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

Chapter 4

Algorithm-Based Designs

Weili He and Jun Liu

4.1 Phase I Dose-Finding Studies

The primary goal of a phase I cancer clinical trial is to determine the maximum tolerated dose (MTD) to be used for subsequent phase II and III trials evaluating efficacy [1, 2]. The MTD is determined as the highest dose level of a potential therapeutic agent at which patients experience an acceptable level of dose-limiting toxicity (DLT) [3]. The acceptable level of DLT is usually referred to as a tolerable or target toxicity level (TTL) [4]. It is generally specified at the design stage of a trial by investigators, and is dependent on the potential therapeutic benefit of the drug, which may include but is not limited to the considerations of disease, disease stage, type of drug being tested, and patient population [4]. Hence, the determination of the MTD level chiefly depends on the TTL that the investigators assign to the study drug.

As with TTL, DLT is specifically defined in a study protocol at the design stage before the start of the study. In the United States, the common toxicity criteria (CTC) of the U.S. National Cancer Institute (NCI) is used [4]. There is a large list of adverse events (AEs) subdivided into organ/symptom categories that can be related to the anticancer treatment. Each AE can be categorized into five classes: grade 0, no toxicity; grade 1, mild toxicity; grade 2, moderate toxicity; grade 3, serious/severe toxicity; and grade 4, very serious or life threatening. Usually, ...