Amending ongoing first-in-human (phase I) oncology clinical trials with the addition of expansion cohorts to address new drug development objectives, historically evaluated in sequential stand-alone trials—a “phased” approach—offers a potential pathway to expedite drug development. Use of a seamless expansion cohort trial as a drug development pathway for drugs that demonstrate preliminary clinical evidence of substantial antitumor activity in first-in-human trials, with appropriate attention to mitigating the risks of this approach, may fit in well with the goals and concepts described by FDA's expedited programs, such as for oncology drugs meeting the criteria for designation as breakthrough therapy. Indeed, seamless expansion cohort trials in oncology have provided the preliminary clinical evidence to support requests for breakthrough therapy designation and, in exceptional circumstances, to support accelerated approvals. Acknowledging the potential efficiencies, seamless expansion cohort trials in oncology present multiple challenges—selection of drugs for this approach; appropriate eligibility criteria for the individual expansion cohorts; adequate statistical justification of sample sizes and analysis plans for additional cohorts; communication plans for safety among sponsors, investigators, patients, IRBs, and regulators; considerations for establishment of an independent, external committee to monitor safety and trial endpoints; and interactions between sponsors and FDA at critical drug development time points where traditional milestones may no longer be identified by submission of new, stand-alone protocols.