  The traditional more-is-better dose selection paradigm, developed based on
cytotoxic chemotherapeutics, is often problematic When applied to the
development of novel molecularly targeted agents (e.g., kinase inhibitors,
monoclonal antibodies, and antibody-drug conjugates). The US Food and Drug
Administration (FDA) initiated Project Optimus to reform the dose optimization
and dose selection paradigm in oncology drug development and call for more
attention to benefit-risk consideration.
  We systematically investigated the operating characteristics of the seamless
phase 2-3 design as a strategy for dose optimization, where in stage 1
(corresponding to phase 2) patients are randomized to multiple doses, with or
without a control; and in stage 2 (corresponding to phase 3) the efficacy of
the selected optimal dose is evaluated with a randomized concurrent control or
historical control. Depending on whether the concurrent control is included and
the type of endpoints used in stages 1 and 2, we describe four types of
seamless phase 2-3 dose-optimization designs, which are suitable for different
clinical settings. The statistical and design considerations that pertain to
dose optimization are discussed. Simulation shows that dose optimization phase
2-3 designs are able to control the familywise type I error rates and yield
appropriate statistical power with substantially smaller sample size than the
conventional approach. The sample size savings range from 16.6% to 27.3%,
depending on the design and scenario, with a mean savings of 22.1%. Due to the
interim dose selection, the phase 2-3 dose-optimization design is logistically
and operationally more challenging, and should be carefully planned and
implemented to ensure trial integrity.
