PHASE I EVALUATION OF PHENYLBUTYRATE IN PT W/ REFRACTORY MALIGNANT G

这一I期方案将评估口服苯丁酸苯酯剂量递增对患有难治性或复发性恶性胶质瘤的成年门诊患者的安全性和毒性。苯丁酸酯是一种潜在的肿瘤分化剂和可能的细胞毒剂，多年来一直安全地用于患有尿素循环障碍的成人和儿童，在这些疾病中，苯丁酸酯充当谷氨酰胺的接收器，从而增加氮损失和预防高氨血症。苯丁酸酯及其代谢物苯乙酸酯(苯乙酸酯是由苯丁酸酯氧化而成)的第一和第二阶段研究正在各种恶性肿瘤患者中进行。临床前和早期临床数据均表明苯乙酸苯酯和苯丁酸苯酯对恶性胶质瘤有效。在恶性胶质瘤患者中静脉注射苯乙酸酯的初步试验结果描述了少数患者的放射学反应和病情稳定。在这项试验中，将测试递增剂量的口服苯丁酸酯的安全性和毒性。目的：确定难治性中枢神经系统肿瘤患者每日三次口服苯丁酸钠的最大耐受量，直至肿瘤进展。描述口服苯丁酸苯酯的药代动力学参数，并增加苯丁酸苯酯的剂量，以试图在评估患者对持续口服暴露计划的耐受性的同时，达到2-6 mm ol/L的血药浓度。+寻找苯丁酸酯在此时间表上对难治性中枢神经系统肿瘤患者的治疗活性的初步证据。+将观察到的任何反应和毒性与生物测定和组织取样苯丁酸酯活性的结果相关联。

This phase I protocol will evaluate the safety and toxicity of escalating doses of oral phenylbutyrate in adult ambulatory patients with refractory or recurrent malignant glioma. Phenylbutyrate, a potential tumor differentiating agent and possible cytotoxic agent, has safely been given for many years to adults and children with urea cycle disorders where it acts as a sink for glutamine and thereby enhances nitrogen loss and prevents hyperammonemia. Phase I and II studies of phenylbutyrate and its metabolite phenylacetate (phenylacetate is formed by oxidation of phenylbutyrate) are ongoing in patients with a variety of malignancies. Both preclinical and early clinical data suggests that phenylacetate and phenylbutyrate are active against malignant gliomas. Preliminary results of a completed trial of intravenous phenylacetate in patients with malignant gliomas described radiographic responses and stable disease in a small number of patients. In this trial, the safety and toxicity of incrementally increasing doses of oral phenylbutyrate will be tested. OBJECTIVES: + To determine the maximum tolerated dose of sodium phenylbutyrate taken orally three times a day in patients with refractory CNS tumors until evidence of tumor progression. + To describe the pharmacokinetic parameters of oral phenylbutyrate and to escalate the dose of phenylbutyrate in an attempt to achieve plasma levels of 2-6 mmol/L while evaluating patient tolerability on the continuous oral exposure schedule. + To seek preliminary evidence of therapeutic activity of phenylbutyrate when administered on this schedule to patients with refractory CNS tumors. + To correlate any observed responses and toxicity with results of bioassaya and tissue sampling for phenylbutyrate activity.