Phase I Clinical Trials of Novel Anticancer Agents

描述（由申请人提供）：本资助申请是基于这样的前提，即表征和理解一种药物的药理学应该允许更好地临床利用该药物。对药物的临床毒性和最大耐受剂量（MTD）进行无可挑剔的表征已不再足够。理想情况下，药物的药理学特征-包括其在分子，细胞和临床水平上的药代动力学，代谢和药效学表现-将在早期临床试验中定义。这种基于药理学的方法将促进科学指导的I期试验的性能，这些试验将有关NCl抗癌剂的作用机制和药效学后果的信息整合到其设计中。将继续对新型微管蛋白相互作用剂进行表征，并将扩大涉及基于德克萨卟啉的光动力和辐射增敏剂的研究。除细胞毒性药物外，还将评价具有新机制的其他药物，包括抗血管生成剂、分化剂、骨肉瘤诱导剂、反义寡核苷酸和相关基因特异性治疗。药物的药理学已被UPCl研究人员充分表征，在NCI赞助的合同“抗肿瘤和抗HIV药物的临床前研究”的保护下，将在I期研究中进一步探索。UPCl将继续在针对特定患者群体（即，肝或肾功能不全者）。机制方面的额外评价和相关科学研究将纳入新药物的I期研究。该申请反映了研究者在进行I期试验时感兴趣的领域和记录在案的专业知识。UPCl的承诺和所描述的设施令人信服地证明，这些研究可以成功完成。希望这些方法将允许更好地理解如何在临床实践中最佳地利用这些药物。

DESCRIPTION (provided by applicant): This grant application is based on the premise that characterization and understanding of an antineoplastic agent's pharmacology should allow better clinical utilization of that agent. Impeccable characterization of the clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, an agent's pharmacologic characteristics--including its pharmacokinetics, metabolism, and pharmacodynamic manifestations on the molecular, cellular, and clinical levels--would be defined during early clinical trials. This pharmacologically-based approach will promote the performance of scientifically directed, phase I trials that integrate information regarding the mechanisms of action and pharmacodynamic consequences of NCl anti-cancer agents into their design. There will be continued characterization of novel tubulin-interactive agents, and the studies involving texaphyrin-based photodynamic and radiation-sensitizing agents will be extended. In addition to cytotoxic agents, other agents with novel mechanisms, including antiangiogenesis agents, differentiating agents, apoptosis-inducing agents, anti-sense oligonucleotides, and related gene-specific therapies will be evaluated. Agents whose pharmacology has been well characterized by the UPCl investigators, under the umbrella of the NCl-sponsored contract "Preclinical Studies of Antitumor and Anti-HIV Agents," will be further explored in phase I studies. The UPCl will continue to assume a leadership role in the study of antineoplastic agents for specific groups of patients (i.e., those with hepatic or renal dysfunction). Additional evaluation of mechanistic aspects and correlative science studies will be incorporated into phase I studies of novel agents. This application reflects the areas of interest and documented expertise of the investigators in conducting phase I trials. The commitment of the UPCl and the facilities described convincingly demonstrates that these studies can be successfully completed. It is hoped that these approaches will allow for better understanding of how these agents can be optimally utilized in clinical practice.