PH I STUDY OF BMS-247550 GIVEN ON CONTINUOUS WEEKLY SCHEDULE IN PTS W/ADV MALIG

在 PTS W/ADV MALIG 中按连续每周时间表进行 BMS-247550 的 PH I 研究

• 批准号: 7378182
• 负责人: CHRIS H. TAKIMOTO
• 金额: $ 0.36万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7378182
• 关键词: PH; STUDY; BMS; 247550; GIVEN

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. OBJECTIVES: BMS 247550 is a cytotoxic agent that promotes and stabilizes the assembly of tubulin into microtubules, a process necessary for mitosis. It is an epothilone, a new class of non-taxane tubulin polymerization agents, which have demonstrated potent cytotoxic activity, working in much the same way as the taxanes to effect mitotoxic arrest. Objectives of this study are: 1. To determine the MTD of BMS-247550 given IV on continuous weekly schedule and to recommend a dose for phase II trials. 2. To determine the qualitative and quantitative toxicities of BMS-247550 given on a continuous weekly schedule. 3. To characterize the pharmacokinetics of BMS-247550 given on a continuous weekly schedule. 4. To explore the pharmacodynamics of a continuous weekly schedule using an assay that measures the amount of endogenous tubulin in peripheral blood mononuclear cells that exists in the polymerized versus unpolymerized state. 5. To collect information about the antitumor effects of BMS-247550 in patients with advanced cancer. RESEARCH PLAN: Patients must have histologically confirmed diagnosis of any malignant solid tumor or lymphoma and both male and female patients of reproductive potential must use an approved contraceptive method during the study and for two months afterwards. METHODS: Patients will be given BMS-247550 as a continuous infusion over one hour weekly on a four week cycle at an initial dose of 1mg/m2/week. Dose will be escalated in cohorts of three patients over four levels: 100% if toxicity is Grade 1 or less, 50% if toxicity is Grade 2, 25-33% if toxicity is Grade 2 or greater but not dose-limiting, and 20% if DLT. Enrollment of about 15 patients is anticipated at the GCRC in the South Texas Veterans Health care System, Audie Murphy Division. CLINICAL RELEVANCE: BMS-247550 is a semi-synthetic analog of the natural product epothilone B, specifically designed to overcome the metabolic instability of the natural product. BMS-247550 is a highly potent cytotoxic agent capable of killing cancer cells at a low nanomolar concentration. After a short IV infusion the terminal half-life in mice, rats, and dogs was 3.1, 9.6 and 24 hours, respectively, with high systemic clearance. In rats peripheral neuropathy, bone marrow/lymphoid depression and gastrointestinal and testicular changes were prominent. Severe gastrointestinal toxicity and death occurred in all dogs at a dose of 100 mg/m2. A dose of 10 mg/m2 was associated with transient minimal leukopenia and/or thrombocytopenia in one male and one female dog.

这个子项目是利用由NIH/NCRR资助的中心拨款提供的资源的许多研究子项目之一。子项目和调查员(PI)可能从另一个NIH来源获得了主要资金，因此可能会出现在其他CRISE条目中。列出的机构是针对中心的，而不一定是针对调查员的机构。目的：BMS 247550是一种细胞毒剂，能促进和稳定微管蛋白组装成微管，这是有丝分裂所必需的过程。它是一种新型的非紫杉烷类微管蛋白聚合剂，已显示出强大的细胞毒活性，其作用方式与紫杉烷基本相同，可实现丝裂毒性停滞。本研究的目的是：1.测定BMS-247550连续每周静脉给药的MTD，并推荐II期试验的剂量。2.确定每周连续给药的BMS-247550的定性和定量毒性。3.每周连续给药一次的药物动力学特征。4.通过测定聚合态与非聚合态外周血单个核细胞内源性微管蛋白的含量，探讨连续每周节律的药效学。5.收集有关BMS-247550在晚期癌症患者中的抗肿瘤作用的信息。研究计划：患者必须有经组织学证实的任何恶性实体肿瘤或淋巴瘤的诊断，在研究期间和之后的两个月内，具有生育潜力的男性和女性患者都必须使用经批准的避孕方法。方法：患者接受BMS-247550持续输注，每周1小时以上，4周为一个周期，起始剂量为1 mg/m2/周。剂量将在四个级别的三名患者队列中逐步增加：如果毒性为1级或以下，则为100%；如果毒性为2级，则为50%；如果毒性为2级或更高，但没有剂量限制，则为25-33%；如果是DLT，则为20%。南得克萨斯州退伍军人医疗保健系统奥迪·墨菲分部的GCRC预计将招收约15名患者。临床意义：BMS-247550是一种天然产物埃博西酮B的半合成类似物，专门设计用于克服天然产品的代谢不稳定性。BMS-247550是一种高效的细胞毒剂，能够在低纳摩尔浓度下杀死癌细胞。小鼠、大鼠和狗静脉注射后的终末半衰期分别为3.1、9.6和24小时，具有较高的体内清除能力。大鼠周围神经病变、骨髓/淋巴组织抑制、胃肠道和睾丸病变明显。剂量为100 mg/m2时，所有犬均出现严重的胃肠道毒性和死亡。剂量为10 mg/m2时，一只雄犬和一只雌犬出现一过性轻微的白细胞减少和/或血小板减少。