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的失调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对人类是否安全有效。我们将使用慢性髓性白血病（CML）作为疾病模型，并采用高特异性的小分子抑制剂组合，直接针对Bcr-Abl和哺乳动物雷帕霉素（mTOR）激酶靶点。这种方法的基本原理是基于我们最近的工作，表明伊马替尼和mTOR抑制剂雷帕霉素联合治疗可协同作用于CML祖细胞，并克服各种形式的伊马替尼耐药性。本建议的目标是：1。开展一项使用雷帕霉素类似物、CCI-779和甲酸伊马替尼联合治疗高危CML患者的I期研究；和2。验证目标评估和反应预测的实验室相关性。这些目标将通过适应性I期设计来实现，在高风险CML患者中使用固定剂量的伊马替尼联合剂量递增计划治疗CCI-779。本研究的一个组成部分将是翻译相关性的验证，包括靶标识别、有效靶向的生物标志物评估和反应预测。本试验中包含的特定实验室相关研究来自主要研究者实验室中使用患者样本的初步数据。这项研究已被批准并由国家癌症研究所癌症治疗评估项目赞助，并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高风险CML患者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.