Phenylbutyrate (PB) is a novel agent that in vitro induces differentiation and apoptosis in a variety of human tumors, including glioma and medulloblastoma cell lines. A phase I trial of PB administered as a 28 day continuous IV infusion (CIVI) was initiated in children with refractory cancer. Cycles are repeated without interruption if there is no disease progression or dose-limiting toxicity (DLT). Patients receive a 4.0 gm/m[2] bolus dose prior to cycle 1 for pharmacokinetic studies. Blood samples are also obtained twice weekly during CIVI for determination of steady-state concentrations (Css) of phenylbutyrate, phenylacetate (PA, active metabolite), and phenylacetylglutamine (PAG, inactive metabolite). Seven patients (4 male), median age 12 yr, (range, 6 to 15), 6 with primary CNS tumors, enrolled at two dose levels have received 12 cycles (median, 2 cycles). The first cohort of patients (n=6) received 10 gm/m[2]/day. Transient grade 4 elevation of serum transaminases (n=1) and nausea/vomiting (n=1) have been observed. The median Css at the 10 gm/m[2] dose level were: PB 34 +/- 17 microgram/m, PA 32 +/- 20 microgram/ml, and PAG 79 +/- 39 microgram/ml. Patient accrual is ongoing at the 12.5 gm/m[2]/day dose level.
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