CCI-779 in Combination with Imatinib Mesylate in Chronic

CCI-779 与甲磺酸伊马替尼联合治疗慢性病

• 批准号: 6936956
• 负责人: TIONG S. ONG
• 金额: $ 27.05万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6936956
• 关键词: antineoplastics; biological signal transduction; biomarker; chronic myelogenous leukemia; clinical research; clinical trial phase I; combination cancer therapy; combination chemotherapy; drug screening /evaluation; human subject; kinase inhibitor; neoplasm /cancer pharmacology; patient oriented research; small molecule

DESCRIPTION (provided by applicant): The identification and targeting of dysregulated signal transduction pathways underlying oncogenic states has heralded a new and exciting approach to cancer therapy. The overall objective of our work is to determine whether simultaneous targeting of multiple oncogenic signaling pathways in cancer is safe and effective in humans. We will use chronic myelogenous leukemia (CML) as a disease model, and employ a combination of highly-specific, small molecular inhibitors directed against the Bcr-Abl and mammalian target of rapamycin (mTOR) kinases. The rationale for this approach is based on our recent work demonstrating that combined treatment with imatinib and the mTOR inhibitor, rapamycin, acts synergistically against CML progenitors, as well as overcomes various forms of imatinib resistance. The objectives of this proposal are: 1. To conduct a phase I study using the combination of the rapamycin analog, CCI-779, and imatinib mesylate in patients with high-risk CML; and 2. To validate laboratory correlates for target evaluation and response prediction. These objectives will be accomplished using an adaptive phase I design, employing a fixed dose of imatinib in combination with a dose-escalation schedule for CCI-779 in patients with high-risk CML. An integral part of this study will be the validation of translational correlates, including target identification, evaluation of biomarkers for effective targeting, and response prediction. The specific laboratory correlative studies included in this trial are derived from preliminary data using patient samples in the Principle Investigator's laboratory. This study has been approved and is sponsored by the Cancer Therapy Evaluation Program of the National Cancer Institute, and will enroll patients from the Irvine, San Diego, and Davis Campuses of the University of California. The clinical data and laboratory studies outlined in our proposal will form the basis for a future phase II trial in patients with high-risk CML. Since deregulated kinase activity is known to contribute to a wide range of malignancies, these studies will have applicability to cancer therapy in general.

描述（由申请人提供）：鉴定和靶向致癌状态下的信号转导途径失调的识别和靶向癌症治疗的新方法。我们工作的总体目的是确定癌症中多种致癌信号通路的同时靶向在人类中是安全有效的。我们将使用慢性粒细胞性白血病（CML）作为疾病模型，并采用针对BCR-ABL和雷帕霉素（MTOR）激酶的高度特异性小分子抑制剂的组合。这种方法的基本原理是基于我们最近的工作，该工作表明，与伊马替尼和MTOR抑制剂雷帕霉素相结合，可以协同作用于CML祖细胞，并克服各种形式的伊替尼抗性。该提案的目标是：1。使用雷帕霉素类似物，CCI-779和伊马替尼麦甲酸酯的组合进行I期研究。 2。验证实验室相关以进行目标评估和响应预测。这些目标将使用自适应I期设计来实现，并采用固定剂量的伊马替尼与高危CML患者的CCI-779剂量降低时间表结合使用。这项研究的一个组成部分将是验证转化相关性，包括目标识别，生物标志物的有效靶向评估以及响应预测。该试验中包括的特定实验室相关研究是使用原则研究者实验室中的患者样本从初步数据中得出的。这项研究已获得批准，并由国家癌症研究所的癌症治疗评估计划赞助，并将招募加利福尼亚大学尔湾，圣地亚哥和戴维斯校园的患者。我们的提案中概述的临床数据和实验室研究将是高危CML患者的未来II期试验的基础。由于已知失控的激酶活性会导致广泛的恶性肿瘤，因此这些研究通常适用于癌症治疗。