Three steps toward dose optimization for oncology dose finding.

Background: Traditional dose selection for oncology registration trials typically employs a one- or two-step single maximum tolerated dose (MTD) approach. However, this approach may not be appropriate for molecularly targeted therapy, which tends to have toxicity profiles that are markedly different than cytotoxic agents. The US Food and Drug Administration launched Project Optimus to reform dose optimization in oncology drug development and has recently released a related guidance for industry. Methods: We propose a "three steps toward dose optimization" procedure, in response to these initiatives, and discuss the details in dose-optimization designs and analyses. The first step is dose escalation to identify the MTD or maximum administered dose with an efficient hybrid design, which can offer good overdose control and increases the likelihood of the recommended MTD being close to the true MTD. The second step is the selection of appropriate recommended doses for expansion (RDEs), based on all available data, including emerging safety, pharmacokinetics, pharmacodynamics, and other biomarker information. The third step is dose optimization, which uses data from a randomized fractional factorial design with multiple RDEs explored in multiple tumor cohorts during the expansion phase to ensure a feasible dose is selected for registration trials, and that the tumor type most sensitive to the investigative treatment is identified. Conclusion: We believe using this three-step approach can increase the likelihood of selecting an optimal dose for a registration trial that demonstrates a balanced safety profile while retaining much of the efficacy observed at the MTD.