The prognosis of children who have malignant glioma, recurrent medulloblastoma, or disseminated neuroblastoma is poor. Pediatric oncologists must therefore develop new and innovative therapies for these inherently difficult to treat neoplasms. A novel approach that has shown dramatic results both in vitro and in animal models involves the use of agents that induce tumor differentiation. The goal of this approach is to convert malignant cells to a state that is responsive to normal environmental cues or more sensitive to chemotherapy or normal immune surveillance mechanisms.1 Recent studies have shown that phenylacetate, a deaminated metabolite of phenylalanine, and phenylbutyrate, which subsequently undergoes conversion to phenylacetate, can induce differentiation in a variety of glial, neuroblastoma, and medulloblastoma cell lines.2-5 For both agents, the observed antitumor effect is time and concentration dependent. However, phenylbutyrate has been shown to be a more potent differentiating agent than phenylacetate in a variety of tumor cell lines. In additions unlike phenylacetate, phenylbutyrate has been shown to exert a cytotoxic effect via apoptosis.6-8 These studies suggest that phenylbutyrate may offer a novel approach for the treatment of refractory neuroblastoma and refractory or high risk central nervous system tumors. We are therefore proposing a phase I of phenylbutyrate administered as a continuous intravenous infusion in children with refractory cancer. The results of this study will serve as the basis for a phase Il clinical study of phenylbutyrate in children with high risk or refractory central nervous system tumors, and recurrent or refractory neuroblastoma. The proposed phase H studies will evaluate the activity and disease free progression of phenylbutyrate administered as a single agent using the maximum tolerated dose (or target concentration) defined in the phase l study. Pharmacokinetic studies are an integral part of the proposed phase l and II clinical trials. The results of the pharmacokinetic studies will be evaluated to determine if there are correlates between serum phenylbutyrate levels and toxicity or response. In addition, strategies for adaptive dosing with feedback or therapeutic drug monitoring will be established and implemented based on the results of the pharmacokinetic analysis.
