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Intratumoral Extracellular Metabolic Impact of DFMO and AMXT 1501 in Patients With Diffuse or High Grade Glioma

Primary Purpose

Diffuse Glioma, Malignant Glioma

Status

Recruiting

Phase

Early Phase 1

Locations

United States

Study Type

Interventional

Intervention

Biospecimen Collection

Computed Tomography

Eflornithine

Magnetic Resonance Imaging

Polyamine Transport Inhibitor AMXT-1501 Dicaprate

Resection

Post-operative Microdialysis

About this trial

This is an interventional basic science trial for Diffuse Glioma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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 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) 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

Sites / Locations

Mayo Clinic in RochesterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Experimental

Placebo Comparator

Active Comparator

Arm Label

Arm I (MRI, resection, DFMO, AMXT 1501)

Arm II (MRI, resection, placebo, DMFO, AMXT 1501)

Arm III (MRI, resection, DMFO, AMXT 1501)

Arm Description

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.

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.

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.

Outcomes

Primary Outcome Measures

Change in the tumor/brain extracellular guanidinoacetate ratio

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

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

Central nervous system free drug levels from microdialysate

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

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

Incidence of adverse events

Full Information

NCT ID

NCT05717153

First Posted

January 23, 2023

Last Updated

August 29, 2023

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT05717153

Brief Title

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

2. Study Status

Record Verification Date

August 2023

Overall Recruitment Status

Recruiting

Study Start Date

August 28, 2023 (Actual)

Primary Completion Date

January 15, 2027 (Anticipated)

Study Completion Date

September 15, 2027 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Principal Investigator

Name of the Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Yes

Product Manufactured in and Exported from the U.S.

Data Monitoring Committee

Yes

5. 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.

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 eflornithine (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 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Diffuse Glioma, Malignant Glioma

7. Study Design

Primary Purpose

Basic Science

Study Phase

Early Phase 1

Interventional Study Model

Parallel Assignment

Masking

ParticipantInvestigator

Masking Description

The patient, principal investigator, and all members of the research team involved in sample collection will be blinded to each patient's assignment.

Allocation

Randomized

Enrollment

15 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Arm I (MRI, resection, DFMO, AMXT 1501)

Arm Type

Experimental

Arm Description

Arm Title

Arm II (MRI, resection, placebo, DMFO, AMXT 1501)

Arm Type

Placebo Comparator

Arm Description

Arm Title

Arm III (MRI, resection, DMFO, AMXT 1501)

Arm Type

Active Comparator

Arm Description

Intervention Type

Procedure

Intervention Name(s)

Biospecimen Collection

Other Intervention Name(s)

Biological Sample Collection, Biospecimen Collected, Specimen Collection

Intervention Description

Undergo collection of blood

Intervention Type

Procedure

Intervention Name(s)

Computed Tomography

Other Intervention Name(s)

CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized Tomography, CT, CT Scan, tomography

Intervention Description

Undergo CT

Intervention Type

Drug

Intervention Name(s)

Eflornithine

Other Intervention Name(s)

Alpha-Difluoromethylornithine, DFMO, Difluoromethylornithine, Difluromethylornithine

Intervention Description

Given PO

Intervention Type

Procedure

Intervention Name(s)

Magnetic Resonance Imaging

Other Intervention Name(s)

Magnetic Resonance, Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging

Intervention Description

Undergo MRI

Intervention Type

Drug

Intervention Name(s)

Polyamine Transport Inhibitor AMXT-1501 Dicaprate

Other Intervention Name(s)

AMX 513 Dicaprate, AMX513 Dicaprate, AMXT 1501 Dicaprate, AMXT-1501 Dicaprate

Intervention Description

Given PO

Intervention Type

Procedure

Intervention Name(s)

Resection

Other Intervention Name(s)

Surgical Resection

Intervention Description

Undergo surgical resection

Intervention Type

Device

Intervention Name(s)

Post-operative Microdialysis

Intervention Description

Post-operative Microdialysis

Primary Outcome Measure Information:

Title

Change in the tumor/brain extracellular guanidinoacetate ratio

Description

Time Frame

Up to 2 months

Secondary Outcome Measure Information:

Title

Measured extracellular levels of glutamate in tumor and brain microdialysates

Description

Time Frame

Up to 2 months

Title

Proportion of longitudinal microdialysis aliquots containing > 30 uL of microdialysate

Description

Time Frame

Up to post-operative day 5

Title

Central nervous system free drug levels from microdialysate

Description

Time Frame

Up to 2 months

Title

Central nervous system free drug levels from microdialysate

Description

Time Frame

Up to 2 months

Title

AMXT1501 brain/plasma ratio over time

Time Frame

Up to 2 months

Title

Incidence of adverse events

Time Frame

Up to 2 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Terence C Burns

Organizational Affiliation

Mayo Clinic in Rochester

Official's Role

Principal Investigator

Facility Information:

Facility Name

Mayo Clinic in Rochester

City

Rochester

State/Province

Minnesota

ZIP/Postal Code

55905

Country

United States

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Clinical Trials Referral Office

Phone

855-776-0015

mayocliniccancerstudies@mayo.edu

First Name & Middle Initial & Last Name & Degree

Terence C. Burns, M.D.

12. IPD Sharing Statement

Links:

URL

https://www.mayo.edu/research/clinical-trials

Description

Mayo Clinic Clinical Trials

Learn more about this trial

Intratumoral Extracellular Metabolic Impact of DFMO and AMXT 1501 in Patients With Diffuse or High Grade Glioma

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