Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma

NCT04530006 | Recruiting

• 1 other identifier: 50604
• Study Type: interventional
• Target: 20
• Locations: 1 country
• Sites: 1

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/ 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.

Conditions

Glioblastoma Multiforme

Keywords

Acetyl-amantadine; GBM; Glioblastoma; Brain; diagnostic biomarker; MRI; tumor volume; amantadine; brain tumor; cancer patients

Outcome Measures

Primary Outcomes (1)

• Blood and Urine Acetyl-Amantadine levels in patients with GBM

  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.

  This outcome will be assessed every 8 to 12 weeks. This will continue through study completion, an average of two years.

Secondary Outcomes (1)

• GBM tumor volume in correlation with serum and urine acetyl-amantadine levels in patients with GBM

  This outcome will be assessed every 8 to 12 weeks. This will continue through study completion, an average of two years.

Study Arms (1)

GBM Patients

EXPERIMENTAL

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

Interventions

Amantadine Hydrochloride DIAGNOSTIC_TEST

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)

GBM Patients

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• CancerCare Manitoba: lead
• University of Manitoba: collaborator
• The Metabolomics Innovation Centre: collaborator
• BioMark Diagnostics Inc.: collaborator
• Canadian Institutes of Health Research (CIHR): collaborator

Study Sites (1)

CancerCare Manitoba

Winnipeg, Manitoba, R3E 0V9, Canada

RECRUITING

Related Publications (6)

• Ostrom QT, Gittleman H, Xu J, Kromer C, Wolinsky Y, Kruchko C, Barnholtz-Sloan JS. CBTRUS Statistical Report: Primary Brain and Other Central Nervous System Tumors Diagnosed in the United States in 2009-2013. Neuro Oncol. 2016 Oct 1;18(suppl_5):v1-v75. doi: 10.1093/neuonc/now207. No abstract available.

  PMID: 28475809 BACKGROUND

• Babbar N, Hacker A, Huang Y, Casero RA Jr. Tumor necrosis factor alpha induces spermidine/spermine N1-acetyltransferase through nuclear factor kappaB in non-small cell lung cancer cells. J Biol Chem. 2006 Aug 25;281(34):24182-92. doi: 10.1074/jbc.M601871200. Epub 2006 Jun 6.

  PMID: 16757480 BACKGROUND

• Gabrielson E, Tully E, Hacker A, Pegg AE, Davidson NE, Casero RA Jr. Induction of spermidine/spermine N1-acetyltransferase in breast cancer tissues treated with the polyamine analogue N1, N11-diethylnorspermine. Cancer Chemother Pharmacol. 2004 Aug;54(2):122-6. doi: 10.1007/s00280-004-0786-1. Epub 2004 May 8.

  PMID: 15138709 BACKGROUND

• Huang W, Eickhoff JC, Mehraein-Ghomi F, Church DR, Wilding G, Basu HS. Expression of spermidine/spermine N(1) -acetyl transferase (SSAT) in human prostate tissues is related to prostate cancer progression and metastasis. Prostate. 2015 Aug 1;75(11):1150-9. doi: 10.1002/pros.22996. Epub 2015 Apr 20.

  PMID: 25893668 BACKGROUND

• Tappia PS, Maksymiuk AW, Sitar DS, Akhtar PS, Khatun N, Parveen R, Ahmed R, Ahmed RB, Cheng B, Huang G, Bach H, Hiebert B, Ramjiawan B. Predictive value and clinical significance of increased SSAT-1 activity in healthy adults. Future Sci OA. 2019 Jul 1;5(7):FSO400. doi: 10.2144/fsoa-2019-0023.

  PMID: 31428447 BACKGROUND

• Wen PY, Macdonald DR, Reardon DA, Cloughesy TF, Sorensen AG, Galanis E, Degroot J, Wick W, Gilbert MR, Lassman AB, Tsien C, Mikkelsen T, Wong ET, Chamberlain MC, Stupp R, Lamborn KR, Vogelbaum MA, van den Bent MJ, Chang SM. Updated response assessment criteria for high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol. 2010 Apr 10;28(11):1963-72. doi: 10.1200/JCO.2009.26.3541. Epub 2010 Mar 15.

  PMID: 20231676 BACKGROUND

MeSH Terms

Conditions

Glioblastoma; Brain Neoplasms

Condition Hierarchy (Ancestors)

Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases

Central Study Contacts

Anmol Mann, BSc.

CONTACT

2049959367; manna34@myumanitoba.ca

Study Design

• Study Type: interventional
• Phase: not applicable
• Allocation: NA
• Masking: NONE
• Purpose: DIAGNOSTIC
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: August 21, 2020
• First Posted: August 28, 2020
• Study Start: December 2, 2020
• Primary Completion: December 1, 2024
• Study Completion: August 1, 2025
• Last Updated: February 23, 2024

Record last verified: 2024-02

Data Sharing

• IPD Sharing: Will not share

Locations

CA (1)