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

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

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

Study Overview

• Status: Terminated
• Conditions: Neuroblastoma; Leptomeningeal Metastases; CNS Metastases
• Intervention / Treatment: Biological: 131I-omburtamab

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 52
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Joris Wilms; Phone Number: +4570261414; Email: clinicaltrials@ymabs.com

Study Locations

• Denmark
  • København, Denmark, 2100
    • Rigshospitalet
• Japan
  • Fukushima City, Japan, 960-1295
    • Department of Pediatric Oncology Fukushima Medical University Hospita
• Spain
  • Barcelona, Spain, 08010
    • Hospital Sant Joan de Deu
• United States
  • California
    • Los Angeles, California, United States, 90027
      • Childrens Hospital Los Angeles
  • Indiana
    • Indianapolis, Indiana, United States, 46202
      • Riley Hospital for Children
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan Kettering Cancer Center
  • Ohio
    • Columbus, Ohio, United States, 43205
      • Nationwide Children's Hospital
  • Texas
    • Houston, Texas, United States, 77030
      • M.D. Anderson Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 18 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 131I-omburtamab; One treatment cycle of 131I-omburtamab consists of one dosimetry dose (2 mCi ) (for subjects enrolled on Version 1-7 of Protocol 101) and one treatment dose (50 mCi) for up to 2 cycles of length 5 weeks (for subjects enrolled on Version 1-7 of Protocol 101) or 4 weeks (for subject enrolled after Version 7 of Protocol 101). For Japan only, the first cycle consisted of one dosimetry dose (2 mCi ) week 1 one treatment dose (50 mCi) week 2. If eligible a second cycle of 50 mCi 131I-omburtamab was given at week 6. For subjects below 3 and 1 years of age, the treatment dose was reduced by 33% and 50%, respectively.

Biological: 131I-omburtamab; Murine IgG1 monoclonal antibody radiolabeled with iodine-131; Other Names: 131I-8H9

What is the study measuring?

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 estimated by the Kaplan-Meier method.	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

Collaborators and Investigators

• Sponsor: Y-mAbs Therapeutics
• Investigators: Study Director: John Roemer, MD, Y-mAbs Therapeutics

Study record dates

Study Major Dates

• Study Start (Actual): December 11, 2018
• Primary Completion (Actual): June 2, 2023
• Study Completion (Actual): June 2, 2023

Study Registration Dates

• First Submitted: September 6, 2017
• First Submitted That Met QC Criteria: September 6, 2017
• First Posted (Actual): September 7, 2017

Study Record Updates

• Last Update Posted (Actual): February 13, 2024
• Last Update Submitted That Met QC Criteria: January 22, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Pediatric; Radioimmunotherapy; Neuroblastoma; CNS Metastases; Leptomeningeal Metastases
• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Neoplastic Processes; Central Nervous System Neoplasms; Nervous System Neoplasms; Neuroectodermal Tumors, Primitive; Neuroectodermal Tumors, Primitive, Peripheral; Meningeal Neoplasms; Neoplasm Metastasis; Neuroblastoma; Neoplasms, Second Primary; Meningeal Carcinomatosis
• Other Study ID Numbers: 101 (Hamilton Integrated Research Ethics Board)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No