All Times EDT
Keywords: RP2D, MTD, dose escalation, adaptive randomization, Optimus
During the past decade, tremendous successes such as checkpoint inhibitors have been achieved in the oncology drug development. The unmet medical needs to fight various cancers are increasingly in demand. To expedite drug development for unmet needs, sponsors often intend to determine a RP2D (recommend Phase II dose) from a dose escalation study, then to conduct a single-arm phase II/III study with RP2D for registration. At present, it is not uncommon that this RP2D is the MTD (maximum tolerated Dose), the highest dose next to the MTD, or the highest dose administered if the MTD was not reached. However, such dose following the paradigm of cytotoxic agents (i.e., the higher dose, the better efficacy outcome) may not be optimal for the new generations of anti-cancer drugs such as targeted and immune therapies. Therefore, the dose finding paradigm is being shifted to identify optimal doses. In 2021, the FDA’s Oncology Center of Excellence initiated the project “Optimus” to reform the dose optimization and dose selection paradigm; FOCR (Friends of Cancer Research) assembled a working group and published a white paper following its annual meeting with experts from the FDA, industry and academia to advance dose optimization. A new FDA guidance on dose optimization is under development. Hence, the message has become clear that the optimal dose of a new anticancer drug should be ascertained through a randomized dose-ranging phase II trial.
Dose optimization implies a wide range of multidiscipline efforts in oncology drug development. In this roundtable discussion, we will focus on statistical designs and considerations for a randomized dose-ranging phase II trial: (1) seamless dose escalation and dose ranging; (2) adaptive randomization of allocating patients to a more proposing dose; (3) dose ranging under master protocol, umbrella trial and platform trial setting. We welcome any related topics to discuss and encourage participants to share their experiences and views.