CWRU/UHICC Phase I Trials of Anticancer Agents

描述（由申请人提供）：克利夫兰大学医院（UHC）和凯斯西储大学（CWRU）爱尔兰综合癌症中心的一个互动和多学科研究小组有效地和创造性地设计了各种基于机械的I期临床试验。我们的I期药物开发工作的支撑植根于非常强大的基于实验室的科学专业知识，开发药效学终点并将其纳入我们研究的能力，专业的药代动力学分析能力，以及使用新的I期研究设计来解决给定药物的作用机制或生物学效应的证据。我们的抗癌药物I期开发方法是让我们的科学家参与进来，开发新的基于组织的放射成像监测策略，并利用药理学专业知识更好地了解和开发特定药物。在过去的资助周期中，这些策略中的每一个都被利用在与NCI癌症治疗评估计划（CTEP）合作开发新型抗癌药物中。在此期间，我们的团队为CTEP开发4种药物提供了科学领导，包括O 6-苄基鸟嘌呤（BG），rebeccamycin类似物，苔藓抑素1和SU 5416等。这4种药物的临床开发清楚地表明，将我们的CTEP申办的I期研究与癌症中心的科学专业知识联系起来，是新抗癌药物早期临床试验的一个强有力的策略，重点是I期。我们将在即将到来的资助周期中研究的新抗癌药物的早期临床开发将大大促进我们自己中心最近由NIH资助的两项相互关联的计划。这些计划补充了NCI在药物发现和临床开发方面的凝聚力和综合计划。第一项倡议是P20奖（1 P20 CA 91710 -01），以建立体内细胞和分子成像中心（ICMIC），以响应RFA-CA-99- 04。该项目的研究人员已经制定了拓扑替康的试点研究，结合放射性药物标记和PET扫描专业知识，以监测抗癌药物的肿瘤组织动力学。另一项倡议是对我们目前U 01合作的补充，题为“结肠癌中的激酶靶点评估”，作为NCI分子靶点评估跨学科研究小组的一部分，以响应RFA-CA-00-001。在该项目中，研究人员正在开发使用磷酸化特异性抗体的免疫组织化学技术，以确定激酶靶点的频率和激活状态（磷酸化）[例如，表皮生长因子受体（EGFR）]。这些举措使我们能够生成有关药物效果的数据，并为优化给药时间表提供了独特的机会。第一阶段计划也是CTEP赞助的器官功能障碍工作组（ODWG）的创始成员，并已将其在第一阶段开发的药物纳入早期第二阶段试验，作为CWRU -匹兹堡大学-亨利福特财团的一部分。本申请的目的是继续建立在这一强大的临床转化研究项目的基础上，更重要的是，为NCI药物筛选项目中有前途的抗癌药物的科学指导的I期试验或从其他来源转介给NCI的抗癌药物的合作评价提供资源。癌症中心的发展治疗计划期待着与CTEP和其他研究人员恢复合作关系，以开发新的抗癌药物，重点是I期。

DESCRIPTION (provided by applicant): An interactive and multidisciplinary team of investigators at the Ireland Comprehensive Cancer Center at University Hospitals of Cleveland (UHC) and Case Western Reserve University (CWRU) have effectively and creatively designed a variety of mechanistically-based Phase I clinical trials. The sustenance of our Phase I drug development effort is rooted in very strong laboratory-based scientific expertise, ability to develop and incorporate pharmacodynamic endpoints into our studies, expert pharmacokinetic analytic capability, and the use of novel phase I study designs to address mechanism of action or proof of biologic effect of a given drug. Our approach to phase I development of anticancer agents is to engage our scientists, develop novel tissue-based and radiological imaging monitoring strategies, and take advantage of pharmacologic expertise to better understand and develop a specific drug. Each of these strategies has been capitalized upon in the cooperative development of novel anticancer agents with the NCI's Cancer Therapy Evaluation Program (CTEP) during the past grant cycle. Our group has provided scientific leadership to CTEP for the development of 4 agents during this period including O6-benzylguanine (BG), rebeccamycin analog, bryostatin 1, and SU5416 among others. The clinical development of these 4 agents clearly demonstrates that linking our CTEP-sponsored Phase I studies with the Cancer Center's scientific expertise is a robust strategy for early clinical trials of new anticancer agents with phase I emphasis. The early clinical development of new anticancer agents we will investigate over the coming grant cycle will be greatly facilitated by two interrelated recently NIH-funded initiatives at our own center. These programs complement NCI's cohesive and integrated program in drug discovery and clinical development. The first initiative is a P20 award (1P20 CA91710-01), to establish a In Vivo Cellular and Molecular Imaging Center (ICMIC), in response to RFA-CA-99-04.Investigators on this project have framed a pilot study of topotecan, combining radiopharmaceutical labeling and PET scan expertise to monitor tumor tissue kinetics of the anticancer agent. The other initiative is a supplement to our current U01 cooperative entitled, "Kinase Target Assessment in Colon Cancer" as part of the NCI's Interdisciplinary Research Teams for Molecular Target Assessment in response to RFA-CA-00-001. In this project, investigators are developing immunohistochemical techniques using phosphoform-specific antibodies to determine the frequency and activation status (phosphorylation) of kinase targets [e.g., epidermal growth factor receptor (EGFR)] in clinical samples. These initiatives allow us to generate data on drug effect and the unique opportunity to optimize schedules of administration. The Phase I program is also a founding member of the CTEP-sponsored Organ Dysfunction Working Group (ODWG) and has taken agents it has developed in the phase I setting into early phase II trials as part of the CWRU - University of Pittsburgh - Henry Ford consortia. It is the intent of this application to continue to build on this strong clinical translational research program 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 at the Cancer Center looks forward to renewing its collaborative relationship with CTEP and other investigators in pursuit of the development of new anticancer agents with Phase I emphasis.