PHENYLBUTYRATE GIVEN IN PEDIATRIC PATIENTS WITH REFACTORY MALIGNANCY

苯丁酸用于难治性恶性肿瘤儿科患者

• 批准号: 6306261
• 负责人: SUSAN M. BLANEY
• 金额: $ 3.6万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-12-01 至 2000-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6306261
• 关键词: adolescence (12-20); antineoplastics; blood chemistry; butyrates; central nervous system neoplasms; child (0-11); clinical research; clinical trial phase I; drug administration rate /duration; drug adverse effect; drug screening /evaluation; human subject; neoplasm /cancer chemotherapy; pediatric neoplasm /cancer; pediatric pharmacology; pharmacokinetics

Phenylbutyrate (PB) is a novel agent that in vitro induces differentiation and apoptosis in a variety of human tumors, including glioma and medulloblastoma cell lines. A phase I trial of PB administered as a 28 day continuous IV infusion (CIVI) was initiated in children with refractory cancer. Cycles are repeated without interruption if there is no disease progression or dose-limiting toxicity (DLT). Patients receive a 4.0 gm/m[2] bolus dose prior to cycle 1 for pharmacokinetic studies. Blood samples are also obtained twice weekly during CIVI for determination of steady-state concentrations (Css) of phenylbutyrate, phenylacetate (PA, active metabolite), and phenylacetylglutamine (PAG, inactive metabolite). Seven patients (4 male), median age 12 yr, (range, 6 to 15), 6 with primary CNS tumors, enrolled at two dose levels have received 12 cycles (median, 2 cycles). The first cohort of patients (n=6) received 10 gm/m[2]/day. Transient grade 4 elevation of serum transaminases (n=1) and nausea/vomiting (n=1) have been observed. The median Css at the 10 gm/m[2] dose level were: PB 34 +/- 17 microgram/m, PA 32 +/- 20 microgram/ml, and PAG 79 +/-39 microgram/ml. Patient accrual is ongoing at the 12.5 gm/m[2]/day dose level.

苯丁酸酯（Pb）是一种在体外诱导的新型药物 各种人类肿瘤的分化和凋亡，包括 胶质瘤和髓母细胞瘤细胞系。 PB的第一阶段试验 在以28天的连续IV输注（CIVI）中管理 难治性癌症的儿童。 无需循环而没有 中断如果没有疾病进展或剂量限制 毒性（DLT）。 患者接受4.0 gm/m [2]剂量 药代动力学研究的周期1。 还获得了血液样本 Civi期间每周两次确定稳态 苯丁酸，苯乙酸酯（PA，活性）的浓度（CSS） 代谢产物）和苯乙酰谷氨酰胺（PAG，非活性代谢产物）。 七名患者（4名男性），中位年龄12岁，（范围为6至15），6，与 在两个剂量水平上招收的主要中枢神经系统肿瘤已接受了12个周期 （中位数，2个周期）。 第一批患者（n = 6）接受了10 gm/m [2]/天。 瞬态4级血清转氨酶的升高（n = 1） 已经观察到和恶心/呕吐（n = 1）。 10位的中位数CSS GM/M [2]剂量水平为：Pb 34 +/- 17微克/m，PA 32 +/- 20 微克/mL，PAG 79 +/- 39微克/ml。 患者应计 在12.5 gm/m [2]/天剂量水平下。