Naxitamab for High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow

Study Overview
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Brief Summary
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Children and adults diagnosed with high-risk neuroblastoma patients with primary refractory disease or incomplete response to salvage treatment in bone and/or bone marrow will be treated for up to 101 weeks with naxitamab and granulocyte-macrophage colony stimulating factor (GM-CSF). Patients will be followed for up to five years after first dose. Naxitamab, also known as hu3F8 is a humanised monoclonal antibody targeting GD2

Detailed Description
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Each patient will receive treatment for up to 101 weeks following the first Naxitamab administration. After the end of trial visit, each patient will enter a long-term follow-up where they will be monitored for up to 5 years after first treatment cycle. Each investigational cycle is started with 5 days, days -4 to 0, of Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) administered at 250 µg/m2/day in advance of the start of Naxitamab administration. GM-CSF is thereafter administered at 500 µg/m2/day on days 1 to 5. As standard treatment, Naxitamab is administered at 3 mg/kg/day on days 1, 3, and 5, totalling 9 mg/kg per cycle. Treatment cycles are repeated every 4 weeks (±1 week) until complete response or partial response followed by 5 additional cycles every 4 weeks (±1 week). Subsequent cycles are repeated every 8 weeks (±2 weeks) through 101 weeks from first infusion at the discretion of the investigator. End of treatment will take place around 8 weeks after the last cycle and thereafter long-term follow-up will continue.

Official Title
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A Pivotal Phase 2 Trial of Antibody Naxitamab (hu3F8) and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) in High-Risk Neuroblastoma Patients With Primary Refractory Disease or Incomplete Response to Salvage Treatment in Bone and/or Bone Marrow

Conditions
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Neuroblastoma

Intervention / Treatment
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* Biological: GM-CSF + Naxitamab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis of neuroblastoma as defined per International Neuroblastoma Response Criteria High-risk neuroblastoma patients with either primary refractory disease or incomplete response to salvage treatment (in both cases including stable disease, minor response and partial response) evaluable in bone and/or bone marrow. Life expectancy ≥ 6 months Exclusion Criteria: Any systemic anti-cancer therapy, including chemotherapy or immunotherapy, within 3 weeks before 1st dose of GM-CSF Evaluable neuroblastoma outside bone and bone marrow Existing major organ dysfunction > Grade 2, with the exception of hearing loss, hematological status, kidney and liver function Active life-threatening infection

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients will receive cycles of GM-CSF and Naxitamab every 4 weeks up to a total of 101 weeks. Safety and efficacy will be investigated with short-term follow-up at minimum 4 weeks after last treatment and with long-term follow-up for up to 3 years after end of treatment visit.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GM-CSF + Naxitamab<br>Each investigational cycle is started with 5 days of GM-CSF administered at 250 µg/m2/day in advance of the start of Naxitamab administration. GM-CSF is thereafter administered at 500 µg/m2/day on days 1 to 5. As standard treatment, Naxitamab is administered at 3 mg/kg/day on days 1, 3, and 5 totalling 9 mg/kg per cycle. Treatment cycles are repeated every 4 weeks until CR or PR followed by 5 additional cycles every 4 weeks (±1 week). Subsequent cycles are repeated every 8 weeks (±2 weeks) through 101 weeks from first infusion at the discretion of the investigator. After end of treatment patients will enter a long-term follow up for up to 3 years after end of treatment visit. | Biological: GM-CSF + Naxitamab<br>* Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) and Humanized IgG1 monoclonal GD2 antibody<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response rate during Naxitamab treatment | Overall objective response rate (ORR) during the Naxitamab treatment period that will be centrally assessed according to the International Neuroblastoma Response Criteria (INRC) modified with 123I-MIBG criteria and following the use of 18F FDG-PET for MIBG non-avid lesions. | 101 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events and serious adverse events | Safety will be evaluated by the incidence of adverse events (AE) and serious adverse events (SAEs) graded according to CTCAE, version 4.0. | 101 weeks | 
| Duration of Response (DoR) | Length of time from patient response to disease progression. | 101 weeks | 
| Complete Response Rate | The complete response (CR) rate is defined as the fraction of patients experiencing a CR according to International Neuroblastoma Response Criteria (INRC) criteria during the treatment period. | 101 weeks | 
| Assessment of the maximum serum concentration (cmax) of naxitamab | Calculation of maximum serum concentration of naxitamab will be calculated and summarized with descriptive statistics. | Pre-naxitamab dose - 552 hours | 
| Assessment of the minimum serum concentration (cmin) of naxitamab | Calculation of minimum serum concentration of naxitamab will be calculated and summarized with descriptive statistics. | Pre-naxitamab dose - 552 hours | 
| Assessment of the clearance of naxitamab | Calculation of clearance of naxitamab will be calculated and summarized with descriptive statistics. | Pre-naxitamab dose - 552 hours | 
| Assessment of the volume of distribution of naxitamab | Calculation of the volume of distribution of naxitamab will be calculated and summarized with descriptive statistics. | Pre-naxitamab dose - 552 hours | 
| Assessment of the Area under the Curve (AUC) of naxitamab | Calculation of the AUC of naxitamab will be calculated and summarized with descriptive statistics. | Pre-naxitamab dose - 552 hours | 
| Assessment of the terminal half-life (t½) of naxitamab | Calculation of the t½ of naxitamab will be calculated and summarized with descriptive statistics. | Pre-naxitamab dose - 552 hours | 
| Assessment of anti-drug antibody (ADA) formation | ADA formation will be investigated following a multi-tiered approach: A screening confirmation-titration analysis plus a ligand binding assay to examine a potential neutralizing effect of anti-naxitamab antibodies. | Pre-naxitamab dose - 552 hours | 
| Intravenous (IV) opioid use (cycle 1) | IV opioid use during cycle 1 defined as total dosage of IV morphine (or equivalent opioid) administered 2 hours before infusion until 4 hours after end of infusion of naxitamab | 6 hours | 
| Intravenous (IV) opioid use (all cycles) | IV opioid use for each cycle during the trial defined as total dosage of IV morphine (or equivalent opioid) administered 2 hours before infusion until 4 hours after end of infusion of naxitamab | 101 weeks | 
| Hospitalization days (cycle 1) | Number of hospitalization days related to naxitamab during cycle 1, defined as number of overnight stays. Hospitalizations required solely for protocol-specified assessments (e.g., PK sampling) or non-medical circumstances are excluded | 4 weeks | 
| Safety of patients with positive human anti-drug antibody (ADA) | In patients with positive ADA at trial inclusion, safety will be evaluated by the incidence of AEs and SAEs graded according to CTCAE, version 4.0 | 101 weeks | 
| Number of infusions done in an outpatient setting | Number of infusions done in an outpatient setting | 101 weeks | 
| Percentage of infusions done in an outpatient setting | Percentage of infusions done in an outpatient setting | 101 weeks | 
| Incidence of adverse events and serious adverse events in ADA positive patients | Safety will be evaluated by the incidence of adverse events (AE) and serious adverse events (SAEs) graded according to CTCAE, version 4.0 in ADA positive patients. | 101 weeks | 
| Progression Free Survival (PFS) | PFS, defined as the time from the first 1st infusion of naxitamab until progressive disease or death, whichever comes first | 5 years | 
| Overall Survival | The interval from the date of first dose of Naxitamab until the date of death due to any cause. | 5 years | 
| Happiness and activity levels | Happiness and activity levels will be measured over time and assessed by caretaker | 39 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Antibody, Neuroblastoma, Pediatric, Adult