Memantine for Brain Tumor

Recruiting in Palo Alto (17 mi)

+137 other locations

Overseen by Nadia N Laack

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Children's Oncology Group

Must not be taking: Anticonvulsants, Carbonic anhydrase inhibitors

Disqualifiers: Intractable seizures, Neurodevelopmental disorders, others

Pivotal Trial (Near Approval)

Prior Safety Data

Trial Summary

What is the purpose of this trial?

This trial tests whether memantine can help children and adolescents with brain tumors maintain their thinking abilities during treatment. Memantine may protect brain function by blocking certain parts of nerve cells that cause thinking problems. Memantine has been used to treat thinking issues in Alzheimer's disease and to prevent thinking problems in patients undergoing brain treatment.

Will I have to stop taking my current medications?

The trial does not specify if you need to stop taking your current medications. However, if you are taking medications that make your urine more alkaline, you may not be eligible to participate.

What data supports the effectiveness of the drug Memantine Hydrochloride for brain tumors?

Memantine has been shown to help reduce cognitive decline in cancer patients with brain metastasis who are receiving whole-brain radiotherapy, suggesting it may offer some protective benefits for brain function during such treatments. ^{1 2 3 4 5}

How does the drug Memantine Hydrochloride differ from other brain tumor treatments?

Memantine Hydrochloride is unique because it is primarily used to treat Alzheimer's disease by blocking NMDA receptors (which are involved in memory and learning), and its use in brain tumors is novel as it may offer a different mechanism of action compared to traditional chemotherapy and radiotherapy, which often struggle with crossing the blood-brain barrier. ^{6 7 8 9 10}

Research Team

Nadia N Laack

Principal Investigator

Children's Oncology Group

Eligibility Criteria

This trial is for children and adolescents aged 4-17 with newly diagnosed or recurrent primary brain tumors who haven't had prior cranial radiotherapy. Participants must weigh at least 15 kg, have adequate organ function, be able to undergo MRI scans, and understand English, French or Spanish. They can't join if they have a life expectancy under 18 months, allergies to memantine, uncontrollable seizures despite medication, severe diseases that could affect the study's outcome or are pregnant.

Inclusion Criteria

All patients and/or their parents or legal guardians must sign a written informed consent

The patient must be able to undergo magnetic resonance imaging

I weigh more than 15 kg.

Exclusion Criteria

Life expectancy of less than 18 months

I have a neurodevelopmental disorder like Down syndrome or Fragile X.

Co-morbid systemic illnesses, psychiatric conditions, social situations, or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens or would limit compliance with the study requirements

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Radiation Therapy

Participants receive cranial or craniospinal radiotherapy as part of treatment for primary central nervous system tumors

6 weeks

Daily visits for radiation therapy

Treatment

Participants receive memantine or placebo orally for 24 weeks, with cognitive testing and MRI assessments

24 weeks

Weekly visits for the first 2 weeks, then bi-weekly visits

Follow-up

Participants are monitored for cognitive function and overall survival, with assessments at 12, 24, and 48 months

48 months

Assessments at 12, 24, and 48 months

Treatment Details

Interventions

• Memantine Hydrochloride (NMDA receptor antagonist)

Trial Overview The trial is testing whether Memantine Hydrochloride can protect cognitive functions like attention and memory in kids receiving radiation therapy for brain tumors compared to usual treatment without Memantine. Cognitive assessments will measure the outcomes.

Participant Groups

Group I: Arm I (memantine hydrochloride) Experimental Treatment 5 Interventions

Patients receive memantine hydrochloride orally PO QD for week 1 and then BID for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial.

Group II: Arm II (placebo) Placebo Group 5 Interventions

Patients receive placebo PO QD for week 1 and then BID for weeks 2-24 in the absence of disease progression or unacceptable toxicity. Patients also complete cognitive testing over 20-30 minutes at baseline, end of radiation therapy, and at 3, 6, 12, 24, and 48 months. Patients undergo MRI and may optionally undergo blood sample collection throughout the trial.

Who Is Running the Clinical Trial?

Children's Oncology Group

Lead Sponsor

Trials

467

Recruited

241,000+

Dr. Doug Hawkins

Children's Oncology Group

Chief Executive Officer since 2020

MD from University of Washington School of Medicine

Dr. Leo Mascarenhas

Children's Oncology Group

Chief Medical Officer since 2024

MD, MS from Cedars-Sinai Guerin Children’s

Findings from Research

Memantine, while generally well-tolerated for neurocognitive protection during cranial radiotherapy, can cause altered mental status, as demonstrated in a case involving an 18-year-old male with medulloblastoma who required ICU admission after starting the medication.

The patient's symptoms improved significantly after memantine was withheld, highlighting the need for clinicians to be cautious and monitor for potential neurocognitive side effects when prescribing memantine, especially in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma. Kim, KN., Shah, YB., Croy, C., et al.[2023]

Whole brain radiation therapy, the primary treatment for brain metastases in low to middle income countries, is linked to irreversible cognitive decline.

Memantine has been shown to help reduce the rate of cognitive decline and delay cognitive failure in cancer patients undergoing whole brain radiotherapy, suggesting it may be a beneficial therapeutic option.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole-brain radiotherapy: a narrative review. Folloso, MC., Torres, M., Ciocon, SL., et al.[2023]

The new dry syrup formulation of memantine hydrochloride demonstrated bioequivalence to the traditional film-coated tablet, meaning it delivers the same amount of the active ingredient effectively, as shown in two crossover studies with specified dosing conditions.

Both formulations were found to have similar safety profiles, indicating that the new syrup can be a suitable alternative for Alzheimer's disease patients, potentially improving medication adherence.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pharmacokinetics and Bioequivalence of Memantine Tablet and a New Dry Syrup Formulation in Healthy Japanese Males: Two Single-Dose Crossover Studies. Maekawa, Y., Hasegawa, S., Ishizuka, T., et al.[2020]

In a study using mice with implanted brain tumors, gemcitabine significantly increased lifespan by 60-89% at a dose of 25 mg/kg, despite its limited ability to cross the blood-brain barrier (BBB) at only 10% permeability.

Compared to other drugs like carmustine and cyclophosphamide, which had higher BBB permeability, gemcitabine still demonstrated a pronounced therapeutic effect, suggesting that even a small concentration of the drug can be effective against intracranial tumors.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Efficacy of Gemcitabine on Intracranial Erlich Tumor and its Determinants. Stukov, AN., Bespalov, VG., Alexandrov, VA., et al.[2022]

Temozolomide is an effective oral treatment for high-grade glioma and anaplastic astrocytoma, showing not only antitumor effects but also improvements in patients' quality of life.

It has potential advantages for treating neoplastic meningitis due to its ability to penetrate the blood-brain barrier and its demonstrated efficacy in increasing survival in preclinical models, making it a promising candidate for further research in central nervous system cancers.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Temozolomide in early stages of newly diagnosed malignant glioma and neoplastic meningitis. Friedman, HS.[2018]

In a study of 158 patients with intrinsic brain tumors, several chemotherapeutic agents showed notable efficacy, with carmustine (BCNU) having a response rate of 47% and a median duration of response of nine months.

When patients who initially responded to one drug were given a second drug, only 15% showed a response, indicating limited effectiveness of switching treatments after initial therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Single-agent chemotherapy of brain tumors. A five-year review. Wilson, CB., Gutin, P., Boldrey, EB., et al.[2019]

Chemotherapy is a key treatment for various malignant brain tumors, including primary central nervous system lymphomas and malignant gliomas, highlighting its importance in oncology.

New therapies, such as cytostatic agents and molecular therapies, are being explored to improve treatment outcomes for brain tumors, indicating ongoing advancements in cancer care.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Brain tumor treatment: chemotherapy and other new developments. Graham, CA., Cloughesy, TF.[2018]

Current treatments for brain tumors are often inadequate, leading to ongoing research into the use of concurrent chemotherapy and radiotherapy to improve patient outcomes.

Trials are exploring new agents that can effectively cross the blood-brain barrier and minimize overlapping toxicities, which may enhance the safety and efficacy of combined therapies for brain tumor patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Concurrent chemotherapy and radiotherapy in patients with brain tumors. Glantz, MJ., Kim, L., Choy, H., et al.[2005]

References

1. England pubmed.ncbi.nlm.nih.gov

Life-threatening altered mental status secondary to memantine in an adolescent undergoing cranial radiotherapy for medulloblastoma. [2023]

2. Brazil pubmed.ncbi.nlm.nih.gov

Therapeutic role of memantine for the prevention of cognitive decline in cancer patients with brain metastasis receiving whole-brain radiotherapy: a narrative review. [2023]

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

Pharmacokinetics and Bioequivalence of Memantine Tablet and a New Dry Syrup Formulation in Healthy Japanese Males: Two Single-Dose Crossover Studies. [2020]

4. Spain pubmed.ncbi.nlm.nih.gov

[Glutamate-related excitotoxicity neuroprotection with memantine, an uncompetitive antagonist of NMDA-glutamate receptor, in Alzheimer's disease and vascular dementia]. [2013]

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

Sustained Preservation of Cognition and Prevention of Patient-Reported Symptoms With Hippocampal Avoidance During Whole-Brain Radiation Therapy for Brain Metastases: Final Results of NRG Oncology CC001. [2023]

6. Germany pubmed.ncbi.nlm.nih.gov

Efficacy of Gemcitabine on Intracranial Erlich Tumor and its Determinants. [2022]

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

Temozolomide in early stages of newly diagnosed malignant glioma and neoplastic meningitis. [2018]

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

Single-agent chemotherapy of brain tumors. A five-year review. [2019]

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

Brain tumor treatment: chemotherapy and other new developments. [2018]

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

Concurrent chemotherapy and radiotherapy in patients with brain tumors. [2005]