Background: Median survival for patients with recurrent GBM is < 6 months. Front-line systemic therapy is temozolomide but resistance due to O⁶-methylguanine-DNA-methyltransferase (MGMT) activity is implicated in poor outcomes. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that accumulates in brain tumor tissue. Previous clinical studies suggest that VAL-083 has anti-tumor activity against a range of cancers including GBM. In in vitro studies VAL-083 demonstrated activity in pediatric and adult GBM cell lines, as well as GBM cancer stem cells. Notably, VAL-083 overcomes resistance to MGMT in vitro. In light of extensive safety data from clinical trials and promising efficacy in CNS tumors, DelMar initiated a new clinical studyto establish the maximum tolerated dose (MTD) and identify a dose and dosing regimen for future efficacy trials in GBM. Dose limiting toxicity is expected to be myelosuppression, the management of which has improved in recent years. Early in the development of VAL-083, a cumulative IV dose of 125 mg/m² delivered in a 35 day cycle in combination with radiation was shown superior to radiation alone in brain cancer (Eagan, et al. 1979). In the present study, the cumulative dose in a 33 day cycle ranges from 9 mg/m² (cohort 1) to 240 mg/m² (cohort 7). Five dose cohorts, with the highest 33 day cycle cumulative dose of 120 mg/m², have completed the trial with no drug-related serious adverse events: MTD was not yet reached. Enrollment for cohort 6 (33 day cumulative dose: 180 mg/m²) has been initiated. The final cohort of this study, cohort 7 (33 day cumulative dose: 240 mg/m²), will be initiated subject to no DLT in cohort 6; the results will determine the design of the safety and efficacy registration trial. Methods: Open-label, single-arm Phase I/II dose-escalation study in patients with histologically-confirmed initial diagnosis of malignant GBM. The study utilizes a 3+3 dose-escalation design. Patients receive VAL-083 IV on days 1, 2, and 3 of a 21 day cycle. GBM patients previously been treated with surgery and/or radiation, if appropriate, must have failed both bevacizumab and temozolomide, unless contraindicated. Clinical trial information: NCT01478178.