Project Optimus: Principles, challenges, and a paradigm shift in dose optimization for cancer therapies.

Abstract

e23019 Background: Traditional phase 1 trial designs for cytotoxic agents assume that both clinical benefit and toxicity increase with higher doses, aiming to establish the maximum tolerated dose (MTD). However, for targeted non-cytotoxic therapies, maximum efficacy may be achieved at doses below the MTD. The FDA's Project Optimus (PO) aims to reform dose optimization in cancer drug development by balancing efficacy with minimized toxicities. Methods: PO guidance recommends that dose escalation decisions in phase 1 trials incorporate preclinical data, toxicity profiles, pharmacokinetics, pharmacodynamics, and efficacy data. Rather than identifying a single dose, phase 1 studies should determine a dose range where efficacy has been observed. Results: Key aspects of PO recommendations include: Utilizing preclinical data to inform trial design and dose selection Identifying a recommended dose range (RDR) for subsequent development Considering all available safety, tolerability, PK, efficacy, and biological data in dose escalation decisions Comparing at least two dose levels through randomization Collecting patient-reported outcomes data where possible. Conclusions: The adoption of PO principles is anticipated to significantly impact early oncology drug development. Challenges include demonstrating efficacy differences between doses with small sample sizes, validating novel endpoints, and increased complexity in early clinical trial design. However, PO represents a fundamental shift towards a more collaborative approach between drug developers and regulatory bodies, aiming to determine the optimal dose and schedule for patients based on emerging risk/benefit data.