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Phase II Study of Phenylacetate in Patients With Recurrent Malignant Glioma: A North American Brain Tumor Consortium Report

From the University of California Medical Center, San Francisco, CA; University of Texas Health Science Center, Dallas, TX; University of Texas, South Western, Dallas, TX; University of Washington Medical Center, Seattle, WA; University of Wisconsin Comprehensive Cancer Center, Madison, WI; Montefiore University Hospital, Pittsburgh, PA; and Southwest Oncology Group Statistical Center, Seattle, WA.

Address reprint requests to Susan M. Chang, MD, 533 Parnassus Ave, Suite U107, San Francisco, CA 94143-0372; email changs@ neuro.ucsf.edu.

PURPOSE: To determine the response rate, time to treatment failure, and toxicity of phenylacetate in patients with recurrent malignant glioma and to identify plasma concentrations achieved during repeated continuous infusion of this agent.

PATIENTS AND METHODS: Adult patients with recurrent malignant glioma were treated with phenylacetate. The schedule consisted of a 2-week continuous, intravenous infusion followed by a 2-week rest period (14 days on, 14 days off). A starting dose of 400 mg/kg total body weight per day of phenylacetate was initially used and subsequently changed to 400 mg/kg/d based on ideal body weight. Intrapatient dose escalations were allowed to a maximum of 450 mg/kg ideal body weight/d. Tumor response was assessed every 8 weeks. The National Cancer Institute common toxicity criteria were used to assess toxicity. Plasma concentrations achieved during the patients' first two 14-day infusions were assessed.

RESULTS: Forty-three patients were enrolled between December 1994 and December 1996. Of these, 40 patients were assessable for toxicity and response to therapy. Reversible symptoms of fatigue and somnolence were the primary toxicities, with only mild hematologic toxicity. Thirty (75%) of the 40 patients failed treatment within 2 months, seven (17.5%) had stable disease, and three (7.5%) had a response defined as more than 50% reduction in the tumor. Median time to treatment failure was 2 months. Thirty-five patients have died, with a median survival of 8 months. Pharmacokinetic data for this dose schedule showed no difference in the mean plasma concentrations of phenylacetate between weeks 1 and 2 or between weeks 5 and 6.

CONCLUSION: Phenylacetate has little activity at this dose schedule in patients with recurrent malignant glioma. Further studies with this drug would necessitate an evaluation of a different dose schedule.

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