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

The New Approaches to Brain Tumor Therapy CNS Consortium, Department of Hematology-Oncology, Winship Cancer Institute, Emory University, Atlanta, GA, 30322 (S.P.); The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21231 (S.D.B., S.A.G., J.D.F., K.A.C., M.A.C.); Department of Neuro-Oncology, M.D. Anderson Cancer Center, Houston, TX 77030 (M.R.G.); USA

² Address correspondence to Surasak Phuphanich, The NABTT CNS Consortium, Cancer Research Building, Room G93, 1650 Orleans Street, Baltimore, MD 21231 USA (s_phuphanich{at}emoryhealthcare.org).

Abstract

We determined the maximum tolerated dose (MTD), toxicity profile, pharmacokinetic parameters, and preliminary efficacy data of oral sodium phenylbutyrate (PB) in patients with recurrent malignant gliomas. Twenty-three patients with supratentorial recurrent malignant gliomas were enrolled on this dose escalation trial. Four dose levels of PB were studied: 9, 18, 27, and 36 g/day. Data were collected to assess toxicity, response, survival, and pharmacokinetics. All PB doses of 9, 18, and 27 g/day were well tolerated. At 36 g/day, two of four patients developed dose-limiting grade 3 fatigue and somnolence. At the MTD of 27 g/day, one of seven patients developed reversible grade 3 somnolence. Median survival from time of study entry was 5.4 months. One patient had a complete response for five years, and no partial responses were noted, which yielded an overall response rate of 5%. Plasma concentrations of 706, 818, 1225, and 1605 µM were achieved with doses of 9, 18, 27, and 36 g/day, respectively. The mean value for PB clearance in this patient population was 22 liters/h, which is significantly higher than the 16 liters/h reported in patients with other malignancies who were not receiving P450 enzyme-inducing anticonvulsant drugs (P = 0.038). This study defines the MTD and recommended phase 2 dose of PB at 27 g/day for heavily pretreated patients with recurrent gliomas. The pharmacology of PB appears to be affected by concomitant administration of P450-inducing anticonvulsants.

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