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

Inclusion Criteria:

• Study subjects will be male and female adults, aged 18 through 80 years, previouslydiagnosed with a GBM who have experienced tumor recurrence as determined byneuroimaging and some degree of symptomatology (e.g., headache, mental statuschange, 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 consideredtreatment failures. Patients with truly unmethylated GBM do not require priortreatment with temozolomide (TMZ).

• Patients will be recruited and studied at Johns Hopkins University, Johns Hopkinsaffiliated Sibley Memorial Hospital, and Wake Forest University. The DCA liquidformulation is on file with the FDA, is identical to that administered in our PhaseI trial of brain tumor patients and can be given by mouth or feeding tube. Patientsmay 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 thefollowing reasons. First, DCA is the only pharmaceutical in clinical use that ismetabolized by GSTZ1. Second, DCA is not known to be metabolized by any other drugmetabolizing enzyme system, thus precluding competition with other agents forbiotransformation. Third, the results of both open label and randomized controlledtrials of orally or parenterally administered DCA in the treatment of childrenand/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 orchronically ill populations, there is nothing to suggest adverse drug-druginteractions should be anticipated in this trial.

• Patients who are diabetic must have a screening hemoglobin A1c (Hgb A1c) level of atleast 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 2diabetes. Therefore, in subjects who are receiving either insulin or a sulfonylurea,coadministration of DCA could lead to symptomatic hypoglycemia and those patientswill be excluded from the trial.

• DCA is dialyzable and its clearance diminishes in patients with end stage renalfailure (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