A Phase 1 Study of CCI-779 in Combination with Imatnib *

描述（由申请人提供）：识别和靶向致癌状态下失调的信号转导通路预示着一种新的令人兴奋的癌症治疗方法。我们工作的总体目标是确定在癌症中同时靶向多种致癌信号通路在人类中是否安全有效。我们将使用慢性髓性白血病（CML）作为疾病模型，并采用针对Bcr-Abl和哺乳动物雷帕霉素靶蛋白（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，证明伊马替尼和mTOR抑制剂雷帕霉素的联合治疗对CML祖细胞具有协同作用，并克服了各种形式的伊马替尼耐药性。本提案的目标是：1.在高危CML患者中使用雷帕霉素类似物CCI-779和甲磺酸伊马替尼的组合进行I期研究;和2.验证目标评估和响应预测的实验室相关性。这些目标将使用适应性I期设计实现，在高危CML患者中采用固定剂量的伊马替尼联合CCI-779剂量递增方案。本研究的一个组成部分将是翻译相关性的验证，包括靶标鉴定、有效靶向生物标志物的评价和反应预测。本试验中纳入的特定实验室相关研究来自主要研究者实验室使用患者样本的初步数据。本研究已获得批准，并由国家癌症研究所的癌症治疗评估项目赞助，将招募来自加州大学欧文分校、圣地亚哥分校和戴维斯分校的患者。我们提案中概述的临床数据和实验室研究将构成未来在高危CML患者中进行II期试验的基础。由于已知激酶活性失调会导致多种恶性肿瘤，因此这些研究将适用于一般的癌症治疗。

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.