Radioimmunotherapy for Recurrent Pediatric Brain Cancer

Not currently recruiting at 2 trial locations

Overseen By Stacye Richardson, MSHS

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Pediatric Brain Tumor Consortium

Must not be taking: NSAIDs, Clopidogrel, Aspirin, others

Disqualifiers: Pregnancy, Serious wounds, Stroke, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Prior Safety Data This treatment has passed at least one previous human trial

Breakthrough Therapy This drug has been fast-tracked for approval by the FDA given its high promise

Compensation: Varies

Number of Visits: 2

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores a potential new treatment for children with recurring brain tumors, specifically medulloblastoma and ependymoma. It adds a special type of targeted radiation therapy (radioimmunotherapy) to existing cancer drugs, including Bevacizumab (Avastin), Irinotecan (Camptosar or CPT-11), Omburtamab I-131, and Temozolomide (Temodar or Temodal). The trial aims to determine if this combination can better manage tumor growth and improve survival rates. Children with recurring brain cancer that has not responded well to past treatments, and who have persistent MRI abnormalities or tumor cells in spinal fluid, might be suitable candidates for this trial. As a Phase 2 trial, the research focuses on measuring the treatment's effectiveness in an initial, smaller group, offering hope for improved tumor growth management.

Do I need to stop my current medications to join the trial?

You may need to stop certain medications before joining the trial. Specifically, you cannot take enzyme-inducing antiepileptic drugs, certain herbal supplements, or medications that strongly affect liver enzymes (CYP3A4/5) within 7 days before enrollment. Check with the trial team for guidance on your specific medications.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Previous studies have tested the drugs irinotecan, temozolomide, and bevacizumab in children with brain tumors. Irinotecan was generally well-tolerated, though some patients experienced side effects such as diarrhea and low white blood cell counts. Temozolomide demonstrated a 42.5% response rate in children with brain tumors, but some encountered serious side effects like low blood cell counts. Bevacizumab appears safe for children, with manageable side effects such as high blood pressure and protein in urine.

Research has shown that 131I-omburtamab, when used in the brain, is safe if proper radiation safety measures are followed. Although 131I-omburtamab is not FDA-approved for certain conditions, studies have found it to be well-tolerated and potentially helpful in treating brain tumors. Overall, these treatments have been tested in children and have shown manageable side effects. It is important to discuss any concerns with a doctor. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about the radioimmunotherapy approach using 131I-omburtamab because it offers a unique strategy for treating recurrent pediatric brain cancers like medulloblastoma and ependymoma. Unlike traditional chemotherapy or radiation, this treatment delivers targeted radiation directly to cancer cells by attaching a radioactive isotope, 131I, to the antibody omburtamab, which specifically targets the B7H3 protein often found on these tumors. This precise delivery method could potentially minimize damage to healthy brain tissue and improve outcomes for children with these challenging cancers. Moreover, the use of intraOmmaya administration allows the radioactive treatment to be directly introduced into the cerebrospinal fluid, targeting tumors more effectively.

What evidence suggests that this trial's treatments could be effective for recurrent pediatric brain cancer?

In this trial, one arm will study the combination of three drugs—irinotecan, temozolomide, and bevacizumab—for children with recurring medulloblastoma, a type of brain tumor. Studies have shown that this combination can significantly lower the risk of death and effectively shrink tumors in about two-thirds of these patients. Another arm will focus on using 131I-omburtamab for patients with recurrent ependymoma. Research suggests that adding 131I-omburtamab might improve survival rates, especially for patients whose cancer is not currently active. This treatment directly targets tumor cells, aiding in the detection and treatment of returning brain tumors. Early results indicate that 131I-omburtamab may help keep patients in remission longer and is considered safe for use in these cases. ^{6 7 8 9 10}

Who Is on the Research Team?

Matthias Karajannis, MD, MS

Principal Investigator

Memorial Sloan Kettering Cancer Center

Are You a Good Fit for This Trial?

This trial is for patients under 22 years old with recurrent, progressive, or refractory medulloblastoma or ependymoma. They must have a performance score of ≥50%, be off growth factors for at least a week, and not have severe organ dysfunction. HIV/Hep B/C patients must be on effective therapy with undetectable viral load. Participants need confirmed tumor reactivity to B7H3 and should agree to use birth control.

Inclusion Criteria

I am younger than 22 years old.

I am under 22 years old.

My ependymoma cancer came back or didn't respond after radiation therapy.

Exclusion Criteria

Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies are not eligible.

I am not currently taking any cancer treatment or experimental drugs.

Patients who in the opinion of the investigator are unwilling or unable to return for required follow-up visits or obtain follow-up studies required to assess toxicity to therapy or to adhere to drug administration plan, other study procedures, and study restrictions.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Induction Chemotherapy

Participants receive induction chemotherapy with irinotecan, temozolomide, and bevacizumab

8-16 weeks

Bi-weekly visits for chemotherapy administration

Radioimmunotherapy

Participants receive 2 therapeutic doses of cRIT 131I-omburtamab

2 weeks

2 visits for radioimmunotherapy administration

Maintenance Chemotherapy

Participants may resume maintenance chemotherapy with irinotecan, temozolomide, and bevacizumab

Up to 12 courses or until disease progression

Follow-up

Participants are monitored for safety and effectiveness after treatment

5 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Irinotecan
• Omburtamab I-131
• Temozolomide

Trial Overview

The study tests the addition of cRIT 131I-omburtamab (a radiolabeled antibody) to chemotherapy drugs irinotecan, temozolomide, and bevacizumab in children with recurrent brain tumors. It explores if direct delivery into the cerebrospinal fluid can better detect/treat these conditions compared to standard treatments.

How Is the Trial Designed?

Group I: Recurrent Medulloblastoma Experimental Treatment 10 Interventions

This arm aims to estimate event-free survival (EFS) and overall survival (OS) following therapy with irinotecan, temozolomide, bevacizumab, and compartmental (intraOmmaya) radioimmunotherapy (cRIT) 131I-omburtamab in patients with recurrent medulloblastoma. Patients with recurrent medulloblastoma will undergo surgery if feasible prior to study entry, followed by Induction Chemotherapy with irinotecan, temozolomide, and bevacizumab on study as per the Children's Oncology Group (COG) trial ACNS0821. Following 2 or 4 courses of chemotherapy and if radiographic disease status is stable or improved, patients will receive 2 therapeutic doses of 50 mCi cRIT 131I-omburtamab during Radioimmunotherapy. Following Radioimmunotherapy, patients may resume to Maintenance Chemotherapy with irinotecan, temozolomide, and bevacizumab for up to 12 total courses of chemotherapy or until disease progression, whichever occurs sooner.

Group II: Recurrent Ependymoma Experimental Treatment 7 Interventions

This is a feasibility cohort. The primary objective is to assess feasibility of incorporating cRIT 131I-omburtamab for patients with recurrent ependymoma and to assess dosimetry. Patients must have progressed after initial surgery, radiation therapy, or other therapies. Patients will undergo surgery (if feasible) prior to study entry with the goal of achieving stable or better disease. Tumor tissue (archived or new) will be tested for B7H3 prior to enrollment. If positive, patients will enroll on Stratum 2 and receive one dosimetry dose (2 mCi) of cRIT 131I-omburtamab with nuclear medicine scintigraphy using SPECT during the Dosimetry Course (14 days in length). Following the Dosimetry Course and within 2 weeks of the dosimetry dose, patients may continue to Radioimmunotherapy to receive 2 therapeutic doses (50 mCi) of cRIT 131I-omburtamab.

Bevacizumab is already approved in European Union, United States, Japan, Canada for the following indications:

Approved in European Union as Avastin for:

• Colorectal cancer
• Breast cancer
• Non-small cell lung cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in United States as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Glioblastoma
• Renal cell carcinoma
• Cervical cancer
• Ovarian cancer

Approved in Japan as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Approved in Canada as Avastin for:

• Colorectal cancer
• Non-small cell lung cancer
• Breast cancer
• Renal cell carcinoma
• Ovarian cancer

Who Is Running the Clinical Trial?

Pediatric Brain Tumor Consortium

Lead Sponsor

Trials

38

Recruited

1,600+

Y-mAbs Therapeutics

Industry Sponsor

Trials

26

Recruited

1,600+

Y-mAbs Therapeutics, Inc

Collaborator

Trials

4

Recruited

490+

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

Memorial Sloan Kettering Cancer Center

Collaborator

Trials

1,998

Recruited

602,000+

Published Research Related to This Trial

Temozolomide is a chemotherapeutic agent that effectively crosses the blood-brain barrier and has shown a good safety profile in treating brain metastases from solid tumors, with clinical activity observed in heavily pretreated patients.

In a randomized phase II trial, temozolomide combined with radiation therapy resulted in a significantly higher objective response rate (96% vs. 67%) compared to radiation alone, particularly benefiting patients with newly diagnosed brain and lung metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide for treating brain metastases. Abrey, LE., Christodoulou, C.[2019]

In a phase 2 trial involving 92 children with recurrent central nervous system tumors, the combination of bevacizumab (BVZ) and irinotecan (CPT-11) was generally well-tolerated, with most severe toxicities being rare and manageable.

The most common adverse effects associated with BVZ included hypertension (38%), fatigue (30%), epistaxis (24%), and proteinuria (22%), with 24% of patients discontinuing therapy due to toxicity.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab (BVZ)-associated toxicities in children with recurrent central nervous system tumors treated with BVZ and irinotecan (CPT-11): a Pediatric Brain Tumor Consortium Study (PBTC-022). Fangusaro, J., Gururangan, S., Poussaint, TY., et al.[2021]

The combination therapy of bevacizumab, irinotecan, and temozolomide showed high objective response rates of 66.6% for medulloblastoma and 75.0% for atypical teratoid/rhabdoid tumors in a study of 13 pediatric patients with relapsed CNS embryonal tumors.

The treatment resulted in favorable survival outcomes, with 12-month progression-free survival rates of 69.2% and overall survival rates of 67.1%, while adverse effects were manageable and mostly mild.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy and safety of bevacizumab, irinotecan, and temozolomide combination for relapsed or refractory pediatric central nervous system embryonal tumor: a single-institution study. Shiba, Y., Motomura, K., Taniguchi, R., et al.[2023]

In a phase II study involving 35 children with recurrent low-grade gliomas, the combination of bevacizumab (BVZ) and irinotecan (CPT-11) resulted in sustained disease control, with 83% of patients maintaining stable disease for at least 6 months.

The treatment showed a promising 6-month progression-free survival rate of 85.4% and a 2-year rate of 47.8%, although common side effects included hypertension, fatigue, and proteinuria.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of bevacizumab plus irinotecan in children with recurrent low-grade gliomas--a Pediatric Brain Tumor Consortium study. Gururangan, S., Fangusaro, J., Poussaint, TY., et al.[2022]

In a phase II study involving 31 children with recurrent malignant glioma and brainstem glioma, the combination of bevacizumab (BVZ) and irinotecan (CPT-11) was well-tolerated but showed minimal efficacy, with no sustained responses observed.

The median time to progression was 127 days for malignant glioma and 71 days for brainstem glioma, indicating limited effectiveness of the treatment despite some patients experiencing temporary benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Lack of efficacy of bevacizumab plus irinotecan in children with recurrent malignant glioma and diffuse brainstem glioma: a Pediatric Brain Tumor Consortium study. Gururangan, S., Chi, SN., Young Poussaint, T., et al.[2022]

Temozolomide is primarily used for treating refractory central nervous system cancers like anaplastic astrocytoma and glioblastoma, but ongoing clinical trials are exploring its efficacy and safety in newly diagnosed gliomas and other types of tumors.

Research is also investigating different dosing schedules and combinations with other treatments, suggesting that temozolomide could be a versatile option in cancer therapy beyond its current approved uses.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Future directions for temozolomide therapy. Yung, WK.[2019]

Temozolomide (tmz) is commonly used in Canadian children with brain tumors, particularly at the time of tumor recurrence, with 137 children treated across 10 pediatric oncology centers from 2000 to 2006.

While some patients showed positive responses to tmz, including complete and partial responses, the overall effectiveness and clear indications for its use in pediatric brain tumors remain uncertain due to a lack of well-designed clinical trials.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The use and effectiveness of temozolomide in children with central nervous system tumours: a survey from the Canadian Paediatric Brain Tumour Consortium. Bartels, U., Baruchel, S., Carret, AS., et al.[2021]

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