CONTINUOUS INFUSION PHENYLBUTYRATE GIVEN FOR 120 HRS EVERY 21 DAYS

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Over the past year, we have completed this clinical study. All 24 patients enrolled on the study were admitted and cared for on the Osler 5 GCRC. The study involved extensive pharmacokinetic monitoring and neurocognitive testing as well as nutritional teaching. Of the 24 patients, 23 male patients and one female patient were enrolled from March 29, 1995 - October 30, 1996. Patients with prostate cancer accounted for 19 of the patients, with 3 renal cancer patients and one patient each with melanoma and clear cell carcinoma of the uterus rounding out the total of 24 patients. The range of ages of treated patients was from 52 - 78. The objectives of the study were to determine the maximum tolerated dose of sodium phenylbutyrate with administered continuously for 120 hours every 21 days. The maximum tolerated dose and recommended Phase II dose of phenylbutyrate in patients with refractory solid tumors is 400 - 410 mg/kg/day. Pharmacokinetic evaluation detailed two clearance patterns. Thirteen of 21 patients achieved and maintained steady state concentrations of phenylbutyrate. Five of 21 patients achieved peak concentration and had a subsequent decline in concentration suggesting increased or induced clearance with continuous exposure. Neurocortical toxicity was dose-limiting. No complete or partial responses were noted in the treated patient population. Average time on study was 86 days with two patients having remained on study greater than 200 days. Bioactivity of the agent is suggested by significant alterations in prostate specific antigen levels, cytokine measurements (Interleukin-6, endothelin-1, and Vascular endothelial growth factor) and an apparent clinical benefit response in a small cohort of patients. The IRB was notified of 6 adverse events during the course of study. One patient died on study, secondary to progressive metastatic renal cell cancer. His death was not felt to be related to or attributable to phenylbutyrate. Five episodes of Grade III neurocortical toxicity were noted and reported. Neuorcortical changes consisted of excessive somnolence, stupor and confusion. These changes were also associated with hyponatremia, hypokalemia, hypocalcemia, and hyperuricemia. These neurocortical changes were reversible in all cases. The consent form was amended in July 1996 to inform patients of these events. Minor Grade I and II toxicity of nausea and emesis was also noted. All of these events were noted promptly by the physicians and staff of Osler 5 GCRC and were expected based on pre-clinical data. Preliminary data from this trial has been reported at the annual meetings of the AACR and ASCO. A final manuscript summarizing in greater detail our findings is in preparation. The data from this study has also been included as preliminary data for a Grant proposal under review by the NIH/NCI (1RO1CA75525-01) entitled "Phenylbutyrate Bioactivity Assessment in Prostate Cancer."