Trial of Dichloroacetate (DCA) in Glioblastoma Multiforme (GBM)

Study Purpose

Conduct a multicenter, open label Phase IIA trial of oral DCA in 40 surgical patients with recurrent GBM who have clinically indicated debulking surgery planned. No patients will be recruited at UF. Patients will be genotyped to establish safe dosing regimens and will be randomized to receive DCA (N=20) or no DCA (N=20) for one week prior to surgery. Deidentified blood and tumor tissue obtained at surgery will be assessed at UF for biochemical markers of DCA dynamics.

Recruitment Criteria

Accepts Healthy Volunteers Healthy volunteers are participants who do not have a disease or condition, or related conditions or symptoms	No
Study Type An interventional clinical study is where participants are assigned to receive one or more interventions (or no intervention) so that researchers can evaluate the effects of the interventions on biomedical or health-related outcomes. An observational clinical study is where participants identified as belonging to study groups are assessed for biomedical or health outcomes. Searching Both is inclusive of interventional and observational studies.	Interventional
Eligible Ages	18 Years - 80 Years
Gender	All

More Inclusion & Exclusion Criteria

Inclusion Criteria:

- 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.

- All subjects will have completed initial, standard- therapy with surgical debulking, followed by radiation and temozolomide (TMZ) and will, therefore, be considered treatment failures.

Patients with truly unmethylated GBM do not require prior treatment with temozolomide (TMZ).

- Patients will be recruited and studied at Johns Hopkins University, Johns Hopkins affiliated Sibley Memorial Hospital, and Wake Forest University.

The DCA liquid formulation is on file with the FDA, is identical to that administered in our Phase I trial of brain tumor patients and can be given by mouth or feeding tube. Patients may retain whatever medications they are receiving for other conditions (e.g., hypertension, seizures), except patients requiring insulin or sulfonylurea therapy (see below).

- The probability of adverse drug-drug interactions is extremely low, for the following reasons.

First, DCA is the only pharmaceutical in clinical use that is metabolized by GSTZ1. Second, DCA is not known to be metabolized by any other drug metabolizing enzyme system, thus precluding competition with other agents for biotransformation. Third, the results of both open label and randomized controlled trials of orally or parenterally administered DCA in the treatment of children and/or adults have never shown evidence of adverse drug-drug interactions (34). Thus, from decades of clinical investigations of use of DCA in various acutely or chronically ill populations, there is nothing to suggest adverse drug-drug interactions should be anticipated in this trial.

- Patients who are diabetic must have a screening hemoglobin A1c (Hgb A1c) level of at least 6.0.

Exclusion Criteria:

- Patients considered pre-terminal (life expectancy ≤ 2 months) - Those who are pregnant 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.

- DCA is dialyzable and its clearance diminishes in patients with end stage renal failure (GFR ≤ 30 ml/min); such patients will be excluded from participating.

- 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.

- Patients with Hgb A1c level less than 6.0 at screening

Trial Details

Trial ID: This trial id was obtained from ClinicalTrials.gov, a service of the U.S. National Institutes of Health, providing information on publicly and privately supported clinical studies of human participants with locations in all 50 States and in 196 countries.	NCT05120284
Phase Phase 1: Studies that emphasize safety and how the drug is metabolized and excreted in humans. Phase 2: Studies that gather preliminary data on effectiveness (whether the drug works in people who have a certain disease or condition) and additional safety data. Phase 3: Studies that gather more information about safety and effectiveness by studying different populations and different dosages and by using the drug in combination with other drugs. Phase 4: Studies occurring after FDA has approved a drug for marketing, efficacy, or optimal use.	Phase 2
Lead Sponsor The sponsor is the organization or person who oversees the clinical study and is responsible for analyzing the study data.	University of Florida
Principal Investigator The person who is responsible for the scientific and technical direction of the entire clinical study.	Peter Stacpoole, PhD, MD
Principal Investigator Affiliation	University of Florida
Agency Class Category of organization(s) involved as sponsor (and collaborator) supporting the trial.	Other, U.S. Fed
Overall Status	Recruiting
Countries	United States
Conditions The disease, disorder, syndrome, illness, or injury that is being studied.	Glioblastoma Multiforme

Additional Details

Evaluate effects of dichloroacetate (DCA) on tumor PDC phosphorylation.

Arms & Interventions

Arms

Active Comparator: Pre-Surgical Dichloroacetate (DCA)

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.

Active Comparator: No Pre-Surgical Dichloroacetate (DCA)

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

Interventions

Drug: - Dichloroacetate (DCA)

Study medication DCA is a liquid formulation mixed with an artificial sweetener containing aspartame and strawberry extract (50mg/mL) Participants will be genotyped to determine GSTZ1 (glutathione S-transferase Zeta-1) haplotype status, which will stratify this group into 1 of 2 dose regimens: EGT carriers will receive 12-14 mg/kg/12hr DCA. EGT non-carriers will receive 6-7 mg/kg/12 hr.

Genetic: - Genotype

Participants will be genotyped to determine GSTZ1 haplotype status.

Contact a Trial Team

If you are interested in learning more about this trial, find the trial site nearest to your location and contact the site coordinator via email or phone. We also strongly recommend that you consult with your healthcare provider about the trials that may interest you and refer to our terms of service below.

Sibley Memorial Hospital, Washington, District of Columbia

Status

Active, not recruiting

Address

Sibley Memorial Hospital

Washington, District of Columbia, 20016

Site Contact

pws@ufl.edu

352-273-9023

Baltimore, Maryland

Status

Recruiting

Address

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Baltimore, Maryland, 21231

Site Contact

Stuart Grossman, MD

pws@ufl.edu

352-273-9023

Wake Forest University, Winston-Salem, North Carolina

Status

Recruiting

Address

Wake Forest University

Winston-Salem, North Carolina, 27587

Site Contact

Roy Strowd, MD

pws@ufl.edu

352-273-9023

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