PHASE IIB STUDY OF PHENYLACETATE IN METASTATIC MELANOMA

苯乙酸治疗转移性黑色素瘤的 IIB 期研究

• 批准号: 2464565
• 负责人: B L GAUSE
• 金额: --
• 依托单位: DIVISION OF CLINICAL SCIENCES - NCI
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/2464565
• 关键词: clinical research; drug screening /evaluation; glutamine; histocompatibility antigens; human subject; human therapy evaluation; melanoma; metastasis; neoplasm /cancer chemotherapy; neoplastic growth; phenylacetates; receptor expression

Phenylacetate is a naturally occurring molecule which conjugates glutamate in the plasma. The PAG complex is excreted in the urine leading to the loss of total body nitrogen. Glutamine is also the major nitrogen source for nucleic acid in protein synthesis as well as a substrate for energy in rapidly dividing normal and tumor cells. Due to the increased production and decreased synthesis, tumor cells operate on the edge of glutamine deprivation; glutamine is therefore a rate-limiting molecule for tumor growth. In addition, phenylacetate has been shown to upregulate class I molecule expression on the cell surface of malignant tumors. One of the mechanisms that tumor cells use to escape immune recognition and killing is by down-regulating the expression of their class I and/or II molecules on the cell surface. Preclinical studies have shown that upregulating expression of these MHC molecules on the surface of nonimmunogenic tumor cells can induce immunorecognition and lead to rejection. The study objectives are: 1) to determine the antitumor response of phenylacetate, 2) determine the toxicities, 3) evaluate the effects of phenylacetate on class I expression, and 4) evaluate the immunologic response to phenylacetate. The dose of phenylacetate will be 450 mg/kd/day based on the patient's ideal body weight (IBW). Phenylacetate will be administered over three weeks, with 6 days of continuous infusion followed by 24 hrs. without treatment on the 7th day. We plan to accrue 35 pts. 5 pts. have been treated on this study thus far. No pt. developed significant toxicity which was felt to be attributable to phenylacetate. 1 pt. developed significant pulmonary hemorrhage from metastatic lesions to the lung and had to be removed from study. There was no evidence of objective response.

乙酸苯酯是一种天然存在的分子，可与谷氨酸结合 在血浆中。 PAG 复合物通过尿液排出，导致 体内总氮的损失。 谷氨酰胺也是主要的氮源 用于蛋白质合成中的核酸以及能量的底物 快速分裂的正常细胞和肿瘤细胞。 由于产量增加 合成减少，肿瘤细胞在谷氨酰胺的边缘运作 剥夺;因此，谷氨酰胺是肿瘤的限速分子 生长。 此外，苯乙酸已被证明可以上调 I 类 恶性肿瘤细胞表面的分子表达。 中的一个 肿瘤细胞逃避免疫识别和杀伤的机制 是通过下调 I 类和/或 II 类分子的表达 在细胞表面。 临床前研究表明，上调 这些 MHC 分子在非免疫原性肿瘤表面的表达 细胞可以诱导免疫识别并导致排斥反应。 研究 目标是：1) 确定乙酸苯酯的抗肿瘤反应， 2) 确定毒性，3) 评估苯乙酸对人体的影响 I 类表达，4) 评估免疫反应 苯乙酸酯。 苯乙酸酯的剂量为 450 mg/kd/天，基于 患者的理想体重 (IBW)。 将给予苯乙酸 超过三周，连续输注 6 天，然后 24 小时。 第7天无需治疗。 我们计划累积 35 分。 5 分。有 迄今为止已接受本研究的治疗。 没有点。发展显着 认为是由苯乙酸引起的毒性。 1 分。 从转移性病灶发展为严重的肺出血 肺，必须从研究中取出。 没有客观证据 回复。