TIPS-03 A PHASE 1 STUDY OF GALLIUM MALTOLATE (GAM) IN PATIENTS WITH RECURRENT GLIOBLASTOMA (GBM)

Glioblastoma remains the most aggressive malignant brain tumor with universally poor prognosis. New treatments are needed which target novelpathways. GBM cells have significantly greater requirements for iron and display markedly higher levels of transferrin receptors for iron uptake and ferritin for iron storage than surrounding normal astrocytes. The increased intracellular iron pool drives GBM activity. Previously, we showed that since gallium shares certain chemical properties with iron, it can inhibit malignant cell growth by disrupting tumor iron homeostasis. Recently, we reported that GaM is cytotoxic to GBM cell lines and stem cells but not to microvascular endothelial cells. In rodent orthotopically implanted human GBM xenografts, orally administered GaM reduced tumor volume and prolonged animal survival. These preclinical studies form the basis for our Phase 1 study which evaluates GaM in patients with recurrent GBM. The trial will follow a 3 + 3 phase 1 dose escalation design. Three to six patients at each dose level will receive GaM 500 mg/d, 1000 mg/d, or 1500 mg/day for a minimum of two 28-day cycles. Patients age >= 18 years with histologically confirmed GBM or molecular GBM with recurrent measurable disease are eligible. In the absence of measurable disease, pathologic confirmation of recurrence is required. Primary objectives are to determine a maximum-tolerated dose and recommended Phase 2 dose. Safety/tolerability will be assessed. Secondary objectives include disease assessments and evaluation of PFS and OS. Correlative studies planned are sequential blood levels of gallium, iron, Tf, ferritin, and hepcidin. Available tumor tissues will be examined for the expression iron biomarkers by immunochemistry. The study is currently enrolling. Patients will receive study drug until disease progression, unacceptable adverse events, patient withdrawal, or death. To date, 5 patients received GaM 500 mg/d without DLT and 4 patients started GaM 1000 mg/d.