What side effects are associated with this type of intervention?

Common treatments for Glioblastoma, such as temozolomide and radiation therapy, often result in side effects including fatigue, nausea, vomiting, and hematologic toxicities like thrombocytopenia and neutropenia. Temozolomide specifically can cause lymphopenia and increased risk of infections. Radiation therapy may lead to localized side effects such as skin irritation, hair loss at the treatment site, and potential cognitive decline. Targeted therapies, which may share mechanisms with DCA, can cause gastrointestinal disturbances, liver enzyme abnormalities, and fatigue. These side effects reflect the broad impact of these treatments on both cancerous and healthy cells.

What prior FDA approvals exist?

The FDA has approved several treatments for Glioblastoma, including temozolomide, which is an oral alkylating agent that interferes with DNA replication in cancer cells, and bevacizumab, a monoclonal antibody that inhibits vascular endothelial growth factor (VEGF) to reduce tumor blood supply. While these treatments do not share the exact mechanism of action as Dichloroacetate (DCA), they are part of the broader category of therapies aimed at disrupting cancer cell metabolism and growth. There are no FDA-approved treatments specifically targeting pyruvate dehydrogenase kinase like DCA, but ongoing research continues to explore metabolic pathways as potential therapeutic targets in Glioblastoma.

What other types of research exist?

Promising novel alternatives to Dichloroacetate (DCA) for Glioblastoma patients include: <ol> <li>BRAF/MEK inhibitors (e.g., Dabrafenib and Trametinib) for patients with BRAF V600E mutations, which have shown sustained tumor control.</li> <li></li> </ol> Triacetin-based acetate supplementation, which may reduce tumor growth in glycolytic and hypoacetylated mesenchymal glioma tumors. 3. IDH inhibitors (e.g., Ivosidenib) for IDH-mutant gliomas, which target metabolic pathways similar to DCA.

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Metabolic Modulator

DCA for Glioblastoma

Phase 2

Recruiting

Led By Peter Stacpoole, PhD, MD

Research Sponsored by University of Florida

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Study subjects will be male and female adults, aged 18 through 80 years, previously diagnosed with a GBM who have experienced tumor recurrence as determined by neuroimaging and some degree of symptomatology (e.g., headache, mental status change, seizure) and have clinically indicated tumor debulking surgery planned

Be older than 18 years old

Must not have

DCA is metabolized by hepatic GSTZ1, so patients with severe liver insufficiency (total bilirubin > 2.0 mg/dl or ALT or AST > 3 x ULN) will be excluded

DCA inhibits gluconeogenesis and lowers blood glucose levels in patients with type 2 diabetes. Therefore, in subjects who are receiving either insulin or a sulfonylurea, coadministration of DCA could lead to symptomatic hypoglycemia and those patients will be excluded from the trial

Timeline

Screening 3 weeks

Treatment Varies

Follow Up within 4 weeks post surgery

Awards & highlights

Summary

This trial tests if DCA, a medication taken by mouth, can help treat patients with returning brain tumors who are scheduled for surgery. DCA may change how tumor cells use energy, potentially slowing their growth. DCA has shown potential activity against several human cancers, including brain tumors.

Who is the study for?

Adults aged 18-80 with recurrent Glioblastoma Multiforme (GBM) who have already undergone surgery, radiation, and chemotherapy with temozolomide are eligible. They must not be pre-terminal or pregnant, nor can they have severe liver insufficiency, end-stage renal failure, or be on insulin/sulfonylurea therapy for diabetes.

What is being tested?

The trial is testing oral Dichloroacetate (DCA) in patients with GBM to establish safe dosing based on genotyping. Participants will either receive DCA or no treatment for one week before their clinically indicated tumor removal surgery.

What are the potential side effects?

Potential side effects of DCA may include lowering blood glucose levels which could lead to hypoglycemia especially in diabetic patients. Since it's metabolized by the liver and cleared by the kidneys, those organs' conditions might affect how the drug works and its safety.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am an adult between 18 and 80 with a GBM diagnosis, my tumor has come back, and I have symptoms like headaches or seizures. Surgery to remove the tumor is planned.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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My liver functions well (bilirubin ≤ 2.0 mg/dl, ALT and AST ≤ 3 times the upper limit).

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I am not taking insulin or sulfonylurea for my type 2 diabetes.

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My kidney function is good (GFR > 30 ml/min).

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ within 4 weeks post surgery

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~within 4 weeks post surgery

This trial's timeline: 3 weeks for screening, Varies for treatment, and within 4 weeks post surgery for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Level of phosphorylated PDC protein expressed in surgical tissue

Trial Design

2Treatment groups

Active Control

Group I: No Pre-Surgical Dichloroacetate (DCA)Active Control2 Interventions

Subject randomized to start DCA after surgery will do so 12-24 hours postoperatively, depending on their ability to safely receive medication.

Group II: Pre-Surgical Dichloroacetate (DCA)Active Control2 Interventions

Study medication begins in subjects randomized to preoperative DCA. All subjects will be given the 12.5 mg/kg/12 hour DCA for pre-surgical dosing. Post-surgery the GSTZ1 haplotype will be utilized to dose all patients.

0 / 4Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Glioblastoma treatments often target the unique metabolic and genetic characteristics of the tumor cells. Dichloroacetate (DCA) works by inhibiting pyruvate dehydrogenase kinase, which shifts the metabolism of cancer cells from glycolysis to glucose oxidation, enhancing mitochondrial function and promoting apoptosis. This is significant because glioblastoma cells typically rely on glycolysis for energy, even in the presence of oxygen (Warburg effect). By disrupting this metabolic pathway, DCA can potentially reduce tumor growth and improve patient outcomes. Other common treatments include temozolomide, an alkylating agent that damages DNA and induces cell death, and bevacizumab, which inhibits angiogenesis by targeting vascular endothelial growth factor (VEGF). These treatments are crucial as they address different aspects of tumor growth and survival, offering a multifaceted approach to managing this aggressive cancer.

Effectiveness of sodium dichloroacetate against glioma C6 depends on administration schedule and dosage.Sensitization of Glioblastoma Cells to Irradiation by Modulating the Glucose Metabolism.