Escalation strategies for combination therapy Phase I trials

Phase I clinical trials aim to identify a maximum tolerated dose (MTD), the highest possible dose that does not cause an unacceptable amount of toxicity in the patients. In trials of combination therapies, however, many different dose combinations may have a similar probability of causing a dose-limiting toxicity, and hence, a number of MTDs may exist. Furthermore, escalation strategies in combination trials are more complex, with possible escalation/de-escalation of either or both drugs. This paper investigates the properties of two existing proposed Bayesian adaptive models for combination therapy dose-escalation when a number of different escalation strategies are applied. We assess operating characteristics through a series of simulation studies and show that strategies that only allow 'non-diagonal' moves in the escalation process (that is, both drugs cannot increase simultaneously) are inefficient and identify fewer MTDs for Phase II comparisons. Such strategies tend to escalate a single agent first while keeping the other agent fixed, which can be a severe restriction when exploring dose surfaces using a limited sample size. Meanwhile, escalation designs based on Bayesian D-optimality allow more varied experimentation around the dose space and, consequently, are better at identifying more MTDs. We argue that for Phase I combination trials it is sensible to take forward a number of identified MTDs for Phase II experimentation so that their efficacy can be directly compared. Researchers, therefore, need to carefully consider the escalation strategy and model that best allows the identification of these MTDs.