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

描述(由申请人提供)：致癌状态下失调信号转导通路的识别和靶向预示着一种新的和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个致癌信号通路是否对人类安全有效。我们将使用慢性粒细胞白血病(CML)作为疾病模型，并使用针对bcr-Abl和哺乳动物靶标雷帕霉素(MTOR)激酶的高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表明，伊马替尼和mTOR抑制剂雷帕霉素联合治疗，对CML祖细胞起协同作用，并克服各种形式的伊马替尼耐药。这项建议的目标是：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；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期设计实现，在高危CML患者中使用固定剂量的伊马替尼与CCI-779的剂量递增时间表相结合。这项研究的一个组成部分将是对翻译相关性的验证，包括目标识别、有效靶向的生物标记物的评估和反应预测。这项试验中包括的特定实验室相关研究是根据首席调查员实验室的患者样本的初步数据得出的。这项研究已经获得批准，并由国家癌症研究所癌症治疗评估计划赞助，将从加州大学欧文、圣地亚哥和戴维斯校区招募患者。我们提案中概述的临床数据和实验室研究将为未来针对高危慢性粒细胞白血病患者的第二阶段试验奠定基础。由于去调节的激酶活性已知与多种恶性肿瘤有关，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.