Early phase trial designs and endpoints for targeted therapies in rare genotype subsets

The primary goal of phase I dose-finding trials has been historically to understand the safety profile of a new treatment/regimen and establish the maximum tolerated dose (MTD) for further investigation in a specific tumor type. These designs hinged on the assumption that the highest safe dose is also likely to be the most efficacious dose. In the current era of stratified medicine and targeted therapies, these assumptions and designs are quickly becoming obsolete. Newer approaches to dose-finding designs are emerging with a focus on not just safety, but also an efficacy (clinical- or biomarker-based) measure to guide the determination of the "optimal" dose (not necessarily the MTD) model, as opposed to rule-based designs. These designs allow for flexibility in trial conduct, with improved precision in estimating the dose to take forward for further testing, patient selection/enrichment strategies to maximize the chance of therapeutic effect, and expansion cohorts to further understand the safety/efficacy of the agent and patient subsets most likely to benefit from the agent under investigation. Although advances in technology have enabled the possibility of using these newer approaches, the acceptance and integration of these approaches in practice can only be accelerated if it is developed in concert with a clinical paradigm.