Bayesian Methods for Complex Precision Biotherapy Trials in Oncology

项目摘要/摘要 大多数临床试验设计使用“一刀切”规则进行治疗分配和评估，其基础是 忽略患者的异质性。这与医疗实践脱节，在医疗实践中，医生使用每个患者的诊断 和预后变量，以做出个性化、精准的药物治疗决策。现代精准医学 利用生物技术，如蛋白质组学、基因组学、基因测序、质谱学或细胞学方法 评估多个细胞表面标记物。这些产生的生物标记物的载体可以用来恢复现有的 疾病亚组划分，建立新的疾病分类，制定临床试验设计和统计 个性化/精准治疗分配规则。在肿瘤学和其他疾病领域， 开发新的生物疗法，包括细胞疗法、免疫疗法和靶向分子制剂。一种生物疗法 可一次或多次给药；与细胞毒性等常规治疗联合使用 化疗、放疗或手术；并经常产生复杂的结果，如反复评估肿瘤状态， 多个生物变量，以及早发和晚发毒性的发生时间。这使判决复杂化了。 反应和毒性，并产生可能在不同亚组之间差异的多维治疗效果。一个 例如，一项优化供者来源的自然杀伤(NK)细胞亚群特异性剂量用于治疗的I-II期试验。 B细胞恶性血液病，捐赠的NK细胞使用嵌合抗原受体进行改造，以增强 他们的癌症杀伤力，然后使用生长因子扩大，以获得足够大的细胞剂量用于治疗。 可以使用疾病亚型和预后变量来确定亚组。共同初选结果可能包括序数 病情，包括完全或部分缓解、病情稳定或病情进展，一次或一次评估 每月间隔；出现严重NK细胞相关毒性的时间，如细胞因子释放综合征；以及 100天的生存时间。考虑(生物疗法、剂量、给药时间表)一种治疗方案、一种或一种临床试验 更多新的生物疗法可能包括每种疗法的亚组-特定风险--基于贸易的剂量或时间表优化 生物治疗，限制在亚组内实现平衡的方案之间的随机化，以及亚组-专科组 选择更好的政权或丢弃不安全或有效政权的顺序规则。拟议的研究将构建 考虑患者异质性的稳健贝叶斯回归模型，包括可能的 政体-亚群相互作用。这些将是顺序决策和制度分配的基础，以及 它们可能包括自适应地将具有相似制度-结果影响的子组组合起来的潜在变量。每个诊所 试验设计将针对特定生物治疗环境中的这些目标的组合进行量身定做。对于每一种设计， 将提供用户友好的计算机软件，包括用于试验模拟以建立设计操作的程序 特点，试验行为，以及执业医生为他们的病人选择最佳方案的使用。这个 拟议研究的首要目标是开发和确定最佳的个性化生物治疗方案，跨越 各种不同的疾病和临床环境，以获得更好的抗病效果、更高的安全性和更高的生存率。

Project Summary/Abstract Most clinical trial designs use \one-size- ts-all" rules for treatment assignment and evaluation based on models that ignore patient heterogeneity. This is disconnected from medical practice, where physicians use each patient's diagnosis and prognostic variables to make personalized, precision medicine treatment decisions. Modern precision medicine exploits biotechnologies such as proteomics, genomics, gene sequencing, mass spectrometry, or cytometry methods that evaluate multiple cell surface markers. These generate vectors of biomarkers that may be used to re ne existing disease subgroup de nitions, construct new disease classi cations, and formulate clinical trial designs and statistical rules for personalized/precision treatment assignment. In oncology and other disease areas, there is rapidly increasing development of new biotherapies, including cell therapies, immunotherapies, and targeted molecular agents. A biotherapy may be administered once or in multiple cycles; used in combination with conventional treatments such as cytotoxic chemotherapy, radiation, or surgery; and often generates complex outcomes, such as repeatedly evaluated tumor status, multiple biological variables, and occurrence times of both early and late onset toxicities. This complicates the de nitions of \response" and \toxicity," and produces multidimensional treatment e ects that may di er between subgroups. An example is a phase I-II trial to optimize subgroup-speci c doses of donor derived natural killer (NK) cells for treating B-cell hematologic malignancies, where donated NK cells are engineered using chimeric antigen receptors to enhance their cancer killing e ects, then expanded using growth factors to obtain cell doses large enough for therapeutic use. Subgroups may be de ned using disease subtypes and prognostic variables. Co-primary outcomes may include ordinal disease status, including complete or partial remission, stable disease, or disease progression, evaluated either once or at monthly intervals; time to severe NK cell-related toxicity, such as cytokine release syndrome; and a binary indicator of 100-day survival. Considering (biotherapy, dose, administration schedule) a treatment regime, a clinical trial of one or more new biotherapies may include a subgroup-speci c risk-bene t tradeo based dose or schedule optimization for each biotherapy, randomization among regimes restricted to achieve balance within subgroups, and subgroup-speci c group sequential rules to select superior regimes or drop unsafe or ine ective regimes. The proposed research will construct robust Bayesian regression models for regime-outcome e ects that account for patient heterogeneity, including possible regime-subgroup interactions. These will be the basis for sequential decision making and regime assignment, and they may include latent variables to adaptively combine subgroups with similar regime-outcome e ects. Each clinical trial design will be tailored to address a combination of these goals in speci c biotherapy settings. For each design, user-friendly computer software will be provided, including programs for trial simulation to establish design operating characteristics, trial conduct, and use by practicing physicians to choose optimal regimes for their patients. The overarching goal of the proposed research is to develop and identify optimal personalized biotherapy regimes, spanning a variety of di erent diseases and clinical settings, for greater anti-disease e ects, increased safety, and improved survival.