Neoplasms

All Conditions

Nervous System Diseases

Rare Diseases

Glioblastoma

Brain Neoplasms

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Neuroepithelioma

Antineoplastic Agents

All Drugs and Chemicals

Anti-Infective Agents

Analgesics

Anti-Dyskinesia Agents

Cardiotonic Agents

Temozolomide

Lomustine

Amantadine

Antiparkinson Agents

Antiviral Agents

Dopamine

Dopamine Agents

Neurotransmitter Agents

Analgesics, Non-Narcotic

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)

Patients who are eligible for the study will be administered a regular 200 mg dose of FDA approved drug amantadine. 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

Anmol Mann, BSc.

Gary Annable

Marshall Pitz, MD, FRCPC

Glioblastoma multiforme (GBM) is the most common brain tumor in adults. The strikingly poor survival for patients with GBM (average survival 14-16 months following diagnosis) is due in part to limited early detection methods and an absence of effective therapeutic options. 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 monitor GBM. The method is based on the overproduction of a key enzyme in GBM cells called spermine/ spermidine n-acetyl transferase (SSAT1). The increased SSAT1 expression in GBM results in increased metabolism of the drug which is detected in the blood or urine of patients with GBM. The levels of acetyl-amantadine captured will be correlated with the tumor burden as seen on the MRIs of these patients. Thus, the study aims to determine the usefulness of amantadine as a diagnostic biomarker for GBM.

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults, with a median age of onset of 55 to 60 years. Most patients are treated with postoperative radiation and chemotherapy following their initial surgery. For newly diagnosed, high grade gliomas, the first post-radiation cycle of temozolomide (an oral chemotherapy drug) typically begins four weeks after completion of radiation therapy1. During radiation, temozolomide or lomustine is given daily (seven days per week). Assessment of response and progression is made through brain magnetic resonance imaging (MRI) with contrast, which is typically obtained within one month after completion of radiation therapy and then every two months during adjuvant temozolomide to assess disease status1. With the available standard of care, the median overall survival of patients with glioblastoma remains very low - approximately 10 to 12 months2.

The poor prognosis with GBM is a result of an absence of early detection and ineffective treatment options. The proposed exploratory pilot project attempts to addresses the problem of accurate tumor progression monitoring in GBM through the development of a drug biomarker that monitors spermidine/spermine N1-acetyltransferase (SSAT1) activity. SSAT1 is an important enzyme involved in polyamine regulation in the cell. As polyamines are essential for tumor proliferation, SSAT1 is over-expressed in many different cancers, as shown in a number of non-clinical trials3,4,5. These trials provide a rationale for our project: if SSAT1 is overexpressed in cancers including glioblastoma, then a substrate of SSAT1 could serve as a biomarker for determining the cellular activity of SSAT1. An effective substrate is amantadine, and following its acetylation by SSAT1, N-acetyl-amantadine levels excreted in the blood and urine samples of patients with glioblastoma could be used to indicate the presence of upregulation of SSAT1, and therefore, indicative of cancer. Recently published clinical trials involving investigators here at University of Manitoba and CancerCare Manitoba have reported a method for assessing tumor progression in lung and breast cancer patients based on acetyl- amantadine levels in blood and urine6,7,8. The assay is predicated on the selective acetylation of the drug amantadine by SSAT1. Published studies indicate increases in acetyl-amantadine in blood and urine from patients receiving a single oral dose of amantadine was predictive of tumor burden. Tappia et.al.7 reported that human cancer is associated with high urinary concentration of acetyl-amantadine with receiver-operating characteristic (ROC) for acetyl-amantadine demonstrated to be 0.689 (CI: 0.591-0.786, 95%) in lung cancer and 0.717 (CI: 0.577-0.858, 95%) for breast cancer.

Given the use of acetyl-amantadine as an early biomarker for lung and breast cancer, the present study protocol examines the extent to which acetyl-amantadine levels in blood and urine can be used to detect glioblastoma progression, particularly tumor recurrence which happens in the majority of patients and is considered inevitable after a median survival time of 32 - 36 weeks1. There are currently no studies that have attempted to determine the diagnostic value of acetyl-amantadine in glioblastoma patients, and therefore, this would be a pilot project. Under this protocol, patients diagnosed with glioblastoma (newly or recurrent) who are following the standard of care (surgical resection and radiation/chemotherapy) will be enrolled in the study. An initial assessment of the participant's baseline acetyl-amantadine levels in blood will be determined at the first visit. Thereafter, participants will be administered a standard 200 mg dose of the Health Canada approved drug amantadine at every visit in which MRI based imaging assessments are being performed (typically, every 8 - 12 weeks). Blood and urine samples will be taken at each visit to assay for acetyl-amantadine levels. These resulting acetyl-amantadine levels will be correlated with MRI based image findings to determine the extent to which this biomarker can be used for treatment monitoring in glioblastoma patients.

While the hypothesis is that acetyl-amantadine levels in blood or urine can be used to track tumor progression, an increase in acetyl-amantadine level would not indicate per se what type of tumor was present. For this reason, a metabolic profile on blood and urine samples collected from glioblastoma patients will be performed, to determine if there is a metabolic signature that can be established for glioblastoma.

All patients eligible for the study who have provided consent will be asked to ingest a regular 200mg dose of FDA approved drug Amantadine, according to timelines proposed in the protocol.

Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma

Samples of plasma and urine will be analyzed by established analytical methods (as developed by Biopharmaceutical Research Inc., Vancouver, B.C.; Health Canada and FDA approved). Quantitative analysis of amantadine and acetyl-amantadine in plasma and urine samples will be performed using liquid chromatography triple quadrupole tandem mass spectroscopy (LC-MS/MS). Samples (50 µl) will be spiked with 50 µl of internal standard, deuterated acetyl-amantadine (d3-Ac-amantidine), and proteins precipitated with 0.5 ml of ice-cold methanol. The lyophilized deproteinated samples are reconstituted in 0.1 ml of 0.1% formic acid. Samples are injected onto a C-18 stationary column and eluted using a gradient mobile phase consisting of 0.1% aqueous formic acid (A) and 0.1% formic acid in methanol (B). The run time for each sample is 9 minutes with the mobile phase starting at 5% B and increasing to 95% B during sample elution.

Standard of care MRI will be used. Definitions of response to standard therapy (progression, stable disease, response) will follow the established Response Assessment in Neuro-Oncology (RANO) guidelines9.

Post-hoc volumetric analysis will be done using quantitative semi-automated Olea Sphere software (Olea Medical, France).

The study does not require additional MRI scans to be performed; Routine MRI images, as per glioblastoma standard of treatment, are posted to Radiology Information System/Picture Archiving and Communication System (RISPACS) and will be accessed for analysis.

University of Manitoba

The Metabolomics Innovation Centre

BioMark Diagnostics Inc.

Canadian Institutes of Health Research (CIHR)

CancerCare Manitoba

Lung cancer patients being prescribed chemotherapy

Amantadine is a drug that has been on the market for several years and is currently approved for the treatment of Parkinson's disease and for prevention against influenza A infection. Amantadine may be of value in detecting the presence of cancer.

Paramjit S Tappia, PhD

Andrew Maksymiuk, MD

Several factors discourage the implementation of cancer screening to the population in general, which would result in earlier diagnosis and an expected improved survival. Concurrent in vivo and in vitro research has shown that drug acetylation activity is increased in cancer. Amantadine may be of value in detecting the presence of cancer. Accordingly, this study will examine how Amantadine is eliminated by the body in cancer patients. This is an important step in validating a cancer detection method that can be implemented economically for screening of large numbers of people.

The study will involve the screening of volunteer patients with various types of cancer to provide a first indication of which types of cancer and at what stage of tumor burden acetylamantadine will be found in patients' plasma, saliva and urine samples. Volunteers will provide complete first morning urine collection prior to amantadine ingestion. The volunteers will then ingest a therapeutic dose of amantadine (200 mg: 2x100mg capsules), at least 2 hours before breakfast (nothing to eat or drink except water after midnight before the scheduled appointment), and their complete urine will be collected at 2 and 4 hours (plus or minus 1 hour) after amantadine ingestion. In addition, blood samples will be taken by venipuncture before and at 2 and 4 hours after drug ingestion. The patients will be asked to provide a saliva sample at the same time as the urine samples are taken after drug ingestion.

Acetylamantadine Excretion by Cancer Patients

Urinary Excretion of Acetylamantadine by Cancer Patients

BioMark Technologies Inc.

St. Boniface Hospital

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Symptoms and General Pathology

Prostatic Neoplasms

Pain

Hyperalgesia

Somatosensory Disorders

Sensation Disorders

Neurologic Manifestations

Central Nervous System Depressants

Amino Acids

Analgesics, Opioid

N-Methylaspartate

Aspartic Acid

Lucia Gagliese, PhD

Vincent Chan, MD

Dirk Snijedelaar, MD

Joel Katz, PhD

Gideon Koren, MD

The primary aim is to determine whether perioperative NMDA-receptor antagonism has differential effects on postoperative pain, hyperalgesia and morbidity in younger and older patients. In order to achieve this aim, the researchers propose to conduct the first randomized, double-blind placebo-controlled study designed to investigate age differences in the effects of perioperative oral administration of an NMDA-receptor antagonist (amantadine) in men undergoing radical prostatectomy. In addition, age differences in psychosocial factors and the pharmacological properties of amantadine and morphine will be measured to control for, and clarify, their contribution to the differences found.

The specific objectives of the study are to:

1. investigate the effects of perioperative NMDA receptor blockade on postoperative hyperalgesia, pain and analgesic consumption in young and elderly men
2. assess age differences in the intensity and course of secondary hyperalgesia after surgery

The immediate postoperative period is associated with spontaneous pain and hyperalgesia, i.e., increased pain response (both intensity and duration) to normally painful stimuli following tissue injury or damage.

The development and maintenance of secondary hyperalgesia depend on complex plastic changes in spinal cord dorsal horn cells after peripheral injury or damage. Afferent impulses signaling the damage are carried to the dorsal horn by slowly conducting, unmyelinated C-fibres. C-fibres release glutamate which acts at three receptor types: metabotropic, kainate/AMPA and NMDA. NMDA receptor activation, through a complex cascade of intracellular events, results in dorsal horn neuron hyperexcitability or central sensitization. These cells have increased spontaneous activity, decreased threshold, increased response to afferent input, prolonged afterdischarge to repeated stimulation, and an expansion of receptive fields. Central sensitization is expressed behaviorally as secondary hyperalgesia and contributes to prolonged postoperative pain. It also may trigger pathological reorganization of neural circuitry leading to the development of chronic postsurgical pain. Through these processes, tissue injury may have profound effects on the CNS that long outlast the injury.

In animal models of pain, NMDA agonists induce central sensitization and hyperalgesia whereas antagonists decrease or prevent hyperalgesia. In humans, NMDA-receptor antagonism decreases secondary hyperalgesia subsequent to experimentally-induced pain.

Perioperative administration of NMDA antagonists, that is, before, during and after surgery, may be the ideal intervention to block the initiation and maintenance of central sensitization. Several studies have found that this intervention reduces postoperative hyperalgesia, pain, and analgesic use; however, others have not found these effects. This is not surprising given the variability across studies in factors such as surgical procedure, extent and nature of tissue damage, duration of surgery, pharmacokinetics of the agent(s) tested, and intraoperative and postoperative analgesia. Nonetheless, the weight of the evidence suggests that preventing or minimizing central sensitization reduces pain and analgesic requirements.

Co-administration of NMDA antagonists and opioids has been advocated as an effective approach. The combination of morphine and amantadine should reduce postoperative pain by inducing analgesia through actions on opioid-mediated receptor systems and by reducing hyperalgesia via NMDA receptor-mediated events . The combination also should produce fewer opioid-related adverse effects due to the anticipated opioid-sparing effect. The present proposal describes the first direct comparison of perioperative NMDA receptor blockade coupled with intra- and post-operative opioid administration in young and elderly patients. In order to minimize the influence of other perioperative factors on the outcome variables, all patients will undergo the same surgical procedure and anesthetic protocol. Furthermore, factors that cannot readily be standardized (e.g., surgical duration, mood) will be measured and controlled for statistically. This increases the internal validity of the proposed study and our ability to detect age and drug effects.

Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy

Effects of NMDA-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy in Young and Elderly Patients

University Health Network, Toronto

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma	NCT04530006	Glioblastoma Mu...	Amantadine Hydr...	18 Years -	CancerCare Manitoba
Acetylamantadine Excretion by Cancer Patients	NCT02277938	Cancer	Amantadine	18 Years - 80 Years	University of Manitoba
Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy	NCT00188383	Hyperalgesia Pain Prostate Cancer	Amantadine	18 Years - 80 Years	University Health Network, Toronto
Effects of N-Methyl-D-Aspartate (NMDA)-Receptor Antagonism on Hyperalgesia, Opioid Use, and Pain After Radical Prostatectomy	NCT00188383	Hyperalgesia Pain Prostate Cancer	Amantadine	18 Years - 80 Years	University Health Network, Toronto
Acetylamantadine Excretion by Cancer Patients	NCT02277938	Cancer	Amantadine	18 Years - 80 Years	University of Manitoba
Acetylamantadine Excretion by Cancer Patients	NCT02277938	Cancer	Amantadine	18 Years - 80 Years	University of Manitoba
Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma	NCT04530006	Glioblastoma Mu...	Amantadine Hydr...	18 Years -	CancerCare Manitoba

Spots Global Cancer Trial Database for amantadine

Every month we try and update this database with for amantadine cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for amantadine

Every month we try and update this database with for amantadine cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for amantadine cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.