Official Title
Acetyl-Amantadine as a Biomarker in Patients With Glioblastoma
Summary:
Glioblastoma multiforme (GBM) is the most common brain tumour 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 tumour 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.
Trial Description
Primary Outcome:
- Blood and Urine Acetyl-Amantadine levels in patients with GBM
Secondary Outcome:
- GBM tumour volume in correlation with serum and urine acetyl-amantadine levels in patients with GBM
Glioblastoma (GBM) is the most common malignant primary brain tumour 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
months.
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 tumour 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 tumour 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-acetylamantadine 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 tumour 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 tumour 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 tumour 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
tumour progression, an increase in acetyl-amantadine level would not indicate per se what type
of tumour 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.
View this trial on ClinicalTrials.gov
