle.

Secondary endpoints include comparing the best response of CR/CRi with the same MRD threshold, regardless of the number of treatment courses required to achieve this response. Additional comparisons will be made between stratified randomization arms using both the LAIP/DfN and LSC methods at various timepoints, including Day 1 of the third treatment cycle and 28-42 days after the last consolidation cycle or before allogeneic hematopoietic stem cell transplantation (HSCT), if applicable. The study will also compare MRD results between bone marrow and peripheral blood, and evaluate NGS-based MRD at specified timepoints.

Other secondary endpoints include overall response rate, cumulative incidence of allogeneic HSCT, early mortality rates at Days 30, 60, and 100 post-randomization, overall survival, relapse-free survival, event-free survival, and cumulative incidence of relapse. Safety and toxicity profiles will be assessed using the NCI common toxicity criteria (CTCAE) version 5.0. The trial will also explore genomic correlations, quality of life using the EORTC QLQ-C30 questionnaire, and changes in the phenotype of leukemic stem cells and hematopoietic progenitors in relation to drug resistance.