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Improving Dose-Finding for New Agents as Monotherapy and Add-On Therapy
Statistics in Biopharmaceutical Research ( IF 1.5 ) Pub Date : 2020-08-03 , DOI: 10.1080/19466315.2020.1784782
Zhen Zeng 1 , Cong Chen 1 , Heng Zhou 1 , Meihua Wang 1
Affiliation  

ABSTRACT

With the recent advancement in immuno-oncology, next-stage early oncology development is focusing on identifying the best combinations of established immunotherapies with new agents to either overcome drug resistance or achieve synergic effects. Although the combination is the focus, safety profile of the new agent alone must be explored. Therefore, many trials have both monotherapy and add-on combination therapy arms. Finding the maximum tolerable dose (MTD) for the new agent in both arms is critical. Traditional oncology dose-finding methods and MTD estimation algorithm do not handle the correlation and interplay between the two arms and the selected MTDs may contradict with each other. To overcome these issues, we applied a two-dimensional pool-adjacent-violators algorithm to MTD estimation and modified the standard Bayesian optimal interval design (BOIN) to allow for information flow between arms during dose-finding. We also showed that a naïve adaptation of standard BOIN that is much simpler to implement demonstrated empirically similar performance. These new approaches were assessed with simulations and demonstrated improvement for trials with both monotherapy and add-on combination therapy arms. Albeit proposed in the context with immunotherapy as the backbone drug, our approaches can be applied to any new agent in combination with a fixed dose of another drug. Supplementary materials for this article are available online.



中文翻译:

改进作为单一疗法和附加疗法的新药物的剂量发现

摘要

随着免疫肿瘤学的最新进展,下一阶段的早期肿瘤学发展重点是确定已建立的免疫疗法与新药物的最佳组合,以克服耐药性或实现协同效应。尽管组合是重点,但必须探索新药单独的安全性。因此,许多试验同时采用单一疗法和附加联合疗法。寻找新药物在双臂中的最大耐受剂量 (MTD) 至关重要。传统的肿瘤学剂量寻找方法和 MTD 估计算法不处理两臂之间的相关性和相互作用,并且所选的 MTD 可能相互矛盾。为了克服这些问题,我们将二维池相邻违反者算法应用于 MTD 估计,并修改了标准贝叶斯最优间隔设计 (BOIN),以允许在剂量发现过程中臂之间的信息流动。我们还表明,对标准 BOIN 的简单改编,实施起来更简单,表现出经验上相似的性能。这些新方法通过模拟进行了评估,并证明了对单一疗法和附加联合疗法臂的试验的改进。尽管是在免疫疗法作为主干药物的背景下提出的,但我们的方法可以应用于与固定剂量的另一种药物组合的任何新药物。本文的补充材料可在线获取。我们还表明,对标准 BOIN 的简单改编,实施起来更简单,表现出经验上相似的性能。这些新方法通过模拟进行了评估,并证明了对单一疗法和附加联合疗法臂的试验的改进。尽管是在免疫疗法作为主干药物的背景下提出的,但我们的方法可以应用于与固定剂量的另一种药物组合的任何新药物。本文的补充材料可在线获取。我们还表明,对标准 BOIN 的简单改编,实施起来更简单,表现出经验上相似的性能。这些新方法通过模拟进行了评估,并证明了对单一疗法和附加联合疗法臂的试验的改进。尽管是在免疫疗法作为主干药物的背景下提出的,但我们的方法可以应用于与固定剂量的另一种药物组合的任何新药物。本文的补充材料可在线获取。我们的方法可以应用于任何新药剂与固定剂量的另一种药物的组合。本文的补充材料可在线获取。我们的方法可以应用于任何新药剂与固定剂量的另一种药物的组合。本文的补充材料可在线获取。

更新日期:2020-08-03
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