Dose Titration Algorithm Tuning (DTAT) should supersede 'the' Maximum Tolerated Dose (MTD) in oncology dose-finding...

Area of Science:

• Pharmacology and Toxicology
• Clinical Trial Design
• Oncology Drug Development

Background:

• Current early-phase oncology trials often lack adaptive, individualized dose-finding, risking suboptimal dosing in later phases.
• The traditional focus on a single maximum tolerated dose (MTD) may not adequately address inter-individual variability.
• There is a need for advanced methodologies to optimize dose selection in early clinical development.

Purpose of the Study:

• To demonstrate that early-phase trials should aim for dose titration algorithm (DTA) finding, not just dose-finding.
• To propose and evaluate a novel DTA for individualized dose optimization in oncology.
• To highlight the importance of individualized dosing concepts over a single MTD.

Main Methods:

• Simulated a Phase I dosing study for a cytotoxic chemotherapy agent, using docetaxel pharmacokinetics and myelosuppression dynamics.
• Investigated the linearization of population pharmacokinetics and myelosuppression under dose and neutrophil concentration transformations.
• Employed a simple DTA with a Newton-Raphson heuristic to target a specific neutrophil nadir in simulated subjects.

Main Results:

• Simulated myelosuppression dynamics showed approximate linearization with dose and neutrophil concentration transformations.
• The developed DTA demonstrated largely satisfactory convergence for dose titration across simulated subjects.
• Significant inter-individual variability in optimal dosing was observed, with some instances of overshooting.

Conclusions:

• The substantial inter-individual variability necessitates a shift from a single MTD to an individualized MTD (MTD_i).
• A simple DTA can effectively realize the concept of individualized MTD, improving dose selection.
• The DTA principle is applicable beyond cytotoxic chemotherapy to other oncology agents like immunotherapies and targeted therapies.