Early Clinical Trials of New Anti-Cancer Agents with Phase I Emphasis

描述(由申请人提供)：Case综合癌症中心(Case CCC)发展治疗计划第一阶段的总体目标是促进癌症患者发现和评估新的、基于机制的治疗方法。该计划汇集了由生物化学家、分子生物学家、生化和临床药理学家、癌症和血管生物学家、病毒学家、成像科学家和放射学家以及临床研究人员组成的互动团队，他们围绕基于特定机制的靶点和成像技术平台进行研究。与NCI/CTEP、制药合作伙伴和癌症中心实验室合作，在模型系统中发现的新的基于机制的疗法通过进行研究人员发起的第一阶段和第二阶段临床试验来评估在癌症患者中的可行性和有效性。该计划还致力于开发和识别潜在的生物标记物，以更好地为我们的发育治疗研究提供信息和指导。有3种基于机制的治疗策略是我们第一阶段研究团队的主要科学关注点：(1)DMA代谢和修复，(2)癌症血管生成，(3)细胞信号和细胞凋亡。第一阶段计划受益于Case CCC的所有科学和临床研究资源，包括9个科学计划和关键核心设施(例如，转译研究、临床试验、生物统计学、癌症药理学、异种移植、影像研究和流式细胞术共享资源)。第一阶段计划在追求基于机制的早期药物开发方面为CTEP提供了全国领先地位，纳入了监测药物和靶向效应的新成像策略，开发了指导药物开发和治疗的新型生物标记物，并为CTEP器官功能障碍工作组做出了重大贡献。在过去的U01资助周期中，Case CCC的研究人员为CTEP I期试验贡献了250名患者，并为CTEP II期试验贡献了另外254名患者，主要使用了我们小组在I期环境下开发的药物(例如O6-苄基鸟嘌呤和雷贝卡霉素类似物)。这项申请的目的是继续建立在这个强大的临床转化研究平台上，更重要的是，为NCI药物筛选计划提供的或从其他来源转介给NCI的有前途的抗癌药物的科学指导的I期试验提供合作评估资源。开发治疗计划期待着与CTEP和其他研究人员重新建立合作关系，以追求第一阶段和选择第二阶段重点的新抗癌药物的开发。

DESCRIPTION (provided by applicant): The overall goal of the Case Comprehensive Cancer Center (Case CCC) Developmental Therapeutics Program Phase I effort is to promote the discovery and evaluation of new, mechanism-based therapeutics for the cancer patient. The program brings together interactive teams of biochemists, molecular biologists, biochemical and clinical pharmacologists, cancer and vascular biologists, virologists, imaging scientists and radiologists, and clinical investigators around specific-mechanism-based targets and imaging technology platforms. New mechanism-based therapies discovered in model systems in a cooperative manner with NCI/CTEP, pharmaceutical partners, and in Cancer Center laboratories are evaluated for feasibility and efficacy in cancer patients by conducting investigator-initiated Phase I and II clinical trials. The Program also pursues development and identification of potential biomarkers to better inform and guide our developmental therapeutics pursuits. There are 3 mechanism-based therapeutic strategies that serve as the primary scientific focus for our Phase I investigative teams: (1) DMA metabolism and repair, (2) cancer angiogenesis, and (3) cell signaling and apoptosis. The Phase I Program benefits from all the scientific and clinical research resources of the Case CCC including the 9 scientific programs and pivotal core facilities (e.g., Translational Research, Clinical Trials, Biostatistics, Cancer Pharmacology, Athymic and Xenograft, Imaging Research, and Flow Cytometry Shared Resources). The Phase I program has provided national leadership to CTEP in the pursuit of mechanism-based early phase drug development, incorporated novel imaging strategies to monitor drug and target effects, developed novel biomarkers to guide drug development and therapeutics, and provided significant contributions to the CTEP Organ Dysfunction Working Group. During this past U01 funding cycle, investigators at the Case CCC contributed 250 patients to CTEP Phase I trials and another 254 patients to CTEP Phase II trials, predominantly with agents that were developed in the Phase I setting (e.g., O6- benzylguanine and rebeccamycin analog) by our group. It is the intent of this application to continue to build on this strong clinical translational research platform and, more importantly, to provide a resource for the cooperative evaluation of scientifically directed Phase I trials of promising anticancer agents available from the NCI drug screening program or referred to NCI from other sources. The Developmental Therapeutics Program looks forward to renewing its collaborative relationship with CTEP and other investigators in pursuit of the development of new anticancer agents with Phase I and select Phase II emphasis.