Randomised Phase 1 clinical trials in oncology.

The aims of Phase 1 trials in oncology have broadened considerably from simply demonstrating that the agent/regimen of interest is well tolerated in a relatively heterogeneous patient population to addressing multiple objectives under the heading of early-phase trials and, if possible, obtaining reliable evidence regarding clinical activity to lead to drug approvals via the Accelerated Approval approach or Breakthrough Therapy designation in cases where the tumours are rare, prognosis is poor or where there might be an unmet therapeutic need. Constructing a Phase 1 design that can address multiple objectives within the context of a single trial is not simple. Randomisation can play an important role, but carrying out such randomisation according to the principles of equipoise is a significant challenge in the Phase 1 setting. If the emerging data are not sufficient to definitively address the aims early on, then a proper design can reduce biases, enhance interpretability, and maximise information so that the Phase 1 data can be more compelling. This article outlines objectives and design considerations that need to be adhered to in order to respect ethical and scientific principles required for research in human subjects in early phase clinical trials.