Development of molecularly targeted agents in early phase clinical trials

There are a significant number of signaling networks that play a key role in living organisms, but which are commonly hijacked during oncogenesis. The identification of these drivers of cancer has led to the clinical development and subsequent regulatory approval of multiple molecularly targeted agents. Nonetheless, drug resistance is almost inevitable due to the development of signaling crosstalk, disruption of negative feedback loops and other mechanisms. In order to overcome these challenges, there has been an expansion of clinical trials investigating novel therapies and rational combinations of different targeted agents. Here, we describe the features of successful early phase clinical trials: strong scientific rationale leading to their initiation; robust preclinical data from model systems; inclusion of pharmacokinetic (PK) and pharmacodynamic (PD) proof-of-mechanism studies; use of optimal trial designs; and incorporation of predictive biomarkers of response to optimize patient selection to these trials. Such approaches may optimize and accelerate the drug development process and lead to monotherapy and combination strategies that benefit patients with different cancers.