Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioma

Glioblastoma multiforme (GBM) is the most common brain cancer. Front-line systemic therapy with temozolomide is often ineffective due to O6-methylguanine-DNA-methyltransferase (MGMT)-mediated resistance. Dianhydrogalactitol (VAL-083) is a bi-functional DNA N7 cross-linking agent that crosses the blood-brain barrier and demonstrated cytotoxic activity independent of MGMT in vitro. The main goal of this clinical trial was to determine an appropriate dose for Phase II/III trials in refractory GBM. METHODS: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed GBM, previously treated with radiation and must have failed both temozolomide and bevacizumab, unless contraindicated. The study utilized 3 + 3 dose-escalation design. Patients received VAL-083 on days 1, 2, 3 of a 21-day cycle. RESULTS: 30 GBM patients were enrolled across 8 dose cohorts ranging from 1.5 to 50mg/m2/d. No drug-related severe adverse events were reported, and myelosuppression was mild at doses ≤40mg/m2/d. Dose limiting toxicities (DLT) consisting of thrombocytopenia were observed at 50mg/m2/d. Platelet nadir occurred around day 20, and DLT-related symptoms resolved rapidly and spontaneously without concomitant treatment. Pharmacokinetic analyses show dose dependent linear systemic exposure with a short 1-2h plasma terminal half-life; Cmax ranged 739-1130ng/mL (5.1-7.7 mM) at 40mg/m2/d resulting in calculated CNS concentrations within the IC50 range observed for multiple GBM cell-lines in vitro. Preliminary analysis shows increasing dose-dependent median survival with median OS = 9.0 months at doses ≥30mg/m2/d vs. 4.4 months at doses ,10mg/m2/d. An expansion cohort of up to 14 patients has been initiated at 40mg/m2/d. A small cohort (n = 3) atan interim 45mg/m2/d dose will also be studied, and the expansion cohort may be continued at this higher dose if safety data warrant. CONCLUSIONS: VAL-083 dosing appears limited by myelosuppression; however, 40mg/m2/d dose exhibited favorable safety profile, with a trend toward improved survival vs. lower doses. Updated safety and efficacy data from the expansion cohort will be presented.