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

Study Overview
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Brief Summary
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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.

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

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

Conditions
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Glioblastoma Multiforme

Intervention / Treatment
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* Drug: Dichloroacetate (DCA)
* Genetic: Genotype


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: subsequent ordered and alternating patients
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Pre-Surgical Dichloroacetate (DCA)<br>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. | Drug: Dichloroacetate (DCA)<br>* 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.<br>* Other names: Sodium Dichloroacetate;Genetic: Genotype<br>* Participants will be genotyped to determine GSTZ1 haplotype status.<br>|
| Active Comparator: No Pre-Surgical Dichloroacetate (DCA)<br>Subject randomized to start DCA after surgery will do so 12-24 hours postoperatively, depending on their ability to safely receive medication. | Drug: Dichloroacetate (DCA)<br>* 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.<br>* Other names: Sodium Dichloroacetate;Genetic: Genotype<br>* Participants will be genotyped to determine GSTZ1 haplotype status.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Level of phosphorylated PDC protein expressed in surgical tissue | The efficacy of dichloroacetate will be determined by the level of phosphorylated PDC protein expressed in surgical tissue. | Within 4 weeks post surgery |