Phase 2 Evaluation of Naxitamab and Sargramostim in High-Risk Neuroblastoma with Refractory or Incomplete Response in Bone/Bone Marrow

The primary objective of this pivotal Phase 2 trial is to evaluate the centrally assessed **objective response rate (ORR)** to the combination of naxitamab and **granulocyte-macrophage colony-stimulating factor (GM-CSF)** in patients with high-risk neuroblastoma who exhibit primary refractory disease or an incomplete response to salvage treatment in bone and/or bone marrow. This assessment is clinically relevant as it aims to determine the efficacy of the treatment regimen in inducing a measurable response in a challenging patient population, potentially guiding future therapeutic strategies.

Secondary objectives include: - Evaluating the safety of naxitamab + GM-CSF. - Assessing the Duration of Response (DoR) to the treatment. - Determining the complete response (CR) rate. - Evaluating the investigator-assessed objective response rate. - Analyzing the pharmacokinetics (PK) of naxitamab. - Investigating the formation of Anti-Drug Antibodies (ADAs). - Evaluating the safety of the treatment in patients with positive ADA at trial entry. - Assessing the quality of life (QoL) of patients. These secondary objectives are crucial for understanding the broader impact of the treatment, including its safety profile, duration and quality of response, and potential immunogenicity, which are essential for comprehensive clinical evaluation and patient management.

The clinical trial involves a total of **41 participants** diagnosed with high-risk **neuroblastoma**, specifically those with primary refractory disease or an incomplete response to salvage treatment in bone and/or bone marrow. The study population includes both male and female subjects, with an age range starting from 12 months. Participants were selected based on their documented diagnosis of neuroblastoma, as defined by specific histopathological criteria, and their disease status, which must be evaluable in bone and/or bone marrow. The trial does not include a vulnerable population. Participants are required to have a life expectancy of at least six months and must meet acceptable hematological, liver, and kidney function criteria. Lifestyle considerations such as diet and physical activity are not specified in the trial data provided. The selection process ensures that participants have a stable health status to undergo the trial, with necessary medical support allowed prior to screening procedures.

The clinical trial is designed to evaluate the efficacy and safety of **naxitamab** in combination with **sargramostim** for the treatment of high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow. This is a pivotal Phase 2 trial employing a randomized, double-blind, controlled design. The trial is expected to span from February 28, 2018, to April 30, 2028, with the primary objective being the assessment of the objective response rate (ORR) to the treatment combination, centrally evaluated according to the International Neuroblastoma Response Criteria (INRC).

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as documented diagnosis of neuroblastoma, high-risk status, and acceptable hematological, liver, and kidney function. Following successful screening, participants will be randomized to receive either the investigational treatment or a control. The treatment period will include multiple follow-up visits to monitor safety and efficacy, with assessments of adverse events, serious adverse events, and other secondary endpoints such as duration of response and complete response rate. The end-of-study visit will conclude the participant's involvement, with a comprehensive evaluation of treatment outcomes.

The expected length of participant involvement in the trial is up to 101 days, corresponding to the maximum treatment period for **naxitamab**. Conditions that may lead to early termination from the study include significant adverse events, withdrawal of consent, or any other medical reasons deemed necessary by the investigator. The trial will adhere to rigorous scientific and ethical standards to ensure the integrity of the data and the safety of the participants.

The clinical trial involves the administration of two experimental medications. The first medication is **Leukine**, which contains the active substance **sargramostim**. It is provided in the pharmaceutical form of a **solution for injection**. The administration route is **subcutaneous use**. The dosage is measured in micrograms per square meter (µg/m²), with a maximum daily dose of 500 µg/m² and a total maximum dose of 2500 µg/m² over a treatment period of 5 days. The medication is classified as a biotechnological product and is not a pediatric formulation. Compliance with the dosing schedule is monitored throughout the trial.

The second experimental medication is a **humanized IgG1 monoclonal antibody against GD2**, known as **naxitamab**. This medication is provided as a **solution for infusion** and is administered via **intravenous use**. The dosage is calculated in milligrams per kilogram (mg/kg), with a maximum daily dose of 3 mg/kg and a total maximum dose of 9 mg/kg over a treatment period of 101 days. This medication is designated as an orphan drug and is also not a pediatric formulation. Participant compliance with the dosing regimen is carefully monitored to ensure adherence to the trial protocol.

No non-experimental treatments, such as standard-of-care therapy, placebo, or comparator treatments, are specified in the trial documentation. The trial's main objective is to evaluate the centrally assessed objective response rate (ORR) to the combination of naxitamab and GM-CSF in patients with high-risk neuroblastoma who have primary refractory disease or an incomplete response to salvage treatment in bone and/or bone marrow.

The efficacy of the treatment in this clinical trial will be assessed primarily through the **Objective Response Rate (ORR)** during the naxitamab treatment period. This will be centrally evaluated according to the International Neuroblastoma Response Criteria (INRC). Secondary endpoints include the complete response rate, also assessed during the naxitamab treatment period and according to the INRC, as well as the duration of response (DoR), which is defined as the time from the first objective response, either complete response (CR) or partial response (PR), to progressive disease (PD). Data for DoR will be censored at the date of the last disease evaluation before the initiation of new anti-neuroblastoma treatment.

Additional secondary endpoints involve the assessment of pharmacokinetics (PK) of naxitamab and the formation of anti-drug antibodies (ADA). The trial will also evaluate intravenous (IV) opioid use during cycle 1 and for each cycle throughout the trial, defined as the total dosage of IV morphine (or equivalent opioid) administered from 2 hours before infusion until 4 hours after the end of infusion of naxitamab. The number of hospitalization days related to naxitamab during cycle 1 will be recorded, excluding hospitalizations required solely for protocol-specified assessments or non-medical circumstances. Furthermore, the number and percentage of infusions conducted in an outpatient setting will be documented. In patients with positive ADA at trial inclusion, safety will be evaluated by the incidence of adverse events (AEs) and serious adverse events (SAEs) graded according to the Common Terminology Criteria for Adverse Events (CTCAE), version 4.0. Pain during naxitamab infusion will be assessed using the Wong Baker and FLACC scales.