Flexible, rule-based dose escalation: The cohort-sequence design

Abstract

Phase I oncology trials seek to acquire preliminary information on the safety of novel treatments. In current practice, most such trials employ rule-based designs that determine whether to escalate the dose using data from the current dose only. The most popular of these, the 3 + 3, is simple and familiar but inflexible and inefficient. We propose a rule-based design that addresses these deficiencies. Our method, which we denote the cohort-sequence design, is defined by a sequence of J increasing cohort sizes $n=\left(n_1,\dots ,n_J\right)$ and corresponding critical values $b=\left(b_1,\dots ,b_J\right)$ . The idea is to begin with a small cohort size $n_1$ and escalate through the planned doses, increasing the cohort size when we encounter toxicities. By selection of J and a safety threshold tuning parameter θ, one can create a design that will efficiently identify a target toxicity rate, potentially including a built-in dose-expansion cohort. We compared our designs to the 3 + 3 under a range of toxicity scenarios, observing that our approach generally rapidly identifies an MTD without enrolling patients unnecessarily at low doses where both toxicity and response rates are likely to be low. We have implemented the design in the R package cohortsequence.

Keywords: Dose-expansion cohort; Dose-finding design; Drug safety; Phase I clinical trial.

Fig. 1

Flow chart for the cohort-sequence design.

Fig. 2

Flow chart for determining the cohort size based on specified DLTs (X), under safety threshold θ.