The Changing Nature of Phase I Trials

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