131I-omburtamab Radioimmunotherapy for Neuroblastoma Central Nervous System/Leptomeningeal Metastases

Study Overview
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Brief Summary
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Children with a neuroblastoma diagnose and central nervous system (CNS)/leptomeningeal metastases will be given up to 2 rounds of intracerebroventricular treatment with a radiolabelled monoclonal antibody, 131I-omburtamab to evaluate efficacy and safety

Detailed Description
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One 131I-omburtamab treatment cycle takes 4 weeks and includes a treatment dose, and an observation period and post-treatment evaluations. One 131I-omburtamab treatment cycle for Japan only takes 5 weeks and includes a dosimetry dose (2mCi) of 131I-omburtamab is administered during week 1 followed by blood/cerebral spinal fluid (CSF) samples and whole-body scintigraphy at predefined intervals during the following 48 hours after treatment. A therapeutic dose (50mCi) of 131I-omburtamab is administered during week 1 (week 2 for Japan) followed by a 3-week observation period that includes a repeated MRI, CSF cytology, and safety monitoring. A second treatment cycle of 131I-omburtamab is administered during week 5 (week 6 for Japan) if there is no objective disease progression week 5 after the first injection, and the participant is presenting without unexpected and clinical significant Grade 4 toxicity. For participants with ongoing Grade 3 toxicity a second doing cycle will take place according to the discretion of the investigator. Participants can be treated in an outpatient setting or may be admitted as inpatients for both the dosimetry and the therapeutic injections. Participants completing at least one treatment period will first enter a follow-up period through week 26 and thereafter the long-term follow-up where patients will be evaluated for up to 3 years post-131I-omburtamab treatment where after the trial is ended Participants will be monitored for adverse events during and after 131I-omburtamab injection and will have pre- and post-treatment clinical assessments including neurologic examination, hematology and serum chemistry, blood and CSF cultures, endocrinology assessments, CSF analysis, and, pre- and post 131I-omburtamab performance testing. Performance testing will be performed at trial baseline, at week 26 and every 6 months during trial period. In case the patient has a subsequent relapse in the CNS/LM after 131I-omburtamab therapy during the follow-up period, re-treatment to target minimal residual disease can be considered and allowed.

Official Title
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A Multicenter Phase 2/3 Trial of the Efficacy and Safety of Intracerebroventricular Radioimmunotherapy Using 131I-omburtamab for Neuroblastoma Central Nervous System/Leptomeningeal Metastases

Conditions
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Neuroblastoma, CNS Metastases, Leptomeningeal Metastases

Intervention / Treatment
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* Biological: 131I-omburtamab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients must have a histologically confirmed diagnosis of neuroblastoma with relapse in the central nervous system or in the meninges (leptomeningeal). Patients must be between the ages of birth and 18 years at the time of screening. Patients must have a life expectancy of at least 3 months. Exclusion Criteria: Patients with primary neuroblastoma in central nervous system. Patients must not have an uncontrolled life-threatening infection. Patients must not have received cranial or spinal irradiation less than 3 weeks prior to first dose of 131I-omburtamab in this trial. Patients must not have received systemic chemotherapy (corticosteroids not included) less than 3 weeks prior to enrollment in this trial. Patients must not have severe major non-hematologic organ toxicity; specifically, any renal, cardiac, hepatic, pulmonary, and gastrointestinal system toxicity must fall below Grade 3 prior to enrollment in this trial. Patients with stable neurological deficits (due to brain tumor) are not excluded. Patients with Grade 3 or lower hearing loss are not excluded.

Ages Eligible for Study
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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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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Patients will receive up to two cycles of intracerebroventricular 131I-omburtamab. Safety and efficacy will be investigated with short-term follow-up at 26 weeks after treatment and with long-term follow-up for up to 3 years following treatment.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 131I-omburtamab<br>One treatment cycle of 131I-omburtamab consists of 1 dose at 50mCi at week 1. For Japan only one treatment cycle of 131I-omburtamab consists of 2 doses: 2mCi at week 1 and 50mCi at week 2. First cycle is initiated right after confirmation of eligibility at week 1. At week 5 (week 6 for Japan) the participant will be evaluated for safety and if eligible, receive a second cycle of 131I-omburtamab. Secondary efficacy endpoints will be evaluated at week 26 and primary efficacy endpoint will be evaluated at week 156. | Biological: 131I-omburtamab<br>* Murine IgG1 monoclonal antibody radiolabeled with iodine-131<br>* Other names: 131I-8H9;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival rate | Overall survival rate at 3 years after the first treatment dose of 131I-omburtamab. | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall survival | Overall survival at 3 years after the first treatment dose of 131I-omburtamab. | 3 years | 
| Objective response rate (ORR) | ORR is defined and assessed as a combination of partial response and complete response as defined by the RANO criteria and CSF cytology. | 3 years | 
| Objective response rate (ORR) | ORR according to CSF cytology. ORR is defined and assessed as a combination of partial response and complete response. | 3 years | 
| CNS progression free survival (PFS) | CNS PFS will be assessed at 6 months after the first treatment dose of 131I-omburtamab by comparing baseline radiological scans by MRI to radiological scans conducted 26 weeks after 131I-omburtamab treatment. | 6 month | 
| Dosimetry of 131I-omburtamab | Whole-body, organ, blood, and CSF radiation dosimetry. | 2 weeks | 
| Assessment of peak plasma concentration (Cmax) of 131I-omburtamab | Cmax will be calculated and summarized with descriptive statistics. | Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days | 
| Assessment of residence time of 131I-omburtamab | Residence time will be calculated and summarized with descriptive statistics. | Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days. | 
| Assessment of elimination half-life of 131I-omburtamab | Elimination half-life will be calculated and summarized with descriptive statistics. | Baseline, 30 minutes, 1 hour, 4 hour, 1, 2, 3 and 7 days. | 
| Safety of 131I-omburtamab | The frequency, type, and duration of treatment-emergent severe adverse events and serious adverse events, including clinically significant laboratory abnormalities. All adverse events will be graded according to CTCAE, version 4.0. | 3 years | 
| Performance assessment | Performance assessment to monitor gross changes in neurological function is performed at week 26 and subsequently every 6 months during trial period using Lansky (< 16 years) and Karnofsky (≥ 16 years). | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Radioimmunotherapy, Neuroblastoma, CNS Metastases, Leptomeningeal Metastases, Pediatric