For many years phase I and phase II clinical trials have been conducted separately, but there has been a recent shift to combine these phases. Although a variety of phase I-II model-based designs for cytotoxic agents have been proposed in the literature, methods for molecularly targeted agents (TAs) are just starting to develop. The main challenge of the TA setting is the unknown dose-efficacy relationship that can have either an increasing, plateau or umbrella shape. To capture these, approaches with more parameters are needed or, alternatively, more orderings are required to account for the uncertainty in the dose-efficacy relationship. As a result, designs for more complex clinical trials, e.g. trials looking at schedules of a combination treatment involving TAs, have not been extensively studied yet. We propose a novel regimen finding design which is based on a derived efficacy-toxicity trade-off function. Because of its special properties, an accurate regimen selection can be achieved without any parametric or monotonicity assumptions. We illustrate how this design can be applied in the context of a complex combination-schedule clinical trial. We discuss practical and ethical issues such as coherence, delayed and missing efficacy responses, safety and futility constraints.

中文翻译：

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分子靶向药物的信息论 I-II 期设计，不需要单调性假设。

多年来，I 期和 II 期临床试验都是分开进行的，但最近出现了将这些阶段结合起来的转变。尽管文献中已经提出了多种基于 I-II 期模型的细胞毒性药物设计，但分子靶向药物 (TA) 的方法才刚刚开始开发。TA 设置的主要挑战是未知的剂量-疗效关系，可能呈递增、稳定或伞状。为了捕获这些，需要具有更多参数的方法，或者需要更多的排序来解释剂量-功效关系的不确定性。因此，更复杂的临床试验的设计，例如涉及 TA 的联合治疗方案的试验，尚未得到广泛研究。我们提出了一种新的治疗方案发现设计，该设计基于衍生的功效-毒性权衡函数。由于其特殊性质，无需任何参数或单调性假设即可实现准确的方案选择。我们说明了如何将这种设计应用于复杂的组合方案临床试验。我们讨论实际和伦理问题，例如一致性、延迟和缺失疗效反应、安全性和无效性限制。