Project Optimus for Radiation Therapy-Drug Combinations: Moving Beyond the Maximum Tolerated Dose

Area of Science:

• Oncology
• Radiation Oncology
• Clinical Trial Design

Background:

• Traditional early-phase radiation therapy (RT) drug development relies on maximum tolerated dose (MTD), a method with limitations in capturing efficacy and tolerability.
• The U.S. Food and Drug Administration's Project Optimus promotes an optimum biologically effective dose approach, integrating efficacy and tolerability for drug development.
• Adapting Project Optimus principles to RT-drug combinations could enhance the development of safe and effective cancer therapies.

Purpose of the Study:

• To adapt Project Optimus principles for optimizing early-phase radiation therapy (RT)-drug combination trials.
• To redefine dose-finding objectives beyond the maximum tolerated dose (MTD) for improved RT-drug development.
• To propose a framework for identifying the optimum combination regimen for radiation therapy and drugs.

Main Methods:

• An international expert panel convened to discuss the adaptation of Project Optimus principles to RT-drug development.
• The panel examined the legacy of MTD in RT-drug trials and explored key considerations for safety and efficacy assessment.
• The discussion included trial design innovations and future directions for implementing the proposed framework.

Main Results:

• The traditional MTD approach has limitations, including inadequate assessment of delayed adverse events and lack of biological relevance for radiosensitization or immune modulation.
• The proposed RT-Optimus framework focuses on identifying the Optimum Radiation Therapy Combination Regimen (OTRR) that optimizes tumor control and minimizes side effects.
• Implementation requires extended assessment windows for side effects, patient-reported outcomes, intermediate efficacy endpoints (e.g., ctDNA, radiomics), and adaptive trial designs.

Conclusions:

• The RT-Optimus framework provides a biologically and ethically sound approach to modernize early-phase RT-drug trials.
• Shifting focus from MTD to OTRR, incorporating mechanistic, biomarker-informed, and patient-centered endpoints, enhances efficiency, reproducibility, and clinical relevance.
• This modernized approach aims to prevent failures in RT-drug combinations and accelerate progress toward safer, more effective multimodality cancer treatments.