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Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma

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ClinicalTrials.gov Identifier: NCT04530006
Recruitment Status : Recruiting
First Posted : August 28, 2020
Last Update Posted : February 15, 2021
Sponsor:
Collaborators:
University of Manitoba
The Metabolomics Innovation Centre
BioMark Diagnostics Inc.
Canadian Institutes of Health Research (CIHR)
Information provided by (Responsible Party):
CancerCare Manitoba

Brief Summary:
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/ spermadine 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.

Condition or disease Intervention/treatment Phase
Glioblastoma Multiforme Diagnostic Test: Amantadine Hydrochloride Not Applicable

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 20 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Intervention Model Description: 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.
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma
Actual Study Start Date : December 2, 2020
Estimated Primary Completion Date : August 2021
Estimated Study Completion Date : August 2024


Arm Intervention/treatment
Experimental: GBM Patients

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)
Diagnostic Test: Amantadine Hydrochloride

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)




Primary Outcome Measures :
  1. Blood and Urine Acetyl-Amantadine levels in patients with GBM [ Time Frame: This outcome will be assessed every 8 to 12 weeks. This will continue through study completion, an average of two years. ]
    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.


Secondary Outcome Measures :
  1. GBM tumor volume in correlation with serum and urine acetyl-amantadine levels in patients with GBM [ Time Frame: This outcome will be assessed every 8 to 12 weeks. This will continue through study completion, an average of two years. ]

    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.




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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Adult (18 years+)
  • Pathologically confirmed Glioblastoma
  • ECOG performance status 0-2
  • Planned treatment with radiation and/or chemotherapy with temozolomide or lomustine
  • Able to return to the study centre for study visits
  • Able to swallow oral pills
  • Serum creatinine and creatinine clearance (>60mL/min)
  • Liver enzymes for liver function (Liver function tests <2.5 times the upper limit of normal)
  • Participants of childbearing potential must agree to use an effective contraceptive method.

Exclusion Criteria:

  • Known hypersensitivity or allergy to amantadine
  • Concurrent infection requiring antiviral medication
  • Concurrent medication with known interaction with amantadine (see below)
  • Previous diagnosis of Parkinson's disease or parkinsonism
  • Previous diagnosis of schizophrenia
  • Current use of methamphetamine or cocaine
  • Inability to swallow oral pills
  • Significant impairment in renal function (Creatinine clearance < 60 mL/min)
  • Women who are pregnant or are breastfeeding

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04530006


Contacts
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Contact: Anmol Mann, BSc. 2049959367 manna34@myumanitoba.ca

Locations
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Canada, Manitoba
CancerCare Manitoba Recruiting
Winnipeg, Manitoba, Canada, R3E 0V9
Contact: Gary Annable       gannable@cancercare.mb.ca   
Principal Investigator: Marshall Pitz, MD, FRCPC         
Sponsors and Collaborators
CancerCare Manitoba
University of Manitoba
The Metabolomics Innovation Centre
BioMark Diagnostics Inc.
Canadian Institutes of Health Research (CIHR)
Publications:

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Responsible Party: CancerCare Manitoba
ClinicalTrials.gov Identifier: NCT04530006    
Other Study ID Numbers: 50604
First Posted: August 28, 2020    Key Record Dates
Last Update Posted: February 15, 2021
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Keywords provided by CancerCare Manitoba:
Acetyl-amantadine
GBM
Glioblastoma
Brain
diagnostic biomarker
MRI
tumor volume
amantadine
brain tumor
cancer patients
Additional relevant MeSH terms:
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Glioblastoma
Astrocytoma
Glioma
Neoplasms, Neuroepithelial
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms by Histologic Type
Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms, Nerve Tissue
Amantadine
Antiparkinson Agents
Anti-Dyskinesia Agents
Antiviral Agents
Anti-Infective Agents
Dopamine Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Physiological Effects of Drugs
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents