BRYOSTATIN 1 THERAPY OF METASTATIC MELANOMA

苔藓抑素 1 治疗转移性黑色素瘤

• 批准号: 2112199
• 负责人: Andrew S Kraft
• 金额: $ 12.98万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-09-15 至 1996-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2112199
• 关键词: antineoplastics; apoptosis; bioassay; biopsy; clinical trials; drug administration rate /duration; drug screening /evaluation; enzyme activity; gene expression; hematopoietic stem cells; human subject; human therapy evaluation; interleukin 6; melanoma; metastasis; monoclonal antibody; neoplasm /cancer chemotherapy; neoplasm /cancer immunology; neoplasm /cancer pharmacology; neoplastic cell; pharmacokinetics; protein kinase C; tumor necrosis factor alpha

DESCRIPTION: (Applicant's Abstract) The applicant proposes to accomplish a phase II study of the novel anticancer agent Bryostatin 1 in metastatic melanoma and use laboratory investigations to evaluate the biochemistry, mechanism of action and pharmacology of this agent. Bryostatin I is a macrocyclic lactone isolated from a marine Bryozoan which functions by activating protein kinase C. He and others have demonstrated that it inhibits the growth of melanoma in animals. These results led to phase I testing of Bryostatin 1 in humans which defined a dose and schedule for the administration of Bryostatin 1 and demonstrated that Bryostatin 1 had a limited set of side effects. In phase I testing two patients with metastatic melanoma had a partial response to this agent. The aims of this phase II trial are: (1) to carry out a phase II study of bryostatin 1 and evaluate the percentage of patients with metastatic melanoma responding to this agent; (2) to determine whether bryostatin 1 induces apoptosis in tumor samples: (3) to examine whether tumor responses correlate with the regulation of protein kinase C or gene induction; (4) to determine whether bryostatin 1 activates lymphocytes to kill tumor tissues; and (5) to accomplish Bryostatin 1 pharmacology using a novel assay. For this pilot study the applicant proposes to treat 14 patients using an established phase I regimen once a week every three out of four weeks at a dose of 25 ug/m2 infused over one hour. If a response is seen in the first 14 patients, a total of 25 patients will be treated. Patients who have not received any chemo- or immunotherapy and have easily biopsied lesions will be eligible. Biopsies of melanoma lesions will be done before and after therapy to assess biomarkers and intermediate end points. Blood will be drawn before, during and after infusion and examined for platelet and neutrophil activation, protein kinase levels and changes in gene transcription. As long as a partial or complete response is evident, treatment will be continued.

描述：(申请者摘要)申请者建议完成 新型抗癌药物Bryostatin-1治疗转移的II期研究 黑色素瘤，并使用实验室研究来评估生物化学， 该药剂的作用机理和药理作用。Bryostatin I是一种 从海洋苔藓虫中分离出的大环内酯，其功能通过 激活蛋白激酶C。他和其他人已经证明 抑制动物黑色素瘤的生长。这些结果导致了阶段 I在人体内测试Bryostatin 1，确定了剂量和时间表 用于给药Bryostatin 1，并证明Bryostatin 1有一组有限的副作用。在I期测试中，两名患者 转移性黑色素瘤对这种药物有部分反应。目标 这项第二阶段试验的内容是：(1)进行第二阶段研究 Bryostatin-1，并评估转移患者的百分比 黑色素瘤对该制剂的反应；(2)确定Bryostatin是否 1诱导肿瘤标本细胞凋亡：(3)检测肿瘤是否 反应与蛋白激酶C或基因的调节有关 诱导；(4)确定Bryostatin 1是否激活淋巴细胞 杀灭肿瘤组织；(5)完成Bryostatin 1药理 使用一种新的化验方法。在这项初步研究中，申请人提议 使用既定的I期方案治疗14名患者，每周一次 每4周中有3周以25ug/m2的剂量输注超过1小时。如果 在第一批14名患者中看到了反应，总共有25名患者将 接受治疗。未接受任何化疗或免疫治疗的患者 并有容易活检的病变将符合条件。黑色素瘤的活检 治疗前后将进行损伤检查，以评估生物标志物和 中间端点。在采血前、采血期间和采后采血 输液和检查血小板和中性粒细胞活化，蛋白质 蛋白激酶水平和基因转录的变化。只要是部分的 或完全缓解，将继续治疗。