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首页> 外文期刊>Statistics and Its Interface >Adaptive oncology phase I trial design of drug combinations with drug-drug interaction modeling
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Adaptive oncology phase I trial design of drug combinations with drug-drug interaction modeling

机译：药物 - 药物相互作用建模的药物组合的自适应肿瘤阶段I试验

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摘要

The goal of a Phase I trial is to find the maximum tolerated dose (MTD). In a single-agent dose finding Phase I trial, the key underlying assumption is that toxicity probability increases monotonically with the dose level. However, in multi-agent trials, this assumption may not hold because the drug-drug interaction potentially can either decrease or increase the joint toxicity as compared to either one used alone, which may lead to an unforeseen toxicity probability surface. Thus there exists multiple MTDs. We first develop a novel adaptive dose-finding approach which can be applied to these kinds of multi-drug combination trials. With this approach, drug-drug interaction and toxicity probability are modeled jointly through a Bliss independence model. The main goal of our dose finding scheme is to search for maximum tolerated region (MTR), as opposed to maximum tolerated dose (MTD), in single agent phase I trials. The method allows exploration of more combinations in the phase I stage, which is of particular relevance in oncology since phase I trials on the combinations may be the only opportunity before launching a costly phase III trial, comparing selected combination(s) with a standard of care. Dose escalation/de-escalation decision rules are determined by the posterior estimates of both joint toxicity probability and the corresponding drug-drug interaction, which can be continuously updated by sequentially assigning new patients into the trial while more data is being observed. We evaluate the operating characteristics of the proposed method through extensive simulation studies under various scenarios. The proposed method demonstrates satisfactory performance. In addition, the MTR offers several combinations that investigators may choose to advance to future trials based on external information from e.g., preclinical antitumor activities and other trials.
机译：I阶段试验的目标是找到最大耐受剂量（MTD）。在单药剂剂量发现阶段I试验中，关键的潜在假设是毒性概率随剂量水平单调增加。然而，在多毒剂试验中，与单独使用的任何一种使用的药物 - 药物相互作用可能会降低或增加关节毒性，这可能不会降低或增加关节毒性，这可能导致不可预见的毒性概率表面。因此存在多个MTD。我们首先开发一种新型的适应剂量发现方法，可以应用于这些种类的多药物组合试验。通过这种方法，药物 - 药物相互作用和毒性概率通过Bliss独立模型共同建模。我们剂量发现方案的主要目的是搜索最大耐受区域（MTR），而不是在单一的药剂期I试验中的最大耐受剂量（MTD）。该方法允许探索I阶段中的更多组合，这在肿瘤学中特别相关，因为我对组合的阶段试验可能是在推出昂贵的阶段III试验之前的唯一机会，比较所选择的组合与标准的选定组合关心。剂量升级/去升级决策规则由关节毒性概率的后估计和相应的药物 - 药物相互作用决定，这可以通过顺序将新患者依次分配到试验中来连续更新，而在观察更多的数据。我们通过各种情况下广泛的模拟研究评估所提出的方法的操作特性。所提出的方法表明了令人满意的性能。此外，MTR还提供了几种组合，调查人员可以选择基于例如来自例如临床前抗肿瘤活动和其他试验的外部信息前进到未来的试验。

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