Phase 1 and 2 Molecular and Clinical Pharmacodynamic Trials ETCTN

项目摘要 作为加州癌症联盟（CCC），四个国家癌症研究所（NCI）指定的癌症中心 建议参加NCI实验治疗药物临床试验网络（ETCTN）， 实验性疗法的临床试验阶段。希望之城（City of Hope，COH） 组织[LAO]）、南加州大学（USC，Affiliated Organization [AO]）、 加州，戴维斯（UCD，AO）和斯坦福大学癌症研究所（SCI，AO），并有25年的历史，作为一个 多学科小组，对NCI申办的研究性新药进行早期临床试验， U 01和UM 1合作协议和N 01合同。我们的多学科研究小组 将通过利用COH，UCD，USC和SCI的综合专业知识为ETCTN项目团队做出贡献， 分子药理学，药代动力学，药效学，药物基因组学，信号转导，细胞 周期调节，非侵入性成像和生物信息学，以进行创新的，实验室指导的早期阶段 发育和药代动力学研究。我们建议利用病人和科学资源 和UCD，COH，USC和SCI的专业知识，以实现以下具体目标：（目标1）使用 CCC现有的相关能力和科学领导力，以加强ETCTN计划;（目标2） 利用COH，USC，UCD和SCI NCI指定的临床项目的综合广度 综合癌症中心，以支持快速完成ETCTN试验;（目标3）使用中心数据 协调中心（DCC）和COH的生物统计核心（BC），以促进 CCC与NCI和ETCTN合作，提供快速开发和有效的试验监督，并确保 遵守政策和程序;以及（目标4）通过以下方式优化从ETCTN临床试验中获得的信息 包括患者恶性肿瘤的分子表征， 终点和研究成像。这些早期研究将导致推荐的，生物学有效的 剂量、对药剂正常组织毒性谱的更深入了解以及功效的初步估计。 它们还将提供药物对关键肿瘤细胞靶点的作用的机制验证， 肿瘤和宿主生物标志物的药物相关变化与临床结局，并对 化合物在实验室和临床中的治疗作用机制。因此，他们将 推进ETCTN的总体目标，即加速开发新型抗癌药物， 个体肿瘤的独特分子特征，并确定适当的生物标志物，以选择 最有可能对特定的药剂有反应。

PROJECT SUMMARY As the California Cancer Consortium (CCC), four National Cancer Institute (NCI)-Designated Cancer Centers propose to participate in the NCI Experimental Therapeutics Clinical Trials Network (ETCTN) to conduct early phase clinical trials of experimental therapeutics. The CCC comprises City of Hope (COH, Lead Academic Organization [LAO]), the University of Southern California (USC, Affiliated Organization [AO]), the University of California, Davis (UCD, AO), and Stanford Cancer Institute (SCI, AO), and has a 25-year history as a multidisciplinary group conducting early phase clinical trials of NCI-sponsored investigational new drugs under previous U01 and UM1 Cooperative Agreements and N01 Contracts. Our multidisciplinary group of investigators will contribute to ETCTN Project Teams by leveraging the combined expertise of COH, UCD, USC, and SCI in molecular pharmacology, pharmacokinetics, pharmacodynamics, pharmacogenomics, signal transduction, cell cycle regulation, non-invasive imaging, and bioinformatics to conduct innovative, laboratory-directed early phase developmental and pharmacokinetic studies. We propose to use the combined patient and scientific resources and expertise of UCD, COH, USC, and SCI to accomplish the following Specific Aims: (Aim 1) to use the existing relevant capabilities and scientific leadership of the CCC to enhance the ETCTN program; (Aim 2) to leverage the combined breadth of the clinical programs at COH, USC, UCD, and SCI NCI-Designated Comprehensive Cancer Centers to support the rapid completion of ETCTN trials; (Aim 3) to use the central Data Coordinating Center (DCC) and Biostatistics Core (BC) at COH to facilitate frequent communication within the CCC and with the NCI and ETCTN, provide rapid development and effective oversight of trials, and ensure adherence to policies and procedures; and (Aim 4) to optimize information gained from ETCTN clinical trials by including molecular characterization of patients’ malignancies and incorporating molecular pharmacodynamic endpoints and investigational imaging. These early phase studies will lead to recommended, biologically effective doses, greater understanding of the spectrum of normal tissue toxicity of agents, and initial estimates of efficacy. They will also provide mechanistic validation of the effects of the agents on critical tumor cell targets, correlate drug-related changes in tumor and host biologic markers with clinical outcome, and develop new insights into the therapeutic mechanisms of action of the compounds both in the laboratory and the clinic. As such, they will advance the ETCTN’s overall goal of accelerating the development of novel anticancer agents that capitalize on unique molecular features of individual tumors and identifying appropriate biomarkers to select patients who are most likely to respond to specific agents.