PHASE I TRIALS OF ANTICANCER AGENTS

本申请描述了临床和实验室框架 在韦恩州立大学进行新抗癌药物的第一阶段研究 大学。这是基于我们对所涉及问题的理解。 而且，在一定程度上，是基于我们第一阶段计划和 转译研究中的联合药理学实验室 临床发展。我们的节目关注的是早期临床 固体肿瘤选择剂的发展，纳入到 由体外和体内疗效和体内外试验设计指导 毒理学检测人类药物代谢和临床前药代动力学 (PK)研究。除了NCI/CTEP赞助的药物(即Bryostatin， KRN5500，黄烷醇)，我们自己的努力贡献了额外的 用于NCI支持的第一阶段试验的化合物，包括吡唑吖啶 (PZA；NSC 366140)、乙酰地那林(CI-994)和WIN33377(a 硫杂蒽酮)。其他化合物(即XK469，第二代 正在等待I期临床试验支持。顺便说一句 例如，本申请描述了PZA、CI994和 WIN33377，从最初的临床前识别到临床 调查。在PZA的情况下，我们的临床前PK研究支持 一项成功的PK引导剂量递增I期试验和我们的体外试验 人类骨髓毒性评估证实，靶向血浆AUC 是可以容忍的。在CI994中，我们的翻译研究帮助定义了 导致最大药物暴露的临床时间表和剂量。 此应用程序建议将我们的实验室专业知识整合到 药代动力学、CYP 450药物代谢和血液毒理学 高效、快速的I期临床试验设计。一个过程就是 详细描述了所有必要的注意事项 适当地进行严密控制的第一阶段研究，包括： 患者资格和妇女和少数族裔患者的快速增加， 初始剂量和剂量递增的哲学，药代动力学， 药效学和药物代谢研究，达到 最大耐受量、药物不良反应报告、数据 管理和质量控制、生物统计资源，包括 电子传输数据和评估的能力 药理研究对该阶段效率的影响 我试着设计。因此，这个建议描述了我们的理解， 关于谨慎控制行为的专门知识和具体想法 新诺明I期临床和药理学研究 抗癌药物在一个包括大量 妇女和少数民族。

This application describes the clinical and laboratory framework for conducting Phase I studies of new anticancer agents at Wayne State University. It is based on our understanding of the issues involved and, in part, predicated on the efforts of our Phase I program and the associated pharmacology laboratories in translational research and clinical development. Our program has focused on the early clinical development of solid tumor selective agents, incorporating into the trial design guidance provided by in vitro and in vivo efficacy and toxicology assays human drug metabolism, and preclinical pharmacokinetic (PK) studies. In addition to NCI/CTEP sponsored drugs (i.e. bryostatin, KRN5500,flavopiradol), our own efforts have contributed additional compounds for NCI-supported Phase I trials, including pyrazoloacridine (PZA; NSC 366140), acetyldinaline (CI-994)and WIN33377 (a thioxanthenone). Other compounds (i.e. XK469, second generation thioxanthenones) are awaiting Phase I clinical trial support. By way of example, this application describes development of PZA, CI994 and WIN33377, from initial preclinical identification through clinical investigation. In the case of PZA, our preclinical PK studies supported a successful PK-guided dose-escalation phase I trial and our in vitro assessment of human myelotoxicity confirmed that the targeted plasma AUC would be tolerated. With CI994, our translational studies helped define the clinical schedule and dose that resulted in maximal drug exposure. This application proposes to incorporate our laboratory expertise in pharmacokinetics, CYP 450 drug metabolism and hematotoxicology into efficient and rapid Phase I clinical trial designs. A process is described in detail with all the considerations necessary for the appropriate conduct of carefully controlled phase I studies to include: patient eligibility and rapid accrual of women and minority patients, philosophy of initial dose and dosage escalation, pharmacokinetic, pharmacodynamic and drug metabolism studies, the attaining of the maximally tolerated dose, reporting of adverse drug reactions, data management and quality control, biostatistical resources to include capabilities for the electronic transmittal of data and an evaluation of the impact of pharmacologic studies on the efficiency of the Phase I trial design. Thus, this proposal describes our understanding, expertise and specific ideas for the conduct of carefully controlled clinical and pharmacologic studies for the Phase I evaluation of new anticancer agents in a population that includes substantial numbers of women and minorities.