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

该I期方案将评估递增剂量口服苯丁酸酯治疗难治性或复发性恶性胶质瘤的成人门诊患者的安全性和毒性。苯基丁酸盐是一种潜在的肿瘤分化剂和可能的细胞毒性剂，多年来已被安全地给予尿素循环紊乱的成人和儿童，在那里它作为谷氨酰胺的汇，从而增加氮的损失并防止高氨血症。苯丁酸酯及其代谢物苯乙酸酯（苯乙酸酯由苯丁酸酯氧化形成）的I期和II期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表明，苯乙酸酯和苯丁酸酯对恶性胶质瘤有活性。对恶性胶质瘤患者静脉注射苯乙酸酯试验的初步结果描述了少数患者的放射学反应和稳定的疾病。在本试验中，将测试逐渐增加口服苯丁酸盐剂量的安全性和毒性。目的：确定难治性中枢神经系统肿瘤患者在肿瘤进展前每日口服三次苯基丁酸钠的最大耐受剂量。+描述口服苯丁酸盐的药代动力学参数，并逐步增加苯丁酸盐的剂量，以达到2-6 mmol/L的血浆水平，同时评估患者对持续口服暴露计划的耐受性。+寻求对难治性中枢神经系统肿瘤患者按此方案给予苯基丁酸盐治疗活性的初步证据。将观察到的反应和毒性与苯丁酸酯活性的生物测定和组织取样结果联系起来。

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.