PHASE-I STUDY OF PHENYLACETATE ADMINISTERED TWICE-DAILY TO PATIENTS WITH CANCER

Background. The growth-inhibiting and differentiating effects of sodiu m phenylacetate against hematopoietic and solid tumor cell lines has a roused clinical interest in its use as an anticancer drug. In an earli er Phase I trial of phenylacetate aimed at maintaining serum drug conc entrations in the range that proved active in vitro (>250 mu g/ml) for 2 consecutive weeks, infusion rates approached the maximum velocity o f drug elimination and commonly resulted in drug accumulation and reve rsible dose-limiting neurologic toxicity. In this study, the authors d escribed the nonlinear pharmacokinetics, metabolism, toxicity, and cli nical activity of phenylacetate. Methods. The treatment regimen of thi s Phase I study was designed to expose patients intermittently to drug concentrations exceeding 250 mu g/ml and to allow time for drug elimi nation to occur between doses to minimize accumulation. Sodium phenyla cetate was administered as a 1-hour infusion twice daily (8 a.m., 5 p. m.) at two dose levels of 125 and 150 mg/kg for a 2-week period. Thera py was repeated at 4-week intervals far patients who did not experienc e dose-limiting toxicity or disease progression. Results. Eighteen pat ients (4 of whom previously were treated with phenylacetate by continu ous intravenous infusion received 27 cycles of therapy. Detailed pharm acokinetic studies for eight patients indicated that phenylacetate ind uced its own clearance by a factor of 27% in a 2-week period. Dose-lim iting toxicity, consisting of reversible central nervous system depres sion, was observed for three patients at the second dose level. One pa tient with refractory malignant glioma had a partial response, and one with hormone-independent prostate cancer achieved a 50% decline in pr ostate specific antigen level, which was maintained for I month. Concl usions. Phenylacetate administered at a dose of 125 mg/kg twice daily for 2 consecutive weeks is well tolerated. High grade gliomas and adva nced prostate cancer are reasonable targets for Phase II clinical tria ls.