ABSTRACT

Many Phase I trial designs have been developed to improve upon the standard $3+3$ design. These designs can be classified as long-memory designs, for example, the continual reassessment method (CRM), and short-memory designs such as the modified toxicity probability interval (mTPI) design. Long-term memory designs use all data but their performance can be negatively affected by the model misspecification. Short-term memory designs only use data at the current dose and might lose efficiency as a result. To overcome these issues, we propose a regularized CRM (rCRM). The rCRM offers a trade-off between long-term memory and short-term memory methods. The rCRM gives more weight to data obtained at the doses with the estimated probability of toxicity closer to the target toxicity rate. The addition of a regularization term has an effect of shrinking the dimension of the model and leads to improved performance of the 2-parameter CRM. The rCRM is a good design choice to guide assignments in an expansion cohort phase of a dose-finding trial since dose assignments do not seem to change as often as in corresponding CRMs.

摘要

已经开发了许多 I 期试验设计以改进标准$3+3$设计。这些设计可以分为长记忆设计，例如持续重新评估方法 (CRM)，以及短记忆设计，例如修正毒性概率区间 (mTPI) 设计。长期记忆设计使用所有数据，但它们的性能可能会受到模型错误指定的负面影响。短期记忆设计仅使用当前剂量的数据，因此可能会降低效率。为了克服这些问题，我们提出了一种规范化的 CRM（rCRM）。rCRM 提供了长期记忆和短期记忆方法之间的权衡。rCRM 对在估计毒性概率更接近目标毒性率的剂量下获得的数据给予更大的权重。添加正则化项具有缩小模型维度的效果，并导致 2 参数 CRM 的性能提高。