Revisiting isotonic phase I design in the era of model-assisted dose-finding.

Abstract

Background/aims In the conduct of phase I trials, the limited use of innovative model-based designs in practice has led to an introduction of a class of "model-assisted" designs with the aim of effectively balancing the trade-off between design simplicity and performance. Prior to the recent surge of these designs, methods that allocated patients to doses based on isotonic toxicity probability estimates were proposed. Like model-assisted methods, isotonic designs allow investigators to avoid difficulties associated with pre-trial parametric specifications of model-based designs. The aim of this work is to take a fresh look at an isotonic design in light of the current landscape of model-assisted methods. Methods The isotonic phase I method of Conaway, Dunbar, and Peddada was proposed in 2004 and has been regarded primarily as a design for dose-finding in drug combinations. It has largely been overlooked in the single-agent setting. Given its strong simulation performance in application to more complex dose-finding problems, such as drug combinations and patient heterogeneity, as well as the recent development of user-friendly software to accompany the method, we take a fresh look at this design and compare it to a current model-assisted method. We generated operating characteristics of the Conaway-Dunbar-Peddada method using a new web application developed for simulating and implementing the design and compared it to the recently proposed Keyboard design that is based on toxicity probability intervals. Results The Conaway-Dunbar-Peddada method has better performance in terms of accuracy of dose recommendation and safety in patient allocation in 17 of 20 scenarios considered. The Conaway-Dunbar-Peddada method also allocated fewer patients to doses above the maximum tolerated dose than the Keyboard method in many of scenarios studied. Overall, the performance of the Conaway-Dunbar-Peddada method is strong when compared to the Keyboard method, making it a viable simple alternative to the model-assisted methods developed in recent years. Conclusion The Conaway-Dunbar-Peddada method does not rely on the specification and fitting of a parametric model for the entire dose-toxicity curve to estimate toxicity probabilities as other model-based designs do. It relies on a similar set of pre-trial specifications to toxicity probability interval-based methods, yet unlike model-assisted methods, it is able to borrow information across all dose levels, increasing its efficiency. We hope this concise study of the Conaway-Dunbar-Peddada method, and the availability of user-friendly software, will augment its use in practice.