Oral sodium phenylbutyrate in patients with recurrent malignant gliomas: A dose escalation and pharmacologic study

Differentiating agents may alter tumor growth and progression, slow or inhibit metastases, and/or affect response to other forms of therapy. Phenyl-butyrate (PB)4 is an aromatic fatty acid that is converted in vivo to phenylacetate (PA) by β-oxidation in liver and kidney mitochondria. The actions of PB as a differentiating agent are primarily related to its activity as an inhibitor of histone deacetylase (Carducci et al., 1996). In vitro PB concentrations required to inhibit histone deacetylase and induce apoptosis begin at 0.5 mM of PB. In solid tumor cell lines, PB induces G1/G0 arrest and induces p21waf1/cip1, a cell cycle checkpoint protein associated with differentiation and an inhibitor of histone deacetylase, within 24 h of treatment. Glioblastoma and prostate cancer cell lines exposed to PA and PB (Gore et al., 2002) at concentrations of 1 to 5 mM in vitro develop time-and dose-dependent growth arrest (Dmitrovsky et al., 1990; Samid et al., 1993). Human glioblastoma cells can undergo cell maturation and revert to a nonmalignant phenotype when exposed to these agents (Dmitrovsky et al., 1990; Hudgins et al., 1994; Sidell et al., 1995). In vivo studies exist for experimental gliomas in rats. Samid and colleagues administered PA to rats bearing intracranial glioma cells and showed suppression of tumor growth, more than 50% of the animals being rendered free of tumor when exposed to continuously administered PA (Samid et al., 1994). Phenylbutyrate had not been tested in these glioma models, but as a precursor in PA, and as a more potent agent, clinical studies of PB were warranted. A phase 1 clinical trial of continuous intravenous infusions of PB in patients with refractory solid tumors demonstrated that this agent is safe and that doses of 410 mg/kg per day for five days every 21 days are well tolerated (Carducci et al., 2001). No complete responses (CRs) were noted; however, one patient with prostate cancer did have a partial response (PR). The dose-limiting toxicity (DLT) in this study was predominantly neurocortical. A phase 1 study of oral PB in 28 patients with solid tumors also showed that this agent was well tolerated. Oral bioavailability was 78%, and the maximum tolerated dose (MTD) was 27 g/day, with nausea/vomiting, neurocortical toxicity, and hypocalcemia being dose limiting at doses ⩾45 g/day (Gilbert et al., 2001). Both of these studies excluded patients with primary CNS tumors. This study was designed to evaluate the safety, toxicity, and pharmacology of orally administered PB given three times daily to patients with recurrent high-grade gliomas until progression. In this clinical trial, we also studied the tolerability of continued exposure to oral PB, the ability to achieve plasma levels of >0.5 mM, and the impact of P450-inducing anticonvulsant drugs on the pharmacology of PB and its metabolites, and we examined preliminary evidence of therapeutic activity.