Author(s): Galanis E, Jaeckle KA, Maurer MJ, Reid JM, Ames MM,
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Abstract PURPOSE: Vorinostat, a histone deacetylase inhibitor, represents a rational therapeutic target in glioblastoma multiforme (GBM). PATIENTS AND METHODS: Patients with recurrent GBM who had received one or fewer chemotherapy regimens for progressive disease were eligible. Vorinostat was administered at a dose of 200 mg orally twice a day for 14 days, followed by a 7-day rest period. RESULTS: A total of 66 patients were treated. Grade 3 or worse nonhematologic toxicity occurred in 26\% of patients and consisted mainly of fatigue (17\%), dehydration (6\%), and hypernatremia (5\%); grade 3 or worse hematologic toxicity occurred in 26\% of patients and consisted mainly of thrombocytopenia (22\%). Pharmacokinetic analysis showed lower vorinostat maximum concentration and area under the curve (0 to 24 hours) values in patients treated with enzyme-inducing anticonvulsants, although this did not reach statistical significance. The trial met the prospectively defined primary efficacy end point, with nine of the first 52 patients being progression-free at 6 months. Median overall survival from study entry was 5.7 months (range, 0.7 to 28+ months). Immunohistochemical analysis performed in paired baseline and post-vorinostat treatment samples in a separate surgical subgroup of five patients with recurrent GBM showed post treatment increase in acetylation of histones H2B and H4 (four of five patients) and of histone H3 (three of five patients). Microarray RNA analysis in the same samples showed changes in genes regulated by vorinostat, such as upregulation of E-cadherin (P = .02). CONCLUSION: Vorinostat monotherapy is well tolerated in patients with recurrent GBM and has modest single-agent activity. Histone acetylation analysis and RNA expression profiling indicate that vorinostat in this dose and schedule affects target pathways in GBM. Additional testing of vorinostat in combination regimens is warranted.
This article was published in J Clin Oncol
and referenced in Journal of Clinical Research & Bioethics