PHASE I TRIALS OF ANTICANCER AGENTS

本申请描述了用于以下的临床和实验室框架： 在韦恩州立大学进行新抗癌药物的I期研究 大学 这是基于我们对所涉问题的理解 而且，在某种程度上，是基于我们的第一阶段计划的努力， 相关药理学实验室在转化研究和 临床发展。 我们的项目专注于早期临床 开发实体瘤选择性药物， 由体外和体内疗效提供的试验设计指南， 毒理学试验人类药物代谢和临床前药代动力学 (PK)问题研究 除了NCI/CTEP赞助的药物（即苔藓抑素， KRN 5500，flavopiradol），我们自己的努力已经贡献了额外的 用于NCI支持的I期试验的化合物，包括吡唑并吖啶 (PZA; NSC 366140）、乙酰地那林（CI-994）和WIN 33377（a 噻吨酮）。 其他化合物（即XK 469，第二代 噻吨酮类）正在等待I期临床试验支持。 通过 例如，本申请描述了PZA、CI 994和 WIN 33377，从初始临床前鉴定到临床 调查 对于PZA，我们的临床前PK研究支持 成功的PK指导剂量递增I期试验和我们的体外 人骨髓毒性评估证实，目标血浆AUC 会被容忍。 通过CI 994，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。 本申请建议将我们的实验室专业知识， 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 详细描述了所有必要的考虑因素， 适当开展严格控制的I期研究，包括： 妇女和少数民族患者的合格性和快速增加， 初始剂量和剂量递增的原理，药代动力学， 药效学和药物代谢研究， 最大耐受剂量，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 药理学研究对该阶段疗效的影响 I试验设计。 因此，本提案阐述了我们的理解， 专业知识和具体的想法进行仔细控制 临床和药理学研究的I期评价新的 在包括大量的抗癌药物的人群中， 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.