A Comparison of Model-Free Phase I Dose Escalation Designs for Dual-Agent Combination Therapies

Abstract

It is increasingly common for therapies in oncology to be given in combination. In some cases, patients can benefit from the interaction between two drugs, although often at the risk of higher toxicity. A large number of designs to conduct phase I trials in this setting are available, where the objective is to select the maximum tolerated dose combination (MTC). Recently, a number of model-free (also called model-assisted) designs have provoked interest, providing several practical advantages over the more conventional approaches of rule-based or model-based designs. In this paper, we demonstrate a novel calibration procedure for model-free designs to determine their most desirable parameters.Under the calibration procedure, we compare the behaviour of model-free designs to a model-based approach in a comprehensive simulation study, covering a number of clinically plausible scenarios. It is found that model-free designs are competitive with the modelbased design in terms of the proportion of correct selections of the MTC. However, there are a number of scenarios in which model-free designs offer a safer alternative. This is also illustrated in the application of the designs to a case study using data from a phase I oncology trial.

Practical implementation of the partial ordering continual reassessment method in a Phase I combination‐schedule dose‐finding trial

“…As a result, a number of methods to identify the MTC have been proposed in the literature in the last two decades. [3][4][5] Despite a number of available alternatives and the fact that more efficient statistical methods in Phase I clinical trials can noticeably increase the probability of the success by the end of Phase III studies, 1 their uptake in clinical practice remains low. 6 Another emerging field in early phase drug development is dose-schedule clinical trials in which the safety and tolerability of a monotherapy administered using various schedules is studied.…”