Amantadine as a Biomarker for Glioblastoma

Overseen By Anmol Mann, BSc.

Age: 18+

Sex: Any

Trial Phase: Academic

Sponsor: CancerCare Manitoba

Must not be taking: Antivirals, Methamphetamine, Cocaine

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

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

Approved in 3 Jurisdictions This treatment is already approved in other countries

Compensation: Varies

Number of Visits: 16

Duration: 32-36 weeks

20 Participants Needed

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial explores whether the drug amantadine (Amantadine Hydrochloride) can aid in monitoring glioblastoma, a common and aggressive brain tumor, by tracking a specific enzyme linked to tumor growth. Researchers are testing if changes in the drug's byproducts in the body align with MRI results, potentially helping doctors track the tumor's size and activity. The trial seeks adults with a confirmed glioblastoma diagnosis who are scheduled to receive radiation or chemotherapy and can attend regular study visits. As an unphased trial, this study offers patients the chance to contribute to innovative research that could enhance glioblastoma monitoring.

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 prior data suggests that this method is safe for monitoring glioblastoma?

Research has shown that amantadine hydrochloride has been tested for safety in other conditions. In one study, among 100 patients taking the drug, a few experienced side effects such as drowsiness, tiredness, and mood changes, but these were uncommon, with less than 3% reporting these issues. Another study found that in children with brain injuries, only 5 out of 54 experienced side effects, all of which were temporary.

Amantadine is already approved in the U.S. and Canada for other uses, providing a wealth of safety information, which is reassuring. However, individual experiences may vary. It is important to consult a healthcare provider to understand the risks and benefits specific to each person. ^{1 2 3 4 5}

Why are researchers excited about this trial?

Researchers are excited about using amantadine hydrochloride as a potential biomarker for glioblastoma because it offers a novel approach to understanding this aggressive brain cancer. Unlike the standard treatments that primarily focus on slowing tumor growth through chemotherapy and radiation, amantadine hydrochloride could help in monitoring and predicting treatment response. This drug is traditionally used for other purposes, but its repurposing for glioblastoma could pave the way for more personalized and effective treatment strategies by providing real-time insights into how the cancer is behaving.

What evidence suggests that amantadine could be an effective biomarker for glioblastoma?

Research has shown that amantadine helps with conditions other than glioblastoma (GBM), such as easing movement problems in Parkinson's disease and aiding recovery from brain injuries. It influences certain chemicals in the brain and may protect brain cells. In this trial, participants with GBM will receive amantadine to explore its use as a tool for assessing tumor activity. It measures a specific enzyme related to GBM, enabling doctors to track the disease more accurately through blood or urine tests. While amantadine is not proven to treat GBM directly, its potential as a diagnostic tool is promising. ^{3 6 7 8 9}

Are You a Good Fit for This Trial?

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.

Timeline for a Trial Participant

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

What Are the Treatments Tested in This Trial?

Interventions

• Amantadine Hydrochloride

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.

How Is the Trial Designed?

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 United States, European Union, Canada for the following indications:

Approved in United States as Gocovri for:

• Dyskinesia associated with Parkinson's disease
• Influenza A viral infection

Approved in European Union as Symmetrel for:

• Parkinson's disease
• Extrapyramidal side effects of medications
• Postherpetic neuralgia

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+

Published Research Related to This Trial

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 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 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]

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]

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]

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 31 participants with Parkinson's disease, daily infusions of 200 mg amantadine sulfate over 3 days led to significant improvements in motor symptoms, particularly in tasks requiring higher cognitive effort.

While amantadine improved cognitive abilities and motor performance in more complex tasks, it did not enhance performance in simpler, automated motion sequences, indicating its specific benefits in cognitive and motor function under certain conditions.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Effects of Amantadine Sulfate on Motor Impairment and Execution of Motor Sequences in Patients With Parkinson Disease. Müller, T., Kuhn, W.[2023]

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]

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]

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]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT04530006

NCT04530006 | Acetyl-Amantadine as a Biomarker in ... The study proposed would establish important evidence for the use of Health Canada approved drugs such as amantadine as a safe, effective and affordable way to ...

2. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC7901515/

Amantadine: reappraisal of the timeless diamond—target ... The first goal of the present review was to analyze possible molecular targets of amantadine considering actual therapeutic concentrations and ...

3. withpower.com withpower.com/trial/phase-glioblastoma-11-2020-39b9e

Amantadine as a Biomarker for Glioblastoma What data supports the effectiveness of the drug Amantadine for treating glioblastoma? Amantadine has shown effectiveness in improving motor symptoms in ...

4. neurologylive.com neurologylive.com/view/switch-from-amantadine-immediate-release-gocovri-results-improved-real-world-parkinson-disease-benefits

Switch From Amantadine Immediate-Release to Gocovri ... Research reveals that delayed-release amantadine significantly reduces Parkinson disease symptoms and medication use, offering patients ...

5. mdpi.com mdpi.com/2227-9059/12/7/1558

Amantadine for Traumatic Brain Injury—Supporting ... Amantadine, the drug combining multiple mechanisms of action, may offer both neuroprotective and neuroactivating effects in TBI patients.

6. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2017/208944lbl.pdf

GOCOVRI (amantadine) extended release capsules Of the 100 patients in the safety population described below, 39 patients were treated with GOCOVRI for 24 weeks. The safety data for these trials were pooled.

7. gocovrihcp.com gocovrihcp.com/safety

Safety Profile | GOCOVRI® (amantadine) Other clinically relevant adverse reactions observed at <3% included somnolence, fatigue, suicide ideation or attempt, apathy, delusions, illusions, and ...

8. accessdata.fda.gov accessdata.fda.gov/drugsatfda_docs/label/2009/016023s041,018101s016lbl.pdf

SYMMETREL® (Amantadine Hydrochloride, USP) Tablets ... The safety margins reported may not accurately reflect the risk considering the questionable quality of the study on which they are based. There are no adequate ...

9. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC11274811/

Amantadine for Traumatic Brain Injury—Supporting Evidence ... Green et al. (2004) evaluated the safety of amantadine in children with TBI, with only 5 of 54 patients experienced side effects, all of which were reversible [ ...