Designs for phase I trials of combinations of agents

药物组合的 I 期试验设计

• 批准号: 8282655
• 负责人: Mark R Conaway
• 金额: $ 27.85万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-12-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282655
• 关键词: Accounting; Bayesian Method; Cancer Vaccines; Clinical Trials Design; Computer software; Cytotoxic agent; Data; Dimensions; Dose; Dose-Limiting; Goals; Internet; Language; Light; Maximum Tolerated Dose; Methods; Modeling; Outcome; Output; Patient Agents; Patients; Phase I Clinical Trials; Probability; Property; Site; Statistical Methods; Testing; Time; Toxic effect; Update; Work; anticancer research; base; design; efficacy testing; indexing; oncology; phase 1 study; preference; response; simulation

The majority of methods for the design of Phase I trials for in oncology are intended for studies involving a single cytotoxic agent. The goal of these studies is to estimate the 'maximally tolerated dose', the highest dose that can be administered with an acceptable level of toxicity. A key assumption of these methods is the monotonicity of the dose- response curve. In this case, the dose-response curve is said to follow a 'simple order' because the ordering of the probabilities of a 'dose-limiting toxicity' (DLT) for any pair of doses is known; administration of greater doses of the agent can be expected to produce DLT's in increasing proportions of patients. It is becoming increasingly common for combinations of agents to be tested in phase I trials. In these studies, the probabilities of a DLT associated with the dose combinations often follow a 'partial order' in that there are pairs of dose combinations for which the ordering of the probabilities is not known. This proposal uses Bayesian methods, combining features of the continual reassessment method and order restricted inference to develop designs for phase I trials in which the probabilities follow a partial order. In addition, we will adapt our methods for cycle-specific toxicities. Finally, we will develop internet-accessible software to assist users in designing and carrying out partially ordered phase I trials. Even though our emphasis is on phase I trials of combinations, the methods we develop can shed light on other issues in phase I trial design, including the study of ordered groups and trials of cancer vaccines.

肿瘤学I期试验设计的大多数方法预期用于 涉及单一细胞毒性剂的研究。这些研究的目的是估计 “最大耐受剂量”，即在可接受的剂量范围内可以给予的最高剂量。 毒性水平。这些方法的一个关键假设是剂量的单调性- 响应曲线在这种情况下，剂量-反应曲线被称为遵循“简单顺序” 因为任何一对药物的“剂量限制性毒性”（DLT）的概率排序 剂量是已知的;可以预期给予更大剂量的药剂， 在越来越多的患者中产生DLT。 在I期试验中，药物组合越来越普遍 审判在这些研究中，与剂量组合相关的DLT的概率 通常遵循“部分顺序”，因为存在成对的剂量组合， 概率的排序是未知的。该提案使用贝叶斯方法， 结合连续再评估方法和顺序限制推理的特点， 为第一阶段试验开发设计，其中概率遵循偏序。 此外，我们将调整我们的方法，用于周期特异性毒性。最后我们将 开发可通过互联网访问的软件，以协助用户设计和执行 第一阶段的部分试验。尽管我们的重点是第一阶段的试验， 组合，我们开发的方法可以阐明I期试验中的其他问题 设计，包括有序组的研究和癌症疫苗的试验。