Project Optimus: An Overview of the Principles and Challenges

Phase 1 trial designs to establish the appropriate dose for cytotoxic agents are based on the assumption that both clinical benefit & toxicity increase with dose. These studies seek to establish the maximum tolerated dose (MTD) for future development, for targeted non-cytotoxic therapies maximum efficacy may be achieved at doses below the MTD. The FDA has set up Project Optimus (PO) to reform the dose optimisation and dose selection paradigm for cancer drug development. PO is a bid for balance: maintaining treatment efficacy at a therapeutic dose that does not generate toxicities that could otherwise be avoided with a different dose. PO guidance includes that dose escalation decisions in Phase I trials should consider preclinical data (ideally using models that predict human efficacy, toxicity, and receptor engagement), toxicity (including early and delayed, low-grade toxicities, and patient-reported outcomes), pharmacokinetic (PK) data, efficacy data and pharmacodynamic (PD) data. Phase I studies should identify a dose range within which efficacy has been observed rather than a single dose for further development. Adherence to PO principles will have a large impact on early oncology development. This presentation summarises the key PO guidance and the challenges that ensue.