List of communications


Update on Phase 1/2 study of VAL-083 (dianhydrogalactitol) in patients with recurrent malignant glioma

Kent C. Shih, Sarah Cannon Research Institute, Nashville, USA; Manish R. Patel, Florida Cancer Specialists & Research Institute, Florida, USA; Nicholas Butowski, University of California San Francisco Division of NeuroOncology; Jeffrey A. Bacha, DelMar Pharmaceuticals, Inc., Vancouver, Canada and California, USA; Dennis M. Brown, DelMar Pharmaceuticals, Inc., Vancouver, Canada and California, USA; Anne Steino, DelMar Pharmaceuticals, Inc., Vancouver, Canada and California, USA; Richard Schwartz, DelMar Pharmaceuticals, Inc., Vancouver, Canada and California, USA; Sarath Kanekal, DelMar Pharmaceuticals, Inc., Vancouver, Canada and California, USA; Lorena M. Lopez, DelMar Pharmaceuticals, Inc., Vancouver, Canada and California, USA; Howard A. Burris, III, Sarah Cannon Research Institute, Nashville, USA


Poor GBM outcomes correlate with high MGMT expression. VAL-083 is a bi-functional alkylating agent causing DNA cross-links at N7 of guanine. Clinical activity against GBM was shown in prior NCI-sponsored trials. We have shown VAL-083 cytotoxic activity against GBM cell lines independent of MGMT. This clinical trial determined an optimized dose regimen to advance VAL-083 into Phase 2/3 trials for refractory GBM. Patients received a single dose of VAL-083 on days 1 - 3 of a 21-day cycle, v. days 1 – 5 in a 35 day cycle in prior NCI trials. 30 patients with histologically-confirmed GBM were enrolled in 8 dose cohorts (1.5 to 50mg/m2/d) in an open-label, single-arm Phase 1/2 dose-escalation study (3+3 design). All patients had failed prior therapy including temozolomide and bevacizumab, unless contraindicated. Preliminary analysis suggested a dose-dependent survival benefit: median OS=9.0 months (≥30mg/m2/d) v. OS=4.4 months (<10mg/m2/d). The optimized regimen achieved a higher single dose and dose intensity v. prior NCI trials without evidence of drug-related SAEs at doses ≤40mg/m2/d. DLTs (thrombocytopenia) were observed at 50mg/m2/d with platelet nadir occurring around day 20, with rapid and spontaneous recovery consistent with prior NCI trials. PK analyses showed dose-dependent linear systemic exposure and calculated CNS concentrations at 40mg/m2/d within the observed IC50 range for GBM cell-lines in vitro. An expansion cohort has been initiated at 40mg/m2/d. CONCLUSIONS: Our optimized VAL-083 dose regimen exhibited favorable safety profile at 40mg/m2/d with a trend toward improved survival v. lower doses. Additional data from this ongoing clinical trial will be presented. ClinicalTrials.gov: NCT01478178.

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