Methods and Applications of Statistics in Clinical Trials, Volume 1: Concepts, Principles, Trials, and Designs

Chapter 54

Phase I/II Clinical Trials

Sarah Zohar

54.1 Introduction

Traditional phase I clinical trials aim to identify the maximum tolerated dose (MTD), and phase II clinical trials aim to evaluate the potential clinical activity of a new drug based on the MTD obtained from phase I. Due to the limited sample size in phase I, the MTD might not be obtained in a reliable way, thus effecting the subsequent phases II and III. The final objective is to select an optimal dose, a dose associated with the highest efficacy, given a tolerable toxicity [1].

In addition, in early phase dose-finding clinical trials, investigators are increasingly interested in selecting not only a dose level but also a treatment schedule. If two different treatment schedules show the same efficacy, the schedule with less toxicity is preferred [2]. Historically, for cancer chemotherapy or cytotoxic agents, the recommendation of the dose level for further studies is based on toxicity considerations. However, this practice is only valid under the assumption that the dose-toxicity and the dose-efficacy relationships are monotonous and increasing; that is, the treatment activity increases with the dose as does potential toxicity [3]. Therefore, the MTD estimated in phase I dose-finding trials is assumed to be the dose level associated with the most promising rate of efficacy.

Phase I trials are not limited to toxicity observation alone, but frequently the therapeutic response is also recorded even if it is not considered ...