The Changing Nature of Phase I Trials

Phase I clinical trials in oncology are critical for characterization of the tolerability and adverse event profiles of new anticancer agents such that a dose and schedule can be recommended for subsequent later phase evaluation. In the traditional drug development framework, phase I oncology trials focus on determining drug safety, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity. By comparison, phase II trials are designed to determine efficacy in specific tumor types, as measured by ORR, time to progression (TTP), and PFS. Phase III trials determine whether investigational regimens provide a meaningful benefit in overall survival (OS) in a randomized setting against existing standard therapy. In the current era of genomics and immunotherapy, however, the traditional drug development paradigm has decreasing relevance for oncology research. Instead, the early stages of drug development focus on a proof of mechanism, including safety and tolerability associated with on-target and off target effects; preliminary tumor activity; and evidence of target engagement with valid pharmacodynamics biomarkers. Laterstage trials delve more deeply into the proof of concept with the exploration of predictive biomarkers; the demonstration of antitumor activity with surrogate endpoints (e.g., ORR, TTP, or PFS); and validation using a clinical endpoint (e.g., OS). In light of the changing drug development process, the nature of phase I trials has changed substantially in recent years, with key changes in multiple areas of trial design, implementation, and interpretation (Table 2). Two of these trends—increased sample size and increased use of expansion cohorts—are explored in detail below.