Project Optimus: Principles, Challenges, and a Paradigm Shift in Dose Optimization for Cancer Therapies

Abstract Phase 1 trial designs for determining appropriate doses of cytotoxic agents have traditionally been based on the assumption that both clinical benefit and toxicity increase with higher doses. These studies aim to establish the maximum tolerated dose (MTD) for further development. However, for targeted non-cytotoxic therapies, maximum efficacy may be achieved at doses below the MTD. To address this, the FDA has introduced Project Optimus (PO) to reform the paradigm of dose optimisation and selection in cancer drug development. PO seeks to strike a balance by ensuring treatment efficacy at doses that minimise avoidable toxicities. According to PO guidance, dose escalation decisions in Phase 1 trials should incorporate preclinical data (preferably from models predicting human efficacy, toxicity, and receptor engagement), toxicity profiles (including early, delayed, low-grade toxicities, and patient-reported outcomes), pharmacokinetics (PK), pharmacodynamics (PD), and efficacy data. Rather than identifying a single dose, Phase 1 studies should determine a dose range where efficacy has been observed. The adoption of PO principles is anticipated to have a significant impact on early oncology drug development. This presentation outlines the key guidance from PO and the challenges that arise.