A Post-Authorisation Safety Study Patient Registry of Patients With Neuroblastoma Being Treated With Dinutuximab Beta

Study Overview
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Brief Summary
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This is a non-interventional, multi-national, observational, prospective patient registry to further evaluate the effectiveness and safety of dinutuximab beta - a monoclonal immunoglobulin G 1 (IgG1) antibody, to obtain information on survival, pain severity and incidence of neuro-toxicity, visual impairment, capillary leak syndrome, cardiovascular events, hypersensitivity reactions and long-term safety.

Detailed Description
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Rationale and Background: Neuroblastoma, is the most common extra-cranial solid tumour in children. Most patients with neuroblastoma are diagnosed under the age of 5 years and most present with metastatic disease and/or high-risk features. Despite the introduction of novel treatment strategies, including high-dose chemotherapy followed by autologous stem cell transplantation (ASCT), the outcome of these patients remains poor. Dinutuximab beta is a chimeric monoclonal immunoglobulin G 1 (IgG1) antibody that is specifically directed against the carbohydrate moiety of disialoganglioside antigen (GD2), which is overexpressed on neuroblastoma cells. By binding to neuroblastoma cells, dinutuximab beta can induce both complement dependent cytotoxicity (CDC) and antibody dependent cell-mediated cytotoxicity (ADCC). The efficacy of dinutuximab beta has been evaluated in a randomised controlled trial comparing the administration of dinutuximab beta with or without interleukin 2 (IL-2) in the first-line treatment of patients with high-risk neuroblastoma and in two singlearm studies in the relapsed/refractory setting. The efficacy and safety of dinutuximab beta will further be evaluated in this registry that will provide information on survival, pain severity and incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events, hypersensitivity reactions and long-term safety. Study Design: This is a non-interventional, multi-national, observational, prospective patient registry of patients with high-risk neuroblastoma being treated with the monoclonal antibody dinutuximab beta. The efficacy and safety of dinutuximab beta will further be evaluated in this registry that will provide information on survival, pain severity and incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events, hypersensitivity reactions and long-term safety. Research Questions and Objectives: Primary objectives: To assess pain severity and use of analgesics during the period of first dose of dinutuximab beta to end of last 35 day course of the 5th cycle of treatment To assess the incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions To assess the long term safety profile Secondary objectives: Progression free survival (PFS) in patients treated with dinutuximab beta. Event Free Survival (EFS) in patients treated with dinutuximab beta Overall survival (OS) in patients treated with dinutuximab beta Population: Patients diagnosed with high-risk neuroblastoma who are starting treatment with dinutuximab beta in the standard clinical practice setting or participating in a clinical trial where dinutuximab beta is provided according to the indication as per the country/regional marketing authorisation, provide consent/assent and are willing to be followed up for up to 10 years. Study Size: It is planned to enroll a sufficient number of patients (estimated at 125) such that 100 patients will have completed all five treatment courses of dinutuximab beta. It is anticipated that this will result in 40-50 patients who are progression free at 10 years. Data Sources: Data will be collected from physicians using an electronic data capture (EDC) system. The electronic case report forms (eCRFs) will be designed to gather data from the medical records at baseline, during treatment and at normal clinical practice follow up visits. Data Analysis: The safety analysis set, containing all patients treated with at least one dose of dinutuximab beta will be considered for safety and efficacy analyses. All baseline, treatment period and follow up characteristics will be summarized using descriptive statistics. Endpoints addressing primary and secondary analysis will include 95% confidence intervals (CIs) including the Clopper Pearson method for binomial, log-log transform for survival. OS, PFS and EFS will be analysed using Kaplan-Meier methods. Variables: Baseline (prior to start of treatment): Demographics, clinical trial participation, neuroblastoma disease history, and presence or absence of neurotoxicity, visual impairment, and cardiovascular abnormality. Treatment period (up to end of last 35 day course of 5th cycle of treatment): Dosing regimen, total cumulative amount of dinutuximab beta per course, concomitant medications during course (IL-2, retinoic acid and/or antihistamines), daily analgesics (opioids, gabapentin/ pregabalin and/or non-opioid analgesics and other neuropathic pain treatments), daily pain assessment during infusion of dinutuximab beta, occurrence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events, and hypersensitivity reactions, adverse events (AEs)/serious adverse events (SAEs) treatment interruptions and discontinuations, progression of disease, date and cause of death, reason for study withdrawal (if applicable) Follow up (from end of last 35 day course of 5th cycle of treatment): Status of neurotoxicity, visual impairment, cardiovascular events, (resolved, not resolved), SAEs and adverse drug reaction (ADRs), progression of disease, date and cause of death, reason for study withdrawal (if applicable).

Official Title
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A Post-Authorisation Safety Study Patient Registry of Patients With High-risk Neuroblastoma Being Treated With the Monoclonal Antibody Dinutuximab Beta

Conditions
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Neuroblastoma

Intervention / Treatment
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* Other: Data-collection


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients meeting the following criteria will be considered for inclusion into the registry: Patients diagnosed with high-risk neuroblastoma and starting treatment with commercially available dinutuximab beta OR Patients diagnosed with high-risk neuroblastoma and starting treatment with dinutuximab beta in a clinical trial where dinutuximab beta is provided according to the country/regional marketing authorisation AND Appropriate consent/assent has been obtained for participation in the registry with a willingness to be followed up for up to 10 years. Exclusion Criteria: Patient will not be eligible for inclusion if the following criterion applies: Patients commencing dinutuximab beta within a clinical trial where the product is being provided outside of the country/regional marketing authorisation OR Appropriate consent/assent has not been obtained for participation in the registry or patient/legal representative is not willing for the patient be followed up for up to 10 years.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 18 Years

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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Arms and Interventions

| Intervention/Treatment |
| --- |
|Other: Data-collection|Data will be collected on dose, total cumulative amount of dinutuximab beta per course, dose interruptions, dose discontinuations, prophylactic treatment, use of all concomitant analgesia, assessments of pain, and occurrence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions and other AEs.|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of the severity of pain experienced by participants during treatment with dinutuximab beta | Assessment of pain severity experienced by participants during the period of first dose of dinutuximab beta to the end of last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 
| Number of participants using analgesics during treatment with dinutuximab beta | Use of analgesics during the period of first dose of dinutuximab beta to end of last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 
| Incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions | Incidence of neurotoxicity, visual impairment, capillary leak syndrome, cardiovascular events and hypersensitivity reactions up to the end of the last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 
| Number of participants experiencing serious adverse events (SAEs) and adverse drug reactions (ADRs) during treatment with dinutuximab beta | Number of participants experiencing serious adverse events (SAEs) and adverse drug reactions (ADRs) following the end of the last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (OS) | Overall Survival (OS) following the end of the last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 
| Progression free survival (PFS) | Progression free survival (PFS) following the end of the last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 
| Event Free Survival (EFS) | Event Free Survival (EFS) following the end of the last 35 day course of 5th cycle of treatment | First dose of dinutuximab beta to the end of the last 35 day course of the 5th cycle of treatment (each cycle is 35 days) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Tumour, Brain tumour, Paediatrics