The landscape of clinical trial development in oncology has evolved from studies primarily evaluating chemotherapeutics, to those that are now evaluating an ever-widening range of novel therapeutics including molecularly targeted agents, biologics and immunotherapies, as single agents or in combination. 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. Close alignment with Project Optimus will be important internationally and will require changes across industry, including for academic units and small biotech. 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. Regulatory agencies outside the US are similarly exploring this. Early clinical development will need to demonstrate the dose-exposure, -pharmacodynamic, -toxicity and -activity relationships, including randomised evaluations for dose selection. 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. 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. 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. However, while many are indeed resulting in dramatic improvements in disease control and patient survival, short- and long-term tolerability has not always accompanied it. Modern cancer therapeutics are increasingly targeted, bringing the promise of new and improved activity, alongside better tolerability.
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