Trial of AEO in New Glioblastoma (GBM) (AEO)

A Phase 2, Randomized, Open-Label Study of Anhydrous Enol-Oxaloacetate in Subjects With Newly Diagnosed Glioblastoma Multiforme

This is a multicenter, Phase 2, Proof-of-concept study in subjects with newly diagnosed glioblastoma multiforme (GBM).

All subjects will receive standard of care therapy for the treatment of their GBM and any Anti-Epileptic Drug (AED) deemed necessary for their surgical resection of the GBM. Patients who are taking concomitant AEDs will be eligible for the study. Treatment with Anhydrous Enol-Oxaloacetate will be added to the Standard of Care.

This study is testing adjuvant Anhydrous Enol-Oxaloacetate (AEO) in GBM, an orally active drug candidate which in animal studies has demonstrated decreased tumor growth rate and increased survival.

Study Overview

• Status: Unknown
• Conditions: Glioblastoma Multiforme
• Intervention / Treatment: Other: Standard of Care; Drug: Anhydrous Enol-Oxaloacetate (AEO)

Detailed Description

Currently, the multidisciplinary Standard of Care treatment for Glioblastoma multiforme includes maximal surgical resection of the tumor followed by radiotherapy plus concomitant and maintenance temozolomide chemotherapy.This study will treat newly diagnosed GBM patients by adding Anhydrous Enol-Oxaloacetate treatment to their current Standard of Care.

In the body, Anhydrous Enol-Oxaloacetate (AEO) converts into "Oxaloacetate", a metabolite important for many biochemical reactions in the body. On a cellular level, oxaloacetate treatment has been found to modify cancer metabolism in GBM cells, reversing the "Warburg Effect", reducing glycolysis and reducing lactate production. In animals, oxaloacetate treatment has increased survival and reduced tumor growth of implanted GBM tumors.

In other animal studies, oxaloacetate has also shown to have neuo-protective effects including positive effects on seizure development.

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• Study Type: Interventional
• Enrollment (Anticipated): 80
• Phase: Phase 2

Contacts and Locations

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• • Histopathologic diagnosis of glioblastoma multiforme

  • Standard of care maximal feasible surgical resection of the glioma
  • Post-operative pre-enrollment MRI-Note: measurable disease is not required
  • Concomitant anti-epileptic drugs
  • Hemoglobin >9 g/dL
  • Platelets >100,000/microliter (mcL)
  • <3.0 Upper Limit of Normal Range (ULN) for Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and/or Alkaline Phosphatase
  • <2.0 Upper Limit of Normal Range (ULN) for serum creatinine
  • Karnofsky performance status >70
  • Mentally competent to follow study procedures
  • 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 until 90 days after the last dose of study drug
  • Able to answer questions on the Patient-Reported Outcomes Measurement Information System (PROMIS) questionnaire
  • Subject is willing and able to give informed consent and to follow instructions as per the protocol

Exclusion Criteria:

• • Concomitant treatment with carmustine wafers or tumor-treating electric fields (TTFields)

  • QT Interval corrected with the fridericia formula (QTcF) >480ms
  • Significant concurrent illness / disease
  • Predicted life expectancy < 6 months from date of randomization
  • Pregnancy
  • Enrollment in another clinical trial during the course of the study

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Standard of Care; Current GBM Treatment of surgery, radiation and chemotherapy with temozolomide.	Other: Standard of Care; Standard of Care Temozolomide; Other Names: Chemotherapy with Temozolomide
Experimental: AEO with Standard of Care; Anhydrous Enol-Oxaloacetate added to the Standard of Care (surgery, radiation and chemotherapy with temozolomide).	Other: Standard of Care; Standard of Care Temozolomide; Other Names: Chemotherapy with Temozolomide; Drug: Anhydrous Enol-Oxaloacetate (AEO); Oral supplementation with AEO along with the Standard of Care (Temozolomide)

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Measurement of Overall Survival	6 months
Progression Free Survival-6	Survival at 6 months	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Seizures	Time from randomization to first seizure	6 months
Chalfont-National Hospital Seizure Severity	Measure of Seizure Severity Ranging from a minimum of 1 to a maximum of 27 with higher score indicating worse outcome	6 months
PROMIS-Cancer - Fatigue	Measure of Fatigue Ranging from a minimum of 0 to a maximum of 95 with the higher score indicating worse outcome.	6 months

Collaborators and Investigators

• Sponsor: MetVital, Inc.

Publications and helpful links

General Publications

• Yamamoto HA, Mohanan PV. Effect of alpha-ketoglutarate and oxaloacetate on brain mitochondrial DNA damage and seizures induced by kainic acid in mice. Toxicol Lett. 2003 Jul 20;143(2):115-22. doi: 10.1016/s0378-4274(03)00114-0.
• Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI. Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs. 2012 Dec;30(6):2226-35. doi: 10.1007/s10637-012-9799-5.
• Augur ZM, Doyle CM, Li M, Mukherjee P, Seyfried TN. Nontoxic Targeting of Energy Metabolism in Preclinical VM-M3 Experimental Glioblastoma. Front Nutr. 2018 Oct 5;5:91. doi: 10.3389/fnut.2018.00091. eCollection 2018.

Helpful Links

• Oxaloacetate alters glucose metabolism in Glioblastoma
• Oxaloacetate increases survival in GBM implanted mice
• New Bioanalytical method and single-dose pharmacokinetics for oxaloacetate

Study record dates

Study Major Dates

• Study Start (Anticipated): December 1, 2020
• Primary Completion (Anticipated): July 1, 2022
• Study Completion (Anticipated): September 1, 2022

Study Registration Dates

• First Submitted: June 23, 2020
• First Submitted That Met QC Criteria: June 25, 2020
• First Posted (Actual): June 29, 2020

Study Record Updates

• Last Update Posted (Actual): June 29, 2020
• Last Update Submitted That Met QC Criteria: June 25, 2020
• Last Verified: June 1, 2020

More Information

Terms related to this study

• Keywords: Glioblastoma; Seizures; Oxaloacetate; Warburg
• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Astrocytoma; Glioma; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioblastoma; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Antineoplastic Agents, Alkylating; Alkylating Agents; Temozolomide
• Other Study ID Numbers: Terra-001-201

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No