Antiangiogenic Therapy for Pediatric Brain Cancer

(MEMMAT Trial)

Recruiting at 21 trial locations

Overseen By Andreas Peyrl, MD

Age: < 65

Sex: Any

Trial Phase: Phase 2

Sponsor: Medical University of Vienna

Must not be taking: Conventional chemotherapy

Disqualifiers: Active infection, Pregnancy, Cardiovascular disease, 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: Unknown

Duration: 6 months

100 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial tests a new treatment approach for children and young adults with certain types of brain cancer, specifically medulloblastoma, ependymoma, and ATRT, that have returned or worsened. The treatment combines an intravenous drug called bevacizumab (an antiangiogenic therapy) with five oral medications, aiming to improve survival and maintain a good quality of life. It targets those who have already tried other treatments like chemotherapy or radiation without success. Ideal candidates are children and young adults with a confirmed diagnosis of these brain cancers who have relapsed or have progressive disease. The trial seeks to determine if this new combination can effectively slow the cancer while minimizing side effects. As a Phase 2 trial, this research focuses on measuring the treatment's effectiveness in an initial, smaller group of people, offering a chance to contribute to important findings.

Will I have to stop taking my current medications?

The trial protocol does not specify whether you need to stop taking your current medications. However, if you are on conventional chemotherapy, antiangiogenic treatment, or have had complete irradiation for your current relapse, you may not be eligible to participate.

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

Research shows that the treatments in this trial have varying safety levels.

Bevacizumab is safe and effective for some children's brain tumors, such as low-grade gliomas. However, it can increase the risk of blood clots and a rare brain condition called PRES, which may cause headaches and seizures.

Celecoxib is used in cancer trials but may raise the risk of heart problems, including heart attacks and strokes. Although high doses haven't shown severe harm, it is not specifically recommended for brain tumors.

Cyclophosphamide, a common chemotherapy drug, can lower bone marrow activity, affecting blood cell production. It may also harm the kidneys and bladder, so patients should stay hydrated.

Etoposide has been effective in treating brain tumors, but its safety for children remains uncertain. Possible side effects include headaches, nausea, and seizures.

Fenofibrate's safety in children isn't well-documented, though it has shown anticancer effects in other studies. Its use in children remains uncertain.

Thalidomide is known for stopping tumor growth. However, it can cause severe birth defects if taken during pregnancy and may lead to tumor lysis syndrome, which can cause kidney problems.

Overall, while these treatments may offer benefits, they also come with various risks and side effects. Discussing these with a healthcare provider is important when considering joining a trial. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about these treatments for pediatric brain cancer because they target tumor growth in a unique way. Unlike traditional chemotherapy, which directly attacks cancer cells, this combination of medications, including bevacizumab and thalidomide, works by inhibiting the formation of new blood vessels that tumors need to grow, a process called antiangiogenesis. This approach can potentially slow down or stop the progression of cancer with fewer side effects compared to conventional treatments. Additionally, using a mix of drugs like celecoxib and fenofibrate alongside standard options offers a multi-faceted attack on cancer, increasing the chances of effectiveness.

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

Research shows that bevacizumab can help control disease in children with brain tumors, with 57.5% of patients experiencing disease control after six months. Celecoxib has successfully stopped the growth of various cancers, including brain tumors. Cyclophosphamide, a common chemotherapy drug, effectively treats children's brain tumors but may cause side effects like reduced bone marrow activity. Etoposide can improve survival rates in patients with aggressive brain tumors. Fenofibrate, typically used to lower cholesterol, also has strong effects against brain tumors. Thalidomide, when combined with other treatments, can improve outcomes and help control tumor growth. Together, these drugs form a multi-drug approach that targets tumor growth and blood supply, offering a potential new option for children with difficult-to-treat brain cancers. ^{6 7 8 9 10}

Who Is on the Research Team?

Andreas Peyrl, MD

Principal Investigator

Medical University of Vienna

Monika Chocholous, MD

Principal Investigator

Medical University of Vienna

Are You a Good Fit for This Trial?

This trial is for children and young adults up to age 20 with recurrent medulloblastoma, ependymoma or ATRT. They must have confirmed diagnosis at relapse, normal organ/bone marrow function, and a performance status indicating they can engage in most activities. Pregnant individuals, those with known drug hypersensitivity, unhealed fractures or infections are excluded.

Inclusion Criteria

Written informed consent of patients and/or parents

I was diagnosed before turning 20 years old.

My liver, kidneys, and bone marrow are functioning within normal ranges required by the study.

Exclusion Criteria

I currently have an infection.

VP-shunt dependency

Pregnancy or breastfeeding

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive biweekly intravenous bevacizumab in combination with five oral drugs, augmented with alternating courses of intrathecal etoposide and cytarabine

6 months

Biweekly visits for intravenous administration

Follow-up

Participants are monitored for progression-free survival, overall survival, and quality of life

8 years

What Are the Treatments Tested in This Trial?

Interventions

• Bevacizumab
• Celecoxib
• Cyclophosphamide
• Etoposide
• Fenofibrate
• Intrathecal Cytarabine
• Intrathecal Etoposide
• Thalidomide

Trial Overview The study tests biweekly intravenous bevacizumab combined with oral thalidomide, celecoxib, fenofibrate and alternating low-dose etoposide/cyclophosphamide. It also includes alternating courses of intrathecal etoposide/cytarabine aiming to prolong survival while maintaining quality of life in heavily pretreated patients.

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?

Medical University of Vienna

Lead Sponsor

Trials

1,200

Recruited

1,924,000+

Published Research Related to This Trial

Bevacizumab, a VEGF inhibitor, may help control pediatric glioma, but its safety and effectiveness remain uncertain due to potential serious side effects.

One rare but life-threatening side effect associated with bevacizumab treatment is sinus venous thrombosis (SVT), which has been reported in only a few cases, highlighting the need for careful monitoring in patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab and Sinus Venous Thrombosis: A Literature Review. Jaiswal, V., Jain, E., Hitawala, G., et al.[2021]

In a phase I trial involving six pediatric patients with treatment-resistant CNS tumors, the combination of bevacizumab and temsirolimus was well-tolerated, with manageable side effects such as anorexia and nausea.

The treatment led to a partial response in one patient and stable disease for at least four months in two others, indicating potential efficacy in this challenging patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pediatric patients with refractory central nervous system tumors: experiences of a clinical trial combining bevacizumab and temsirolimus. Piha-Paul, SA., Shin, SJ., Vats, T., et al.[2022]

In a retrospective study of 30 children with central nervous system tumors treated with bevacizumab, no cases of intratumoral hemorrhage were reported, suggesting that it can be safely administered in this population.

While some manageable adverse effects were observed, such as hypertension and lymphopenia, bevacizumab did not lead to any treatment-related deaths, indicating a favorable safety profile for pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Feasibility and tolerability of bevacizumab in children with primary CNS tumors. Reismüller, B., Azizi, AA., Peyrl, A., et al.[2015]

The combination of celecoxib with low-dose metronomic chemotherapy (vinblastine or cyclophosphamide) was well tolerated in 33 children with recurrent solid tumors, indicating a safe treatment option for pediatric patients.

While 13% of patients experienced durable stable disease for up to 78 weeks, no complete or partial responses were observed, suggesting that while the treatment is safe, its efficacy in significantly reducing tumor size may need further investigation.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A pilot pharmacokinetic and antiangiogenic biomarker study of celecoxib and low-dose metronomic vinblastine or cyclophosphamide in pediatric recurrent solid tumors. Stempak, D., Gammon, J., Halton, J., et al.[2015]

In a retrospective analysis of 28 children with refractory or recurrent brain tumors, bevacizumab was found to have low acute toxicity, with only mild side effects reported, such as hypertension and proteinuria.

While bevacizumab showed some efficacy in reducing tumors in children with low-grade gliomas, it did not demonstrate effectiveness in high-grade gliomas or other tumor types, indicating a need for further research to confirm its potential benefits.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. Couec, ML., André, N., Thebaud, E., et al.[2022]

In the HERBY trial involving 113 pediatric patients with high-grade glioma, the addition of Bevacizumab to radiotherapy and temozolomide did not significantly improve overall survival or event-free survival compared to standard treatment.

Midline tumors showed significantly poorer outcomes than cerebral tumors, likely due to less effective surgical resection, the presence of H3 K27M mutations, and a higher rate of leptomeningeal metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Radiological Evaluation of Newly Diagnosed Non-Brainstem Pediatric High-Grade Glioma in the HERBY Phase II Trial. Rodriguez Gutierrez, D., Jones, C., Varlet, P., et al.[2021]

Anti-angiogenic therapies targeting the blood supply of pediatric brain tumors are currently in clinical trials and have shown to be well tolerated, lacking many of the traditional side effects associated with chemotherapy and radiation.

These therapies do not need to penetrate the blood-brain barrier and focus on a crucial pathway in tumor development, highlighting their potential as novel biologic treatments for brain tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Anti-angiogenic therapy in pediatric neuro-oncology. Kieran, MW.[2018]

In a trial involving 27 pediatric patients with advanced malignancies, the combination of thalidomide and cyclophosphamide showed limited efficacy, with only one patient achieving a partial response and most experiencing disease progression.

The treatment was associated with a modest and tolerable toxicity profile, primarily involving hematological and gastrointestinal side effects, with no cases of peripheral neuropathy reported.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies. Gilheeney, SW., Lyden, DC., Sgouros, S., et al.[2013]

Citations

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A nationwide evaluation of bevacizumab-based treatments in ... Bevacizumab is a safe and effective treatment for pediatric low-grade glioma. Benefits of BBT included speed to visual stability/improvement as sight-saving ...

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Use of bevacizumab in pediatric low-grade glioma Progression free survival at 12 and 36 months was 91.4% and 31.4%, respectively, and no severe adverse events were observed. Conclusions. In our series, ...

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Bevacizumab (intravenous route) - Side effects & uses This medicine may increase your chance of having blood clots or a brain condition called posterior reversible encephalopathy syndrome (PRES).