Curve-free phase I/II clinical trial designs for molecularly targeted agents and immunotherapy

分子靶向药物和免疫治疗的无曲线 I/II 期临床试验设计

• 批准号: 10304652
• 负责人: Yong Zang
• 金额: $ 14万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10304652
• 关键词: Address; Algorithms; Area; Binomial Model; Clinical; Clinical Trials Design; Communities; Complex; Cytotoxic agent; Data; Decision Making; Development; Dimensions; Dose; Drug Combinations; Goals; Immunotherapeutic agent; Immunotherapy; Joints; Lead; Learning; Likelihood Functions; Literature; Maximum Tolerated Dose; Methods; Modeling; Molecular Target; Monitor; Outcome; Patients; Pattern; Performance; Phase; Phase I Clinical Trials; Phase I/II Clinical Trial; Phase I/II Trial; Physicians; Probability; Research; Series; Testing; Therapeutic Effect; Time; Toxic effect; Translations; Weight; base; cancer therapy; clinical practice; cost; design; efficacy outcomes; flexibility; follow-up; interest; mathematical model; novel; response; simulation; targeted agent; trial design; two-dimensional; unpublished works; user-friendly; web app

Project Summary/Abstract The primary goal of this proposal is to develop transparent, flexible and efficient phase I/II clinical trial designs identifying optimal doses for molecularly targeted agents (MTA) and immunotherapy (IT). Conventional phase I/II clinical trial designs often use sophisticated parametric models to characterize the joint toxicity-efficacy distribu- tions and to conduct the trials. However, the parametric models are hard to justify in practice, and misspecification of parametric models can lead to substantially undesirable performances of phase I/II trials. Moreover, it is difficult for the physicians conducting the trials to clinically interpret the parameters of these sophisticated models, and such great learning costs impede the translation of novel statistical designs into real-world trial implementation. To solve these issues, in this proposal we will propose transparent curve-free phase I/II clinical trial designs. The proposed designs make no parametric assumptions on either dose-response relationship or toxicity-efficacy correlation and therefore performs robustly under any clinically meaningful dose-response curves. The concise clinically interpretable model expression and dose-finding algorithm make the proposed designs highly transla- tional from the statistical community to the clinical community. The proposed designs are also highly flexible because they are applicable for both single-agent trial and drug-combination trial with either quickly observable outcomes or delayed outcomes. The preliminary simulation studies show that the proposed designs are highly efficient in optimal dose selection and patient allocation. In addition, we will develop user-friendly web apps to facilitate the widespread application of the proposed designs in clinical practice.

项目摘要/摘要 该提案的主要目标是发展透明，灵活和有效的I/II临床试验设计 鉴定分子靶向药物（MTA）和免疫疗法（IT）的最佳剂量。常规I/II期 临床试验设计经常使用复杂的参数模型来表征联合毒性 - 耐耐性分布 - 进行试验。但是，参数模型在实践中很难证明是合理的，并且拼写错误 参数模型可以导致I/II期试验的基本不良性能。而且，这很难 对于进行试验的医师，以临床解释这些复杂模型的参数，并 如此出色的学习成本阻碍了将新颖的统计设计转化为现实世界中的试验实施。 为了解决这些问题，在此提案中，我们将提出无透明曲线I/II期临床试验设计。 所提出的设计对剂量反应关系或毒性 - 耐药性没有任何参数假设 相关性，因此在任何临床意义有意义的剂量反应曲线下都能稳健。简洁 临床上可解释的模型表达和剂量发现算法使所提出的设计高度翻译 从统计社区到临床社区的统治。所提出的设计也具有很高的灵活性 因为它们适用于单药试验和药物组合试验，并可以快速可观察到 结果或延迟结果。初步模拟研究表明，提出的设计很高 最佳剂量选择和患者分配方面有效。此外，我们将开发用户友好的Web应用程序 促进拟议设计在临床实践中的广泛应用。