Convection-Enhanced Delivery of 124I-Omburtamab for Patients With Non-Progressive Diffuse Pontine Gliomas Previously Treated With External Beam Radiation Therapy

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of a new method to treat Diffuse Intrinsic Pontine Glioma (DIPG). The researchers will use convection-enhanced delivery (CED) to deliver an agent called 124I-omburtamab. CED is performed during surgery. The study agent is infused through a small tube placed into the tumor in the brain. Many studies have shown this can safely be done in animals but this study is the first time 124I-omburtamab will be given by CED in humans. This will be one of the first times that CED has been performed in the brain stem. Omburtamab is something called an antibody. Antibodies are made by the body to fight infections and sometimes cancer. The antibody omburtamab is produced by mice and can attack many kinds of tumors. A radioactive substance, 124I-omburtamab, is attached to omburtamab. 124I-omburtamab sticks to parts of tumor cells and can cause the tumor cells to die from radiation. Studies have also been done on humans using 124I-omburtamab to treat other kinds of cancer. Our studies of some DPG and related tumors suggest that omburtamab will bind to the tumor, but the investigators don't know that for sure. In this study, the researchers want to find out how safe 124I-omburtamab given by CED is at different dose levels. They will look to see what effects (both good and bad) it has on the patient. The dose of 124I-omburtamab will increase for each new group of patients. The procedure has already been safely performed with lower doses and infusion volumes in a number of patients here at MSKCC. The amount they get will depend on when they enter the study. If too many serious side effects are seen with a certain dose, no one will be treated with a higher dose, and some more patients may be treated with a lower dose to make sure that dose is safe.

Official Title
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A Phase I Study of Convection-Enhanced Delivery of 124I-Omburtamab for Patients With Non-Progressive Diffuse Pontine Gliomas Previously Treated With External Beam Radiation Therapy

Conditions
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Brain Cancer, Brain Stem Glioma

Intervention / Treatment
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* Drug: Radioactive iodine-labeled monoclonal antibody omburtamab
* Radiation: External Beam Radiotherapy


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Consensus of diagnosis must be reached by a multidisciplinary pediatric neuro-oncology team by considering both clinical evidence and MRI presentation. Tissue diagnosis is not required. The patient must have undergone prior external beam radiotherapy to a dose of 54-60 Gy to the brain stem. At least 4 weeks but no more than 14 weeks must have elapsed from the completion of radiotherapy. The patient must be in adequate general condition for study, with Lansky or Karnofsky Performance Score of ≥ 50 at study entry . Lansky Performance scale will be used for patients ≤16 years of age. The patient must be ≥ 2 and ≤ 21 years old. Patient must weigh a minimum of 8 kg. Exclusion Criteria: Clinical and/or radiographic (MRI) progression of tumor following external beam radiation therapy. Metastatic disease. Untreated symptomatic hydrocephalus determined by treating physician. AST or ALT > 2x the upper limit of normal. Platelets < 100,000/mcL. ANC < 1000/mcL. Abnormal PT (Inr) >1.5 INR or PTT > 42 sec (may be corrected with FFP, cryoprecipitate, vitamin K, etc). Total bilirubin > 2.0 mg/dl. Serum creatinine > 1.5x the upper limit of normal for age, or calculated creatinine clearance or nuclear GFR < 70 ml/min/1.73 m2.

Ages Eligible for Study
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Minimum Age: 2 Years
Maximum Age: 21 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: Other
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Radioactive iodine-labeled monoclonal antibody omburtamab<br>This is a therapeutic Phase I study intended to assess the safety of convection-enhanced delivery (CED) of radioimmunotherapy in the treatment of children with diffuse pontine glioma. | Drug: Radioactive iodine-labeled monoclonal antibody omburtamab<br>* Prior to treatment children will be pre-medicated with super-saturated potassium iodide & liothyronine to prevent thyroid uptake of the therapeutic radioisotopes. The proposed intervention is a surgical procedure using interstitial infusion of the radiolabeled monoclonal antibody 124I-omburtamab into the brain stem tumor. This will be performed by stereotactic placement of a small caliber infusion cannula into the tumor followed by a slow infusion (CED) of 124I-omburtamab. Following treatment, these children will be monitored during inpatient hospitalization with clinical evaluations & PET/CT or PET/MRI scans of the brain & other organs. Clinical observations, intensive care unit monitoring, routine blood & interval imaging studies (MRI & PET/CT or PET/MRI scans) will be performed at predetermined time points. If the PET/CT scan happens to fall on a weekend or holiday, the scan may be done before or after at the discretion of the Study PI. This will not affect dosimetry interpretation.<br>Radiation: External Beam Radiotherapy<br>* Standard radiation therapy is given 4-6 weeks prior to study entry.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| maximum tolerated dose | Determination that a dose is safe will be made following the treatment of at least 3 but no more than 6 patients at a particular dose level. The dose levels are DL1 (0.25 mCi), DL2 (0.5 mCi), DL3 (0.75 mCi), DL4 (1.0 mCi) DL5 (2.5mCi), DL6 (3.25mCi), DL7 (4.0mCi), DL 7.1(4.0mCi), DL 7.2 (4.0mCi), DL 8 (6.0mCi), DL 9 (8.0mCi), DL 10 (10.0mCi), DL 11 (12.0mCi) ,fallback DL0 (0.125 mCi) FB1 (1.50mCi) and FB2 (2.0mCi). An incidence of dose-limiting toxicity (DLT) in the range of 25% is considered acceptable in this population. A maximum tolerated dose (MTD) will be defined as the dose level below that at which 2 DLTs have occurred. | 2 years | 
| assess the toxicity profile | Adverse events (toxicity) will be assessed and classified according to the Clinical Terminology Criteria for Adverse Events version 4.0 (CTCAE). Generally, grade 3 toxicities interfere with activities of daily living (ADLs) and grade 4 toxicities are life-threatening. Grade 5 toxicities cause death. | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| overall survival | Overall survival from the time of diagnosis will be recorded for every patient in this study. Overall survival will be estimated by Kaplan-Meier methodology. | 2 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Brain stem glioma, CNS, MAB 124I-omburtamab, infusion cannula, DIPG, Diffuse Intrinsic Pontine Glioma, 11-011