A review of seamless phase I/II trial designs towards oncology dose optimization with examples of clinical pharmacology considerations in early drug development.

BACKGROUND: Deeper understanding of innovative trial designs is beneficial to clinical pharmacologists. This includes seamless designs in oncology. From the data in an appropriately designed trial, mechanistic modeling uses information that is rich in content for generating clinical pharmacology (CP) evidence. However, as more advanced statistical designs are proposed, it becomes less straightforward for clinical pharmacologists to identify pros and cons of these designs from their perspective. OBJECTIVE: This review article focuses on seamless Phase I/II designs for dose optimization in oncology and provides practical CP consideration examples in evaluating modern designs. The practical considerations span from the alignment with translational dose predictions to traditional CP assessment (e.g., QTc, and intrinsic/extrinsic factors). RESULTS: A comprehensive table of 23 seamless designs classified by CP consideration criteria, including a selected narrative review was developed. Example features include design compatibility with the type of modality, endpoints beyond maximum tolerated dose, translationally predicted efficacious dose range, dose escalation scheme, regimens for special populations, flexibility of the go/no-go decision algorithm integrating pharmacokinetic/pharmacodynamic (PK/PD) relationships, and future CP strategies. CONCLUSION: To achieve the benefit of optimal trial data generated in seamless designs, one should ensure essential features to inform CP packages are included as part of the trial design in a cross-functional team setting. Proactively getting involved in choosing a trial design with its go/no-go decision framework would allow clinical pharmacologists to make a positive impact. Optimizing designs will contribute to successful decision-making based on the totality of evidence in alignment with Project Optimus.