Historically, the dosing strategy for oncology drugs centered around the maximum tolerated dose, assuming a linear drug response. Typically, based on preclinical studies, the starting dose would be administered to a group of three individuals. If no toxicities were observed, the next higher dose would be given to the next set of three individuals, and so on. The dose escalation would continue until a dose was reached where ⅔ of patients experienced toxicities. The dose would then be stepped down one level, and the process would be repeated. If it didn’t reach ⅔ DLT (Dose-Limiting Toxicity), it would be considered the Maximum Tolerated Dose (MTD). This MTD would be incorporated into a regimen with mono or combination therapy or applied to different tumor types, continuing through the end of the program (Phase 2 and 3) until approval. It is uncommon for Phase 2 or 3 studies of oncology drugs to evaluate more than one dose, which is more common in other therapeutic areas. The traditional approach to oncology drug development/dose optimization primarily focused on toxicity.

This approach has led to the neglect of drugs’ pharmacokinetic (PK) profiles and pharmacokinetic/pharmacodynamic (PK/PD) relationships. Consequently, cancer patients often struggle to tolerate their medication doses long-term, necessitating dose modifications, including reductions and holidays. This poses an additional set of problems with immuno- and targeted approaches, where delayed toxicities may manifest much later. Targeted agents are typically administered daily for an extended period. While they generally exhibit low-grade adverse events, the cumulative effect over time can be detrimental to patients. 

The FDA’s new initiative, Project Optimus, aims to address these challenges and develop new strategies to reevaluate dosing strategies and reform dose optimization of oncology drugs. This program shifts from the traditional approach to more of a dose-finding approach, considering both therapeutic effects and toxicity effects.

What does this mean?:

• Evaluation of additional dose levels for safety and efficacy.
• Phase 1 involves intense PK sampling, and PD endpoints can be incorporated.
• Exploration of multiple doses and regimens in Phase 1b or Phase 2.
• Focus on dose intensity and adverse event time courses.
• Consideration of toxicity beyond the dose-limiting toxicity criteria.
• Scrutiny of adverse events that affect patient quality of life.
• If efficacy and safety are similar at lower and higher doses, should select the lower dose for registration.

It is crucial to emphasize that more does not necessarily mean better; increasing the dose will not necessarily increase efficacy. It is time to move away from the cytotoxic-MTD approach and adopt a more rationalized, dose-optimized approach.

Check out the link for more information and updates: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

Guidance document by FDA: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/optimizing-dosage-human-prescription-drugs-and-biological-products-treatment-oncologic-diseases