Phase I cancer clinical trials

Abstract

An efficient phase I trial is a crucial step in developing a new drug in a safe and timely manner. The main objective of a phase I trial is to determine the maximum tolerated dose in order to recommend the dose for a phase II trial. There are many designs that are implemented in phase I trials. Rule-based designs such as the traditional 3 + 3 method and rolling six design are easy to implement and assess for safety using a conservative approach. Model-based designs such as the continual reassessment method and the time-to-event continual reassessment method use mathematical models to increase the precision of dose estimation. The advantages and shortcomings of these designs, along with other designs, are reviewed.

Keywords: clinical trials; phase I; trial design..

Fig. 1.

Dose-toxicity curve. The curve demonstrates the monotonic increasing relationship between dosage and the probability of experiencing a toxicity. The threshold on the curve indicates the point in which no negative effects are experienced from exposure to the intervention.

Fig. 2.

3 + 3 design. Dose escalation occurs if there are no DLTs. If there is only 1 DLT that occurs, an additional 3 subjects will be treated at this same dose. Dose escalation stops if a DLT is observed in 2 or more patients.

Fig. 3.

Traditional best-of-five design. Dose escalation occurs when no more than 0 out of 3, 1 out of 4, or 2 out of 5 patients experience a DLT. When 3 or more DLTs are observed, the trial ends.

Fig. 4.

Rolling six design. The trial ends when 6 patients from a new cohort have entered at the next lowest dose or if all patients from the initial cohort experience a DLT.