Project Optimus, an FDA initiative: considerations for cancer drug development internationally, from an academic perspective

Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better
tolerability. However, while many are indeed resulting in dramatic improvements in disease control and patient survival, shortand
long-term tolerability has not always accompanied it. The choice of dose and schedule is often in the upper range of the
therapeutic window, driven by the maximum tolerated dose (MTD) model of previous cytotoxic agents. There is increasing
recognition that this needs to change, by taking a more holistic approach to determine the optimal dose for desired biological
effects and tolerability early in clinical development.

In the US, the FDA's Oncology Centre of Excellence is addressing this via the Project Optimus initiative: aiming to reform dose
optimisation studies so that they can demonstrate the most appropriate dose selection. Early clinical development will need to
demonstrate the dose-exposure, -pharmacodynamic, -toxicity and -activity relationships, including randomised evaluations for
dose selection.

Regulatory agencies outside the US are similarly exploring this. Along with Australia, Brazil, Canada, Israel, Singapore and
Switzerland, the UK participates in Project Orbis, a collaborative program with the FDA to accelerate patient access to new
cancer medicines through coordinated regulatory review. Close alignment with Project Optimus will be important internationally
and will require changes across industry, including for academic units and small biotech. We discuss our perspective on the
implications, and opportunities, for early phase oncology trials as a uniquely charity-funded drug development facility, the Centre
for Drug Development within the Cancer Research UK charity.