CONTINUOUS INFUSION PHENYLBUTYRATE GIVEN FOR 120 HRS EVERY 21 DAYS

在过去的一年里，我们完成了这项临床研究。 所有24 入选研究的患者在Osler 5上接受住院和护理， GCRC。 该研究涉及广泛的药代动力学监测， 神经认知测试和营养教学。 的24 从3月起，23例男性患者和1例女性患者入选 1995年29日至1996年10月30日。 前列腺癌患者占 其中19名患者，3名肾癌患者， 黑色素瘤和子宫透明细胞癌 共24名患者。 治疗患者的年龄范围为52 - 78. 本研究的目的是确定最大耐受剂量 苯丁酸钠连续给药120小时 每21天。 最大耐受剂量和II期推荐剂量 苯丁酸在难治性实体瘤患者中的应用范围为400 - 410 mg/kg/天。 药代动力学评价详细描述了两种清除模式。 21例患者中有13例达到并维持稳态 苯丁酸的浓度。 21例患者中有5例达到峰值 浓度和浓度随后下降，表明 持续暴露增加或诱导清除。 神经皮质的 毒性是剂量限制性的。 未观察到完全或部分缓解 在接受治疗的患者人群中。 平均研究时间为86天， 2例患者继续参加研究超过200天。生物活性 前列腺特异性抗体的显著变化表明， 抗原水平、细胞因子测量（白细胞介素-6、内皮素-1和 血管内皮生长因子）和明显的临床获益 在一小群患者中的反应。 在研究过程中向IRB报告了6起不良事件。 一 患者在研究期间死亡，继发于进行性转移性肾细胞 癌 他的死被认为与 苯丁酸盐 5次III级神经皮质毒性发作， 注意到并报告。神经皮质变化包括过度的 嗜睡、昏迷和意识模糊。 这些变化也与 低钠血症、低钾血症、低钙血症和高尿酸血症。 这些 所有病例的神经皮质变化均可逆。 同意书是 1996年7月进行了修订，以告知患者这些事件。 小一级 II级毒性反应为恶心、呕吐。 所有这些事件 Osler 5 GCRC的医生和工作人员及时注意到， 基于临床前数据的预期。 该试验的初步数据已在年度会议上报告 AACR和ASCO。 最后一份手稿， 我们正在准备调查结果。 这项研究的数据也被 包括作为赠款提案的初步数据， NIH/NCI（1 RO 1CA 75525 -01），标题为“苯丁酸盐生物活性评估 前列腺癌的症状"

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."