Abstract
Abstract BACKGROUND No significant progress has been made over the last decade in therapies available for glioblastoma (GBM) with survival remaining poor. Meaningful advances in treating this deadly malignancy may rely on precision medicine. A novel pharmacogenomic biomarker, Denovo Genomic Marker 1 (DGM1), for enzastaurin (enz) in treating lymphoma was discovered. It was evaluated to predict enz response in GBM. METHODS Biomarker discovery was performed by a genome-wide screen using DNA extracted from blood samples of a ph 3 enz lymphoma trial and confirmed in an independent ph 2 lymphoma trial. The biomarker was evaluated for its predictability in GBM using the archived DNA samples from a ph 1/2 enz GBM trial. RESULTS DGM1, a germline polymorphism on chromosome 8, was found to be highly correlated with response to enz in the two lymphoma trials. Using DNA extracted from pts blood of the single-arm ph 1/2 study with newly diagnosed GBM receiving enz added to radiation and temozolomide (tmz), we found median OS for DGM1+ pts treated with enz was 18 mon vs 12.8 mon for DGM1- pts, HR (95% CI) 0.68 (0.25, 1.81), p = 0.12. Pts receiving a mean daily dose of enz ≥ 245 mg had an OS of 19.8 mon vs 14.9 mon for pts receiving a mean daily dose of < 245 mg [HR (95% CI) 0.55 (0.34, 0.90)]. CONCLUSION These data are supportive of DGM1 as a potentially predictive biomarker for enz response in both lymphoma and GBM. There is an ongoing biomarker-driven pivotal study in lymphoma. DGM1 in GBM will be further evaluated in a planned randomized ph 2b study in newly diagnosed GBM with 500 mg/day of enz in combination with tmz.
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