Neoplasms

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Diffuse Intrinsic Pontine Glioma

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Brain Neoplasms

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Nervous System Neoplasms

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Carbamide Peroxide

Iodine

Cadexomer iodine

Omburtamab is a murine IgG1 monoclonal antibody, recognizing CD276 (also known as B7-H3).

131I-Omburtamab

The planned intervention includes surgical placement of a small caliber cannula into the tumor located in the pons using standard stereotactic techniques followed by CED of 131Iomburtamb.

Convention Enhanced Delivery

Omburtamab is a murine IgG1 monoclonal antibody, recognizing CD276 (also known as B7- H3). Omburtamab is 131I-labeled at designated radio pharmacies and will be provided as a final radiolabeled product to treatment site. The proposed intervention includes surgical placement using standard stereotactic techniques of a small caliber cannula into the tumor in the pons followed by positive pressure infusion (i.e. CED) of 131I-omburtamab. Iodine-131 conjugated omburtamab (131I-omburtamab) administered via the intracerebroventricular route for the treatment of metastatic CNS neuroblastoma was shown to be tolerable and improve survival. Furthermore, 124I-omburtamab administered by convection enhanced delivery (CED) was shown to have a tolerable safety profile in an ongoing dose escalation trial (in doses up to 4mCi) in patients with diffuse pontine gliomas that have not progressed following external beam radiation therapy. The aim of this trial is to determine the efficacy and safety of 131I-omburtamab in patients with DIPG that have not progressed following external beam radiation therapy.

The IMP infusion volume for CED will be adjusted to 4, 6 or 8 mL dependent on the size of the tumor as estimated by MRI. The maximum volume of 8 mL was tested, and safety cleared in the 11-011 trial. Assuming a ratio of approximately 1:3 between the infusion volume and the distribution volume the infusion volume will be adjusted to ensure coverage of the tumor and 0.5 cm of the surrounding margin. The infusion volume will be 4 mL if tumor size (+0.5 cm margin) \<10 cm3, 6 mL if tumor size (+0.5 cm margin) ≥10 and \<15 cm3, and 8 mL if tumor size (+0.5 cm margin) ≥15 and ≤20 cm3. The maximum infusion rate will be 10 μL/min. Infusions will be initiated using an escalating flow rate plan with 10-min intervals until the maximum rate is achieved (0·5 μL/min, 1·0 μL/min, 2·0 μL/min, 5·0 μL/min, 7·5 μL/min and 10 μL/min).

131I-omburtamab Delivered by Convection-Enhanced Delivery in Patients With Diffuse Intrinsic Pontine Glioma

Safety of 131I-omburtamab Delivered by Convection-Enhanced Delivery in Patients With Diffuse Intrinsic Pontine Glioma Previously Treated With External Beam Radiation Therapy

Up to 36 patients may be enrolled in the dose escalation phase in planned cohorts of 3 patients with a maximum of 3 cohorts at a dose level.All patients may receive up to three cycles of 131I-omburtamab. Patients will be followed until the last patient has had the last follow-up visit at 2 years after the 131I-omburtamab administration. End of trial is defined as last patient's last visit in the two-year follow-up period, or death whichever comes first. All Non-serious AEs should be reported from the time of CED placement surgery administration until 30 days after the IMP administration. All SAEs should be captured from signing the ICF until 30 days after IMP administration. Starting at day 31 after dosing of 131I-omburtamab only SAE's or ≥ grade 3 non-serious AEs considered at least possibly related to 131I-omburtamab or new onset of cancers regardless of causality should be reported.

MRI of the brain will be used to assess PD.

PD is defined as:

A greater than 25 percent increase in the 2D product of the perpendicular diameters of the lesion using T2-weighted or FLAIR sequences and not considered pseudo-progression, taking as a reference the smallest disease measurement recorded since the baseline MRI OR the appearance of new extrapontine tumor, i.e. lesions non-contiguous to the primary pontine lesion.

MRI of the spine will be used to assess PD.

PD is defined as:

A greater than 25 percent increase in the 2D product of the perpendicular diameters of the lesion using T2-weighted or FLAIR sequences and not considered pseudo-progression, taking as a reference the smallest disease measurement recorded since the baseline MRI OR the appearance of new extrapontine tumor, i.e. lesions non-contiguous to the primary pontine lesion.

Neurological examination indicating clinical deterioration not attributable to other causes such as anticonvulsant or corticosteroid toxicity, electrolyte disturbances, sepsis, hyperglycemia, etc.

PD is defined as:

A greater than 25 percent increase in the 2D product of the perpendicular diameters of the lesion. The scale is intended to be performed at baseline and at follow-up visits. An overall score will be determined following assessment of each domain and will include one of 5 possible outcomes: neurologic response, neurologic progression, neurologic stability, not assessed, and non-evaluable.

Neurologic response is defined as a ≥2 level improvement in at least one domain without worsening in other domains from baseline.

Neurologic stability indicates a score of neurologic function that does not meet criteria for neurologic response, neurologic progression, non-evaluable, or not assessed.

SPECT/CT scans will be performed at 4h, 12h, 24h, 72h and 7 days after the first administration of 131I-omburtamab.

will be performed at 4h, 12h, 24h, 72h and 7 days after the first administration of 131I-omburtamab.

Changes in neurological function will be assessed 1, 2, 7, 14, and 30 days after dosing with 131I-omburtamab by summarizing changes from baseline of a neurological examination using the Neurologic Assessment in Neuro-Oncology (NANO) scale. The NANO scale is intended to be performed at baseline and at follow-up visits, especially those where neuroimaging is obtained. An overall NANO score will be determined following assessment of each domain and will include one of 5 possible outcomes: neurologic response, neurologic progression, neurologic stability, not assessed, and non-evaluable. In general, assessment and scoring of all domains is encouraged.

Changes from baseline in the Lansky/Karnofsky performance score evaluated 6, 12, and 24 months after last dosing. Lansky or Karnofsky Performance Score of ≥ 70 at study entry. Lansky Performance scale to be used for patients ≤16 years of age. The score is determined on a scale ranging from 0-100. A higher score means the patient is better able to carry out daily activities.

Monitoring the frequency, type, and duration of serious adverse events after up to 3 CED infusions of 131I-omburtamab

Overall survival will be followed as a secondary efficacy endpoint dictated by the absence of suitable and validated surrogate markers of efficacy in DIPG.

Response Assessment in Pediatric Neuro-Oncology (RAPNO) and Response Assessment in Pediatric Neuro-Oncology High Grade Glioma (RAPNO-HCG) will be used to assess progression free survival.

Response Assessment in Pediatric Neuro-Oncology (RAPNO) and Response Assessment in Pediatric Neuro-Oncology High Grade Glioma (RAPNO-HCG) will be used to assess objective response rate at 6 months and 12 months after first CED infusion of 131I-omburtamab.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
131I-omburtamab Delivered by Convection-Enhanced Delivery in Patients With Diffuse Intrinsic Pontine Glioma	NCT05063357	DIPG	131I-Omburtamab Convention Enha...	3 Years - 21 Years	Y-mAbs Therapeutics
131I-omburtamab Delivered by Convection-Enhanced Delivery in Patients With Diffuse Intrinsic Pontine Glioma	NCT05063357	DIPG	131I-Omburtamab Convention Enha...	3 Years - 21 Years	Y-mAbs Therapeutics

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