Maximum-tolerated dose, optimum biologic dose, or optimum clinical value: Dosing determination of cancer therapies

摘要

One of the key goals of early-phase cancer clinical trials is to determine the best dose of a drug to take forward into subsequent, outcomes-oriented, clinical trials. Typically, once a dose and schedule are recommended for phase II and III trials, we rarely, if ever, go back to explore alternatives. We then assume a one-size-fits-all dosing of our drugs, modifying only using our traditional mg/m2 or mg/kg dosing approaches, neither of which have solid pharmacologic rationale themselves,1 and ignore any personalized medicine approach. Instead of pausing after phase I to refine our understanding of how to choose the right dose and schedule for a given patient, we push forward as quickly as possible, urgently moving toward the critical phase III trial—the straightest line between drug discovery and approval. We do this because in today s world, finding a small benefit among a large patient population is often enough to obtain regulatory approval and to influence equally important practice guidelines.