Abstract
3169 Background: Altered histone deacetylase (HDAC) activity has been identified in several cancers. Recently a number of HDAC inhibitors (e.g. VPA) have been characterized that inhibit tumor growth in vitro and in vivo. The following study was designed to determine the maximum tolerated dose and toxicity of infusional VPA in cancer patients. Methods: 26 pts with pretreated and progressive malignant disease were enrolled in escalating dose-level cohorts of 3 patients. The pts received VPA as an 1-hour infusion split in two doses daily for 5 consecutive days. After a two weeks therapy-free interval the treatment was repeated. We started at a dose of 30 mg/kg and day and escalated to 60, 75, 90 and 120 mg/kg. Results: 26 pts were evaluable for toxicity. Main toxicity was neurological (grade 3/ 4) occurring in 9 of 26 pat at dose levels of 75 mg, 90mg and 120 mg/kg. No hematological toxicity grade 3/ 4 was observed. The maximum tolerated dose of infusional VPA was 60 mg/kg. Biomonitoring of peripheral blood cells demonstrated the induction of hyperacetylation in the majority of pts Conclusions: Neurotoxicity was the dose limiting factor of infusional VPA in the treatment of pts with advanced cancer. The maximum tolerated dose of 60 mg/kg is used in an ongoing Phase II study to further confirm the efficacy of VPA to inhibit HDAC activity in tumor tissue and to evaluate tumor response in pts with pre-treated malignant disease. No significant financial relationships to disclose.
Published Version
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