Amantadine as a Biomarker for Glioblastoma

Age: 18+

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Academic

Recruiting

Sponsor: CancerCare Manitoba

Must not be taking: Antivirals, Methamphetamine, Cocaine

Disqualifiers: Parkinson's, Schizophrenia, Renal impairment, others

No Placebo Group

Approved in 3 Jurisdictions

Trial Summary

What is the purpose of this trial?

This trial uses the drug amantadine to help monitor brain tumors in patients with glioblastoma. By measuring how much of the drug is changed into another form in the body, doctors can track tumor activity. This could provide a better way to monitor these aggressive brain tumors.

Will I have to stop taking my current medications?

You may need to stop taking certain medications if they are known to interact with amantadine, which is part of the trial. The trial does not specify all medications that interact, so it's important to discuss your current medications with the trial team.

What data supports the effectiveness of the drug Amantadine for treating glioblastoma?

Amantadine has shown effectiveness in improving motor symptoms in Parkinson's disease and walking speed in multiple sclerosis, suggesting it may have beneficial effects on the nervous system. However, there is no direct evidence supporting its effectiveness for glioblastoma. ^{1 2 3 4 5}

Is Amantadine generally safe for humans?

Amantadine has been used safely in humans for conditions like Parkinson's disease and multiple sclerosis, with side effects similar to placebo in studies. Some mild side effects like skin discoloration and blurred vision have been reported, but overall, it is considered generally safe. ^{1 2 3 6 7}

How does the drug Amantadine Hydrochloride differ from other treatments for glioblastoma?

Amantadine Hydrochloride is unique because it targets multiple pathways, including NMDA receptors and sigma-1 receptors, which may offer neuroprotective benefits and potential therapeutic effects in glioblastoma, unlike standard treatments that primarily focus on direct tumor reduction. ^{2 6 8 9 10}

Eligibility Criteria

This trial is for adults with confirmed Glioblastoma who are planning to undergo radiation and/or chemotherapy. They must be able to swallow pills, have good kidney and liver function, not be pregnant or breastfeeding, and agree to use contraception. Excluded are those with allergies to amantadine, drug abuse issues, severe kidney problems, Parkinson's disease or schizophrenia.

Inclusion Criteria

I can visit the study center for follow-up appointments.

I can take care of myself and am up and about more than half of my waking hours.

I can swallow pills.

Exclusion Criteria

I am not taking any medications that interact with amantadine.

You have been diagnosed with schizophrenia in the past.

I am currently taking antiviral medication for an infection.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive a 200 mg dose of amantadine at each visit where MRI is obtained, typically every 8-12 weeks, alongside standard care treatments such as radiation and chemotherapy

32-36 weeks

Visits every 8-12 weeks for MRI and biomarker assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment, with continued assessment of acetyl-amantadine levels and MRI imaging

up to 2 years

Visits every 8-12 weeks

Treatment Details

Interventions

• Amantadine Hydrochloride (Diagnostic Biomarker)

Trial Overview The study tests if the drug Amantadine Hydrochloride can help monitor brain tumor burden in patients by measuring its metabolite levels in blood/urine against MRI results. It explores whether this method could serve as a new diagnostic biomarker for Glioblastoma.

Participant Groups

Group I: GBM Patients Experimental Treatment 1 Intervention

This cohort of patients will be asked to orally ingest 200mg dose of FDA approved drug amantadine hydrochloride. This will be done at the following timepoints: 1. Within 4 weeks of the start of treatment; but as close to commencement of treatment (Day 1 of radiotherapy) as possible for newly diagnosed patients. 2. Cycle 1, Day 1 of chemotherapy (temozolomide or lomustine) +/- 7 days 3. Day 1 +/- 7 days for each visit where MRI is obtained (typically every 8-12 weeks - pre-cycles 4, 7, 10, for temozolomide or pre-cycles 3, 5, and 7 for lomustine)

Amantadine Hydrochloride is already approved in Canada for the following indications:

Approved in Canada as Amantadine Hydrochloride for:

• Parkinson's disease
• Influenza A viral infection

Who Is Running the Clinical Trial?

CancerCare Manitoba

Lead Sponsor

Trials

29

Recruited

5,600+

The Metabolomics Innovation Centre

Collaborator

Trials

1

Recruited

20+

University of Manitoba

Collaborator

Trials

628

Recruited

209,000+

Canadian Institutes of Health Research (CIHR)

Collaborator

Trials

1,417

Recruited

26,550,000+

BioMark Diagnostics Inc.

Collaborator

Trials

1

Recruited

20+

Findings from Research

In a Phase 3 trial involving 558 participants with multiple sclerosis (MS), the 274 mg dose of ADS-5102 significantly improved walking speed, with 21.1% of participants showing a meaningful response compared to 11.3% in the placebo group.

While the primary outcome was met, indicating efficacy, there was a notable increase in adverse events leading to discontinuation, particularly at the higher dose (20.5% for 274 mg), suggesting a need for careful monitoring of side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment. Cohen, JA., Cameron, MH., Goldman, MD., et al.[2022]

In a study of 42 patients with Parkinson's disease, amantadine significantly improved symptoms and activity impairment scores by 92% and 95% respectively, compared to only 4% and 18% improvements with placebo, demonstrating its efficacy when combined with levodopa and carbidopa.

The side effects of amantadine were generally similar to those of placebo, with only a few mild cases reported, indicating that it is a safe addition to existing Parkinson's treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine and a fixed combination of levodopa and carbidopa in the treatment of Parkinson's disease. Savery, F.[2013]

In a study involving 9 Parkinson's disease patients, intravenous amantadine significantly reduced levodopa-induced dyskinesias by 50% without compromising the benefits of levodopa for motor symptoms.

This research supports the use of amantadine as an effective antidyskinetic treatment and highlights the potential of antiglutamatergic drugs in managing motor fluctuations in Parkinson's disease.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study. Del Dotto, P., Pavese, N., Gambaccini, G., et al.[2019]

Amantadine therapy led to significant improvements in mental status for three patients diagnosed with Alzheimer's disease, with two experiencing dramatic reversals from mute and immobile states to being able to speak coherently during treatment.

The observed improvements were linked to changes in EEG patterns, suggesting that amantadine may enhance dopamine release and act as a central stimulant, although the benefits diminished upon withdrawal of the drug.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine and the end-stage dementia of Alzheimer's type. Erkulwater, S., Pillai, R.[2019]

Amantadine shows potential as a therapeutic agent beyond its current uses for Parkinson's disease and viral infections, targeting various receptors and pathways such as aromatic amino acids decarboxylase and sigma-1 receptors.

Clinical studies suggest that amantadine may be effective for conditions like traumatic brain injury, fatigue in multiple sclerosis, and chorea in Huntington's disease, with ongoing research exploring its use in areas like depression and neuroprotection.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. Danysz, W., Dekundy, A., Scheschonka, A., et al.[2021]

Amantadine hydrochloride, at doses of 2.5 and 5 mg/kg, significantly reduced the stimulating effects of d-amphetamine on motor activity in mice, indicating its potential to modulate CNS stimulation.

Additionally, amantadine increased the anorexic effects of d-amphetamine, as shown by reduced milk intake, suggesting it may influence appetite regulation in the context of stimulant use.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Amantadine decreases d-amphetamine stimulation and increases d-amphetamine anorexia in mice. Clark, R., Smith, DH., Vernier, VG., et al.[2020]

A new LC-MS/MS method for analyzing amantadine in serum simplifies the process by eliminating the need for laborious sample pretreatment steps like extraction and derivatization, making it more efficient.

This method demonstrated high specificity and accuracy, with a detection limit of 20 mg/l and a recovery rate of 99-101%, showing it is comparable to traditional gas chromatography without significant bias.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Determination of serum amantadine by liquid chromatography-tandem mass spectrometry. Arndt, T., Guessregen, B., Hohl, A., et al.[2019]

Amantadine concentrations in the brain tissue of patients treated for over 10 days can reach levels between 48.2 to 386 microM, significantly higher than the low micromolar concentrations found in cerebrospinal fluid (CSF) and serum, indicating effective central nervous system penetration.

The study suggests that the extracellular concentrations of amantadine in the brain are within the range of its effective blocking concentration at NMDA receptors, which may contribute to its therapeutic effects in managing Parkinson's disease and drug-induced symptoms.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapeutic brain concentration of the NMDA receptor antagonist amantadine. Kornhuber, J., Quack, G., Danysz, W., et al.[2019]

A new HPLC method was developed to simultaneously detect amantadine and four related compounds with very low detection limits, making it effective for analyzing these drugs in solution.

The study also revealed that ADAMA, rimantadine, and memantine bind to human alpha(1)-acid glycoprotein with varying affinities, which could influence their therapeutic effects and interactions in the body.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Simultaneous liquid chromatographic assay of amantadine and its four related compounds in phosphate-buffered saline using 4-fluoro-7-nitro-2,1,3-benzoxadiazole as a fluorescent derivatization reagent. Higashi, Y., Nakamura, S., Matsumura, H., et al.[2015]

References

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

A Phase 3, double-blind, placebo-controlled efficacy and safety study of ADS-5102 (Amantadine) extended-release capsules in people with multiple sclerosis and walking impairment. [2022]

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

Effects of Amantadine Sulfate on Motor Impairment and Execution of Motor Sequences in Patients With Parkinson Disease. [2023]

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

Amantadine and a fixed combination of levodopa and carbidopa in the treatment of Parkinson's disease. [2013]

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

Intravenous amantadine improves levadopa-induced dyskinesias: an acute double-blind placebo-controlled study. [2019]

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

Amantadine and the end-stage dementia of Alzheimer's type. [2019]

6. Austria pubmed.ncbi.nlm.nih.gov

Amantadine: reappraisal of the timeless diamond-target updates and novel therapeutic potentials. [2021]

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

Amantadine decreases d-amphetamine stimulation and increases d-amphetamine anorexia in mice. [2020]

8. Netherlands pubmed.ncbi.nlm.nih.gov

Determination of serum amantadine by liquid chromatography-tandem mass spectrometry. [2019]

9. England pubmed.ncbi.nlm.nih.gov

Therapeutic brain concentration of the NMDA receptor antagonist amantadine. [2019]

10. England pubmed.ncbi.nlm.nih.gov

Simultaneous liquid chromatographic assay of amantadine and its four related compounds in phosphate-buffered saline using 4-fluoro-7-nitro-2,1,3-benzoxadiazole as a fluorescent derivatization reagent. [2015]