学术文献库

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.