The changing landscape of phase I trials in oncology

Several aspects of the design of phase I trials have evolved in the era of molecular targeted agents to enable better assessment of these novel therapies and maximize the efficiency of drug developmentCurrent phase I trial designs increasingly use new dose-escalation approaches and biomarker-driven patient selection, while expanding study objectives to include efficacy evaluation and pharmacokinetics/ pharmacodynamics (PK/PD), in addition to safetyPreclinical evidence supporting a biological or pharmacological rationale and exploration of PK/PD interactions between drug partners are necessary for phase I trials of combination therapies that include targeted agentsChanges to the regulatory approval process help to expedite drug development, particularly for novel agents with a well-established biological mechanism, a predictive biomarker, and clear evidence of efficacy in early trialsChanges in the goals and conduct of phase I trials have resulted in a shift towards multi-institutional studies and centralized management, with a significant impact on the structure of phase I programmesBoth the efficiency and rate of drug approval need to improve despite the limited acceptance of novel trial designs and difficulties associated with early phase biomarker integration