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

TL;DR

This paper compares model-free and model-based phase I dose escalation designs for dual-agent cancer therapies, showing that model-free methods are competitive and sometimes safer in selecting optimal dose combinations.

Contribution

It introduces a novel calibration procedure for model-free designs and provides a comprehensive simulation comparison with model-based approaches.

Findings

Model-free designs are competitive in selecting the MTC.

Model-free designs can be safer in certain scenarios.

Application to real trial data supports simulation results.

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 model-based 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.