1+1=? Combinations and combination strategies in early cancer-drug development

Abstract

The path towards an established medical anticancer treatment is a long and winding road. After thorough pre-clinical studies, novel drugs or combinations of drugs enter clinical development usually in a so-called phase I dose-finding study. These studies primarily aim to determine the dose that can safely be administered and is recommended for further studies. Subsequently, in phase II studies patients with a specific tumor entity are enrolled to screen whether in that specific population the drug or combination of interest exerts antitumor activity considered worthwhile enough for further studies and to gather additional information on the tolerability. Lastly, the decision whether or not the novel regimen should be implemented in clinical practice is generated from a phase III trial in which the novel regimen is compared to standard care in the population of interest. Early cancer drug development refers to phase I studies and to a lesser extent to phase II studies. Although the development of a specific agent towards the phase III trial seems pretty straight forward, there are many important factors relevant to the dose and dosing strategy of the anticancer drug entering phase III. These include initial choices regarding dose-escalation steps as well as the determination of the maximally tolerated dose (MTD; the maximum dose that can be tolerated by patients) versus the biological optimal dose, the dose at which drug-mediated effects important for anti-tumor activity are exerted.