Intratumoral Extracellular Metabolic Impact of DFMO and AMXT 1501 in Patients With Diffuse or High Grade Glioma
Study Details
Study Description
Brief Summary
This early phase I trial studies brain tumor (glioma) metabolism in response to difluoromethylornithine (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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Early Phase 1 |
Detailed Description
PRIMARY OBJECTIVE:
- Determine how polyamine depletion impacts extracellular guanidinoacetate abundance.
SECONDARY OBJECTIVES:
-
Determine the impact of polyamine depletion on polyamine abundance and the global extracellular metabolome within live human gliomas, in situ.
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Assess the feasibility of longitudinal microdialysis to evaluate pharmacodynamic responses of in situ gliomas to therapeutic intervention in a post-operative setting.
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Assess the central nervous system (CNS) pharmacokinetics of eflornithine (DFMO) and AMXT
- 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 magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine orally (PO) in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo computed tomography (CT) after surgery and collection of blood on study.
ARM II: Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study.
ARM III: Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine 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. Patients also undergo CT after surgery and collection of blood on study.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Arm I (MRI, resection, DFMO, AMXT 1501) Patients undergo magnetic resonance imaging (MRI) and surgical resection at baseline. Patients receive eflornithine PO in combination with AMXT 1501 PO on days 1-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study. |
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Eflornithine
Given PO
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Drug: Polyamine Transport Inhibitor AMXT-1501 Dicaprate
Given PO
Other Names:
Procedure: Resection
Undergo surgical resection
Other Names:
|
| Placebo Comparator: Arm II (MRI, resection, placebo, DMFO, AMXT 1501) Patients undergo magnetic MRI and surgical resection at baseline. Patients receive placebo PO on days 1 and 2 post-surgery, and then receive eflornithine PO and AMXT 1501 PO on days 3-5 post-surgery. Patients also undergo CT after surgery and collection of blood on study. |
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Eflornithine
Given PO
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Drug: Placebo Administration
Given PO
Drug: Polyamine Transport Inhibitor AMXT-1501 Dicaprate
Given PO
Other Names:
Procedure: Resection
Undergo surgical resection
Other Names:
|
| Active Comparator: Arm III (MRI, resection, DMFO, AMXT 1501) Patients undergo magnetic MRI and surgical resection at baseline. Patients receive eflornithine 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. Patients also undergo CT after surgery and collection of blood on study. |
Procedure: Biospecimen Collection
Undergo collection of blood
Other Names:
Procedure: Computed Tomography
Undergo CT
Other Names:
Drug: Eflornithine
Given PO
Other Names:
Procedure: Magnetic Resonance Imaging
Undergo MRI
Other Names:
Drug: Polyamine Transport Inhibitor AMXT-1501 Dicaprate
Given PO
Other Names:
Procedure: Resection
Undergo surgical resection
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Change in the tumor/brain extracellular guanidinoacetate ratio [Up to 2 months]
Targeted metabolomics will be performed using the microdialysate aliquot collected at each time point to quantify guanidinoacetate content. Fold change values will be calculated between each time point within a patient. Fold changes values between time points will be compared across the three arms for statistically significant differences using a Wilcoxon signed rank test; p < 0.05 will be considered statistically significant.
Secondary Outcome Measures
- Measured extracellular levels of glutamate in tumor and brain microdialysates [Up to 2 months]
Targeted metabolomics will be performed for each time point's microdialysate, assaying for polyamines (putrescine, spermine, and spermidine), in addition to ornithine and glutamate. Fold change values will be calculated between each time point within a patient. Fold changes values between time points will be compared across the three arms for statistically significant differences using a Wilcoxon signed rank test; p < 0.05 will be considered statistically significant.
- Proportion of longitudinal microdialysis aliquots containing > 30 uL of microdialysate [Up to post-operative day 5]
Targeted metabolomics will be performed for each time point's microdialysate, assaying for polyamines (putrescine, spermine, and spermidine), in addition to ornithine and glutamate. Fold change values will be calculated between each time point within a patient. Fold changes values between time points will be compared across the three arms for statistically significant differences using a Wilcoxon signed rank test; p < 0.05 will be considered statistically significant.
- Central nervous system free drug levels from microdialysate [Up to 2 months]
Drug levels of difluoromethylornithine (eflornithine [DFMO]) at each time point will be calculated for pharmacokinetic analyses by Aminex Therapeutics to determine time of peak concentration (hr), maximum drug concentration (ng/mL), and area under the curve 0-t (hr*ng/mL).
- Central nervous system free drug levels from microdialysate [Up to 2 months]
Polyamine transport inhibitor AMXT-1501 dicaprate (AMXT 1501) at each time point will be calculated for pharmacokinetic analyses by Aminex Therapeutics to determine time of peak concentration (hr), maximum drug concentration (ng/mL), and area under the curve 0-t (hr*ng/mL).
- AMXT1501 brain/plasma ratio over time [Up to 2 months]
- Incidence of adverse events [Up to 2 months]
Eligibility Criteria
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
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Provide written informed consent for the current study and the Neuro-Oncology biorepository for archiving of ceerebal spinal 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)
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Platelet >= 100 x 10^9/L, without transfusion within 7 days preceding the lab assessment (obtained =< 14 days prior to registration)
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Hemoglobin >= 9 g/dL, without transfusion support within 7 days preceding the lab assessment (obtained =< 14 days prior to registration)
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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)
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The patient is clinically euthyroid
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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)
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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
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Vulnerable populations: pregnant or nursing women, prisoners, mentally handicapped
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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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Mayo Clinic in Rochester | Rochester | Minnesota | United States | 55905 |
Sponsors and Collaborators
- Mayo Clinic
- National Cancer Institute (NCI)
Investigators
- Principal Investigator: Terence C Burns, Mayo Clinic in Rochester
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- 22-005690
- NCI-2022-10375
- 22-005690
- P30CA015083