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

以 I 期为重点的新型抗癌药物的早期临床试验

• 批准号: 7885768
• 负责人: EDWARD CHU
• 金额: $ 74.99万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885768
• 关键词: Advanced Malignant Neoplasm; Antineoplastic Agents; Applications Grants; Biochemical; Biological; Biological Markers; Characteristics; Clinical; Clinical Trials; Colony-Stimulating Factors; Development; Dose; Drug Delivery Systems; Drug Kinetics; Drug Labeling; Drug effect disorder; Elderly; Enzymes; Ethnic group; Image; Laboratories; Malignant Neoplasms; Maximum Tolerated Dose; Metabolic Pathway; Metabolism; Molecular; Molecular Target; NMR Spectroscopy; National Cancer Institute; Organ; Patients; Performance; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacology; Phase; Phase I Clinical Trials; Phase II Clinical Trials; Philosophy; Race; Radio; Schedule; Science; Techniques; Toxic effect; Treatment Protocols; absorption; antitumor agent; base; novel; patient population; sex

DESCRIPTION (provided by applicant): The premise behind this grant application is that impeccable characterization and understanding of a systemically administered new antineoplastic agent's pharmacology and effect on molecular targets in cancer should allow better clinical utilization of that agent. Determination of clinical toxicities and maximum tolerated dose (MTD) of an agent is no longer sufficient. Ideally, early clinical trials of an investigational agent should define pharmacokinetic (PK) disposition and metabolism, with correlation to pharmacodynamic (PD) manifestations at molecular, cellular, and clinical levels. With this abiding philosophy and hypothesis, performance of scientifically directed phase I trials of promising novel anti-cancer agents available through the National Cancer Institute is warranted. Integrating information regarding the mechanism of action and effect on molecular targets with development of biomarkers in phase I trials is the strategy that will be pursued with the following objectives to : define the toxicities of new antineoplastic agents in patients with advanced cancer; re-define (as necessary)the toxicities and PK of existing anticancer agents administered in combination with molecularly targeted agents, colony stimulating factors and other toxicity-ameliorating agents that may facilitate the exploration of more effective doses and schedules; provide information on the absorption, distribution, metabolism, and elimination of antitumor agents; define treatment regimens for use in phase II trials; establish, based on clinical and pharmacologic characteristics, appropriate phase II doses in special patient populations (e.g., patients with impaired organ function; heavily pretreated patients or geriatric patient populations), explore PK and PD differences based on sex, race, or ethnic group; obtain preliminary information on PK/PD correlations that can then be extended in phase II trials; incorporate basic laboratory and correlative science studies, when possible and appropriate, to enhance the understanding of the biochemical and/or biological mechanisms of drug actions; study the PK and the PD impact of drugs on specific metabolic pathways and molecular targets using non-invasive techniques such as magnetic resonance spectroscopy and nuclear imaging with radio-labeled drugs; and integrate pharmacogenomic studies to characterize differences in relevant drug metabolizing enzymes and drug targets related to toxicity and efficacy.

描述（由申请人提供）：此赠款申请的前提是对系统管理的新抗塑料药理学的无可挑剔的表征和理解，以及对癌症分子靶标的影响，应使该药物更好地临床利用。确定药物的临床毒性和最大耐受剂量（MTD）不再足够。理想情况下，研究剂的早期临床试验应定义药代动力学（PK）处置和代谢，并在分子，细胞和临床水平上与药效学（PD）表现相关。有了这种持久的哲学和假设，有必要通过国家癌症研究所获得的有前途的新型反癌代理的科学定向I期试验。将有关作用机理和对分子靶标的作用机理的信息与I期试验中生物标志物的发展进行整合是一种策略，该策略将采用以下目标来：确定晚期癌症患者的新抗塑料的毒性；重新定义（必要的）（必要）与分子靶向剂，菌落刺激因子和其他毒性明显的毒性相结合的现有抗癌剂的毒性和PK，这些药物可能促进更有效的剂量和时间表的探索；提供有关抗肿瘤剂的吸收，分布，代谢和消除的信息；定义用于在II期试验中使用的治疗方案；基于临床和药理特征，在特殊患者人群（例如，器官功能受损；大量预处理患者或老年患者人群）中确立适当的II期剂量，探索基于性别，种族或种族的PK和PD差异；获取有关PK/PD相关性的初步信息，然后可以在II期试验中扩展；在可能和适当的情况下纳入基本的实验室和相关科学研究，以增强对药物作用的生化和/或生物学机制的理解；研究使用非侵入性技术（例如磁共振光谱和核成像）使用无线电标记的药物来研究药物对特定代谢途径和分子靶标的PD影响；并整合药物基因组学研究以表征相关药物代谢酶和与毒性和功效有关的药物靶标的差异。