Clinical trial NCT05717153: Intratumoral Extracellular Metabolic Impact of DFMO and AMXT 1501 in Patients With Diffuse or High Grade Glioma
Official title: Intratumoral Extracellular Metabolic Impact of DFMO and AMXT 1501
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: EARLY_PHASE1
Conditions: Diffuse Glioma
Malignant Glioma
Lead sponsor: Mayo Clinic
Sponsor class: OTHER
Collaborators: name: National Cancer Institute (NCI)
First posted: 2023-02-08
Enrollment: 15
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: BASIC_SCIENCE

Brief summary: This early phase I trial studies brain tumor (glioma) metabolism in response to eflornithine (DFMO) and polyamine transport inhibitor AMXT-1501 dicaprate (AMXT 1501) in patients with diffused or high grade glioma. Brain tumors use and produce certain molecules to survive and grow. DFMO is an irreversible inhibitor of ornithine decarboxylase, the enzyme catalyzing polyamine synthesis. AMXT 1501 is a polyamine transport inhibitor which prevents uptake of polyamines from the extracellular environment. This trial is being done to analyze how DFMO and AMXT 1501 affect brain tumor metabolism based on the molecules in the tumor's fluid.

Detailed description: PRIMARY OBJECTIVE:

I. Determine how polyamine depletion impacts extracellular guanidinoacetate abundance.

SECONDARY OBJECTIVES:

I. Determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ.

II. Assess the feasibility of longitudinal microdialysis to evaluate pharmacodynamic responses of in situ gliomas to therapeutic intervention in a post-operative setting.

III. Assess the central nervous system (CNS) pharmacokinetics of DFMO and AMXT 1501.

IV. Adverse effects of study drugs in the immediate postoperative setting during microdialysis.

OUTLINE: Patients are randomized to 1 of 3 arms.

ARM I: Patients undergo surgical resection with magnetic resonance imaging (MRI) and placement of catheters for microdialysis at baseline. Patients receive DFMO orally (PO) in combination with AMXT 1501 PO on days 1-5 post-surgery in the absence of disease progression or unacceptable toxicity. Patients also continue microdialysate collection as well as undergo computed tomography (CT) and collection of blood on study.

ARM II: Patients undergo surgical resection with MRI and placement of catheters for microdialysis at baseline. Patients receive DFMO PO and AMXT 1501 PO on days 3-5 post-surgery in the absence of disease progression or unacceptable toxicity. Patients also continue microdialysate collection, as well as undergo CT and collection of blood on study.

ARM III: Patients undergo surgical resection with MRI and placement of catheters for microdialysis at baseline. Patients receive DFMO PO alone on days 1 and 2 post-surgery, then receive eflornithine PO in combination with AMXT 1501 PO on days 3-5 post-surgery in the absence of disease progression or unacceptable toxicity. Patients also continue microdialysate collection, as well as undergo CT and collection of blood on study.

Eligibility criteria: Inclusion Criteria:

* Age \>= 18 years
* Clinical and radiographic evidence suggesting a diagnosis of a diffuse high grade glioma (HGG), or a prior diagnosis of a diffuse glioma
* Planned subtotal resection due to tumor location, size, or other clinical indication deemed appropriate by the surgeon
* Provide written informed consent for the current study and the Neuro-Oncology biorepository for archiving of cerebrospinal fluid (CSF) and blood samples collected on this protocol. Willing to remain in the hospital at Mayo Clinic (Rochester, MN) for three days added to their standard post-operative stay to undergo longitudinal microdialysis
* Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L without transfusion within 7 days preceding the lab assessment (obtained =\< 14 days prior to registration)
* Platelet \>= 100 x 10\^9/L, without transfusion within 7 days preceding the lab assessment (obtained =\< 14 days prior to registration)
* Hemoglobin \>= 9 g/dL, without transfusion support within 7 days preceding the lab assessment (obtained =\< 14 days prior to registration)
* Activated partial thromboplastin time/ partial thromboplastin time (aPTT/PTT) =\< 1.5 x upper limit of normal (ULN) (obtained =\< 14 days prior to registration)
* Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =\< 2.5 x ULN (obtained =\< 14 days prior to registration)
* Total serum bilirubin =\< 1.5 x ULN (obtained =\< 14 days prior to registration)
* The patient is clinically euthyroid
* Serum creatinine =\< 1.5 x ULN or creatinine clearance \>= 60 mL/min/1.73 m\^2 for patients with serum creatinine levels above 1.5 x ULN (obtained =\< 14 days prior to registration)
* Negative serum or urine pregnancy test is required for female subjects of childbearing age

Exclusion Criteria:

* Patients who are not appropriate surgical candidates due to current or past medical history or uncontrolled concurrent illness which limits safety of or compliance to study proceedings
* Vulnerable populations: pregnant or nursing women, prisoners, mentally handicapped
* Participants who are unable to swallow tablets or who are at risk for impaired absorption of oral medication. NOTE: This includes but not limited to, refractory vomiting, gastric resection/bypass, and duodenal/jejunal resection
* Patients with known hypersensitivity or allergy to DFMO or AMXT 1501
* Contraindication to MRI or administration of gadolinium

Primary outcomes:
measure: Change in the tumor/brain extracellular guanidinoacetate ratio
timeFrame: Baseline up to 2 months
Secondary outcomes:
measure: Measured extracellular levels of glutamate in tumor and brain microdialysates
timeFrame: Up to 2 months
measure: Proportion of longitudinal microdialysis aliquots containing > 30 uL of microdialysate
timeFrame: Up to post-operative day 5
measure: Central nervous system free drug levels from microdialysate - DFMO
timeFrame: Up to 2 months
measure: Central nervous system free drug levels from microdialysate - AMXT 1501
timeFrame: Up to 2 months
measure: AMXT 1501 brain/plasma ratio over time
timeFrame: Up to 2 months
measure: Incidence of adverse events
timeFrame: Up to 2 months
Other outcomes:
Locations:
city: Rochester
country: United States
facility: Mayo Clinic in Rochester
state: Minnesota
Study officials:
affiliation: Mayo Clinic in Rochester
name: Terence C. Burns, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References: