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Pharmacodynamic Analyses of Metabolic Agents Following Brain Radiation

Primary Purpose

Malignant Central Nervous System Neoplasm

Status
Not yet recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Anhydrous Enol-oxaloacetate
Best Practice
Biospecimen Collection
Magnetic Resonance Spectroscopic Imaging
Questionnaire Administration
Sponsored by
Mayo Clinic
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Malignant Central Nervous System Neoplasm

Eligibility Criteria

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

Inclusion Criteria: Age >= 18 years. Radiographic evidence or histopathologic confirmation of central nervous system (CNS) malignancy, with or without prior resection. Planned (cohort 1) or completed (cohort 2) fractionated brain radiation. The therapeutic brain radiation treatment volume should exceed 30 cubic cm, including the volume of brain tissue occupied by infiltrative disease. Volume occupied by solid non-infiltrative disease (e.g. meningioma, metastatic disease, cystic cavity, resection cavity), should be excluded from the estimated treatment volume. Provide written informed consent for the current study and the Neuro-oncology biorepository for archiving of CSF and blood samples collected on this protocol. Expected survival >6 months and Karnofsky performance status >= 60. Willing and able to adhere with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations. Alanine aminotransferase (ALT) and aspartate transaminase (AST) <3 x upper limit of normal (ULN) (=< 5 x ULN for patients with baseline liver disease). Serum creatinine =< 1.5 mg/dL. Ability to complete questionnaire(s) by themselves or with assistance. Willingness to provide mandatory CSF and blood and able to undergo magnetic resonance spectroscopy (MRS)/magnetic resonance imaging (MRI) with gadolinium. Male and female patients of childbearing potential must agree to use a dual method of contraception (a highly effective method of contraception in conjunction with barrier contraception) consistently and correctly from the first dose of study drug (Arm B only) until 90 days after the last dose of study drug. Exclusion Criteria: Uncontrolled and/or intercurrent illness which limits safety of or compliance to study proceedings. Vulnerable populations: pregnant or nursing women (Arm B exempt), prisoners, mentally handicapped. Patients with recurrent brain tumor after prior radiation. Cohort 1 only: History of prior brain radiation, with prior cumulative target radiation treatment volume exceeding 2 cubic centimeters. Patients who do not have an implanted CSF access device (who would thus require multiple lumbar punctures [LPs] for participation) should be excluded if they have any contra-indication to lumbar puncture. This includes but is not limited to obstructive hydrocephalus or posterior fossa mass or cerebral edema that could increase the risk of brain herniation. Patients who do not have an implanted CSF device and are on anti-platelet therapy (other than Aspirin which is considered low risk) or anticoagulation (coumadin, Eliquis) must discontinue these prior to each lumbar puncture to participate. Patients unwilling or unable to safely do so should not be enrolled. 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 recent (<3 months [mo]) administration of, or known hypersensitivity or allergy to any active study drug currently available for randomization (initially oxaloacetate). Current use of resveratrol, CoQ10 (coenzyme Q10), coconut oil/other medium chain triglyceride-containing (i.e. Axona) supplements, or curcumin will be excluded unless willing to discontinue them 14 days prior to the start of baseline visits and remain off for study duration.

Sites / Locations

  • Mayo Clinic in Rochester

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Active Comparator

Experimental

Active Comparator

Experimental

Arm Label

Cohort I, Arm A (standard of care therapy)

Cohort I, Arm B ( standard of care therapy, AEO)

Cohort II, Arm A (standard of care therapy)

Cohort II, Arm B (standard of care therapy, AEO)

Arm Description

Patients in Cohort I, Arm A receive standard of care therapy. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.

Patients in Cohort I, Arm B receive standard of care therapy and receive AEO PO BID for 1 month on study. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.

Patients in Cohort II, Arm A receive standard of care therapy. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.

Patients in Cohort II, Arm B receive standard of care therapy and receive AEO PO BID for 3 months on study. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.

Outcomes

Primary Outcome Measures

Determine the feasibility of completing serial cerebrospinal fluid (CSF) collections for pharmacodynamic analyses.
Successful collection of at least 1cc of CSF at each of 3 timepoints with successful quantification of glutamate and lactate from each sample.

Secondary Outcome Measures

Incidence of treatment emergent adverse events (AEs) related to oxaloacetate following brain radiation (Arms B and Future Arms)
To assess the safety and tolerability of the study drug(s). Safety will be assessed in that the study drug will not have a Common Terminology Criteria for Adverse Events (CTCAE) (version [v] 5.0) grade >3 in >20% of participants. Tolerability will be assessed in that >60% of participants are able to complete the initial 28-day study treatment period without AE precluding continuation of study drug (even if not CTCAE >3).

Full Information

First Posted
January 17, 2023
Last Updated
August 29, 2023
Sponsor
Mayo Clinic
Collaborators
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT05720624
Brief Title
Pharmacodynamic Analyses of Metabolic Agents Following Brain Radiation
Official Title
Pharmacodynamic Analyses of Metabolic Agents Following Brain Radiation
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
December 1, 2023 (Anticipated)
Primary Completion Date
February 15, 2026 (Anticipated)
Study Completion Date
June 15, 2026 (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
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
This phase I trial studies the impact of taking drugs (agents) that target altered brain metabolism following standard of care brain radiotherapy. Radiotherapy uses high energy x-rays, particles, or radioactive seeds to kill cancer cells and shrink tumors. However, radiotherapy can also cause harmful effects to normal brain functioning. One drug, called anhydrous enol-oxaloacetate (AEO), has previously been studied in ischemic stroke, Alzheimer's disease, Parkinson's disease, and glioma. Drugs such as AEO may help preserve or restore healthy brain function after brain radiotherapy compared to the standard practice which consists of no drugs.
Detailed Description
PRIMARY OBJECTIVE: I. Determine the feasibility of serial cerebrospinal fluid (CSF) assessments to evaluate the pharmacodynamic impact of agents targeting radiation-induced biology administered following completion of brain radiation. SECONDARY OBJECTIVE: I. Assess the safety of study drug(s) as quantified by dose-limiting toxicities. CORRELATIVE RESEARCH OBJECTIVES: I. Investigate the relationship of the global CSF metabolome with magnetic resonance spectroscopy metabolite profile. II. Investigate the relationship between brain radiation dose/volume and metabolic alterations in CSF. III. Investigate the impact of metabolic therapy on early cognitive effects of radiotherapy in patients with brain tumors. IV. Utilize paired blood samples to investigate association between the CSF and systemic metabolome. V. Utilize paired stool samples to investigate association between the blood and CSF metabolome with the gastrointestinal microbiome. OUTLINE: Patients are assigned to 1 of 2 cohorts. COHORT I (EARLY POST-RADIATION): Patients within Cohort I are assigned to 1 of 2 arms. ARM A: Patients receive standard of care therapy. ARM B: Patients receive standard of care therapy and receive AEO orally (PO) two times daily (BID) for 1 month on study. COHORT II (DELAYED POST-RADIATION): Patients within Cohort II are assigned to 1 of 2 arms. ARM A: Patients receive standard of care therapy. ARM B: Patients receive standard of care therapy and receive AEO PO BID for 3 months on study. Patients in all cohorts and arms also undergo magnetic resonance spectroscopy (MRS) imaging, collection of cerebrospinal fluid (CSF), 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
Malignant Central Nervous System Neoplasm

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Cohort I, Arm A (standard of care therapy)
Arm Type
Active Comparator
Arm Description
Patients in Cohort I, Arm A receive standard of care therapy. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.
Arm Title
Cohort I, Arm B ( standard of care therapy, AEO)
Arm Type
Experimental
Arm Description
Patients in Cohort I, Arm B receive standard of care therapy and receive AEO PO BID for 1 month on study. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.
Arm Title
Cohort II, Arm A (standard of care therapy)
Arm Type
Active Comparator
Arm Description
Patients in Cohort II, Arm A receive standard of care therapy. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.
Arm Title
Cohort II, Arm B (standard of care therapy, AEO)
Arm Type
Experimental
Arm Description
Patients in Cohort II, Arm B receive standard of care therapy and receive AEO PO BID for 3 months on study. Patients also undergo MRS imaging, collection of CSF, and collection of blood on study.
Intervention Type
Drug
Intervention Name(s)
Anhydrous Enol-oxaloacetate
Other Intervention Name(s)
AEO, OXALOACETIC ACID
Intervention Description
Given PO
Intervention Type
Other
Intervention Name(s)
Best Practice
Other Intervention Name(s)
standard of care, standard therapy
Intervention Description
Receive standard of care therapy
Intervention Type
Procedure
Intervention Name(s)
Biospecimen Collection
Other Intervention Name(s)
Biological Sample Collection, Biospecimen Collected, Specimen Collection
Intervention Description
Undergo collection of CSF and blood
Intervention Type
Procedure
Intervention Name(s)
Magnetic Resonance Spectroscopic Imaging
Other Intervention Name(s)
1H- Nuclear Magnetic Resonance Spectroscopic Imaging, 1H-nuclear magnetic resonance spectroscopic imaging, Magnetic Resonance Spectroscopy, MRS, MRS Imaging, MRSI, MS, Proton Magnetic Resonance Spectroscopic Imaging
Intervention Description
Undergo MRS imaging
Intervention Type
Other
Intervention Name(s)
Questionnaire Administration
Intervention Description
Ancillary studies
Primary Outcome Measure Information:
Title
Determine the feasibility of completing serial cerebrospinal fluid (CSF) collections for pharmacodynamic analyses.
Description
Successful collection of at least 1cc of CSF at each of 3 timepoints with successful quantification of glutamate and lactate from each sample.
Time Frame
Up to 3 months
Secondary Outcome Measure Information:
Title
Incidence of treatment emergent adverse events (AEs) related to oxaloacetate following brain radiation (Arms B and Future Arms)
Description
To assess the safety and tolerability of the study drug(s). Safety will be assessed in that the study drug will not have a Common Terminology Criteria for Adverse Events (CTCAE) (version [v] 5.0) grade >3 in >20% of participants. Tolerability will be assessed in that >60% of participants are able to complete the initial 28-day study treatment period without AE precluding continuation of study drug (even if not CTCAE >3).
Time Frame
Up to 3 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age >= 18 years. Radiographic evidence or histopathologic confirmation of central nervous system (CNS) malignancy, with or without prior resection. Planned (cohort 1) or completed (cohort 2) fractionated brain radiation. The therapeutic brain radiation treatment volume should exceed 30 cubic cm, including the volume of brain tissue occupied by infiltrative disease. Volume occupied by solid non-infiltrative disease (e.g. meningioma, metastatic disease, cystic cavity, resection cavity), should be excluded from the estimated treatment volume. Provide written informed consent for the current study and the Neuro-oncology biorepository for archiving of CSF and blood samples collected on this protocol. Expected survival >6 months and Karnofsky performance status >= 60. Willing and able to adhere with the protocol for the duration of the study including undergoing treatment and scheduled visits, and examinations. Alanine aminotransferase (ALT) and aspartate transaminase (AST) <3 x upper limit of normal (ULN) (=< 5 x ULN for patients with baseline liver disease). Serum creatinine =< 1.5 mg/dL. Ability to complete questionnaire(s) by themselves or with assistance. Willingness to provide mandatory CSF and blood and able to undergo magnetic resonance spectroscopy (MRS)/magnetic resonance imaging (MRI) with gadolinium. Male and female patients of childbearing potential must agree to use a dual method of contraception (a highly effective method of contraception in conjunction with barrier contraception) consistently and correctly from the first dose of study drug (Arm B only) until 90 days after the last dose of study drug. Exclusion Criteria: Uncontrolled and/or intercurrent illness which limits safety of or compliance to study proceedings. Vulnerable populations: pregnant or nursing women (Arm B exempt), prisoners, mentally handicapped. Patients with recurrent brain tumor after prior radiation. Cohort 1 only: History of prior brain radiation, with prior cumulative target radiation treatment volume exceeding 2 cubic centimeters. Patients who do not have an implanted CSF access device (who would thus require multiple lumbar punctures [LPs] for participation) should be excluded if they have any contra-indication to lumbar puncture. This includes but is not limited to obstructive hydrocephalus or posterior fossa mass or cerebral edema that could increase the risk of brain herniation. Patients who do not have an implanted CSF device and are on anti-platelet therapy (other than Aspirin which is considered low risk) or anticoagulation (coumadin, Eliquis) must discontinue these prior to each lumbar puncture to participate. Patients unwilling or unable to safely do so should not be enrolled. 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 recent (<3 months [mo]) administration of, or known hypersensitivity or allergy to any active study drug currently available for randomization (initially oxaloacetate). Current use of resveratrol, CoQ10 (coenzyme Q10), coconut oil/other medium chain triglyceride-containing (i.e. Axona) supplements, or curcumin will be excluded unless willing to discontinue them 14 days prior to the start of baseline visits and remain off for study duration.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
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
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Clinical Trials Referral Office
Phone
855-776-0015
Email
mayocliniccancerstudies@mayo.edu
First Name & Middle Initial & Last Name & Degree
Terence C. Burns, M.D.

12. IPD Sharing Statement

Learn more about this trial

Pharmacodynamic Analyses of Metabolic Agents Following Brain Radiation

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