Antiangiogenic Therapy for Pediatric Brain Cancer

(MEMMAT Trial)

Recruiting at 20 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

Trial Summary

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.

What data supports the effectiveness of the drug combination used in the Antiangiogenic Therapy for Pediatric Brain Cancer trial?

Research suggests that Bevacizumab, an antiangiogenic drug, may help control disease in pediatric brain tumors, although its safety and effectiveness are still being studied. Additionally, a study found that Celecoxib combined with low-dose chemotherapy was well tolerated in children with solid tumors, showing some potential for stable disease. ^{1 2 3 4 5}

How is the drug for pediatric brain cancer different from other treatments?

This treatment is unique because it targets the blood vessels that supply the tumor, using a combination of drugs like Bevacizumab, which blocks a protein that helps tumors grow new blood vessels. Unlike traditional chemotherapy, it doesn't need to penetrate the blood-brain barrier and may have fewer side effects. ^{1 3 6 7 8}

What is the purpose of this trial?

Patients with relapsed medulloblastoma, ependymoma and ATRT have a very poor prognosis whether treated with conventional chemotherapy, high-dose chemotherapy with stem cell rescue, irradiation or combinations of these modalities. Antiangiogenetic therapy has emerged as new treatment option in solid malignancies. The frequent, metronomic schedule targets both proliferating tumor cells and endothelial cells, and minimizes toxicity. In this study the investigators will evaluate the use of biweekly intravenous bevacizumab in combination with five oral drugs (thalidomide, celecoxib, fenofibrate, and alternating cycles of daily low-dose oral etoposide and cyclophosphamide), augmented with alternating courses of intrathecal etoposide and cytarabine. The aim of the study is to extend therapy options for children with recurrent or progressive medulloblastoma, ependymoma and ATRT, for whom no known curative therapy exists, by prolonging survival while maintaining good quality of life. The primary objective of the MEMMAT trial is to evaluate the activity of this multidrug antiangiogenic approach in these heavily pretreated children and young adults. Additionally, progression-free survival (PFS), overall survival (OS), as well as feasibility and toxicity will be examined.

Research Team

Andreas Peyrl, MD

Principal Investigator

Medical University of Vienna

Monika Chocholous, MD

Principal Investigator

Medical University of Vienna

Eligibility Criteria

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

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

Treatment Details

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+

Findings from Research

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 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]

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]

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 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]

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 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 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]

References

1. Greece pubmed.ncbi.nlm.nih.gov

Pediatric patients with refractory central nervous system tumors: experiences of a clinical trial combining bevacizumab and temsirolimus. [2022]

2. United States pubmed.ncbi.nlm.nih.gov

Radiological Evaluation of Newly Diagnosed Non-Brainstem Pediatric High-Grade Glioma in the HERBY Phase II Trial. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab and Sinus Venous Thrombosis: A Literature Review. [2021]

4. United States 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. [2015]

5. United States pubmed.ncbi.nlm.nih.gov

A phase II trial of thalidomide and cyclophosphamide in patients with recurrent or refractory pediatric malignancies. [2013]

6. United States pubmed.ncbi.nlm.nih.gov

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

7. United States pubmed.ncbi.nlm.nih.gov

Bevacizumab and irinotecan in children with recurrent or refractory brain tumors: toxicity and efficacy trends. [2022]

8. United States pubmed.ncbi.nlm.nih.gov

Feasibility and tolerability of bevacizumab in children with primary CNS tumors. [2015]