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The highest dose of a drug at which about a third of patients or fewer have dose-limiting side effects, the traditional target of phase 1 trials. For chemotherapy more was better; targeted drugs and antibodies often saturate their target far below it, which is why the FDA's Project Optimus now asks for two doses to be compared.
Classic dose-finding assumed efficacy and toxicity rise together, so the MTD was the dose at which about a third of patients had dose-limiting toxicity. Many targeted drugs and biologics saturate their target well below the MTD ('MTD not reached'), and approving at the MTD has led to poor tolerability, dose reductions in half of patients and post-marketing dose changes (sotorasib 960 vs 240 mg, belantamab, cabozantinib). Project Optimus (FDA, 2022) now expects randomised comparison of at least two doses before pivotal trials to identify an optimal rather than maximal dose, and the recommended phase 2 dose is chosen on exposure-response, not toxicity alone.
Shares Dose-limiting toxicity (DLT), Dose reduction, interruption and discontinuation.
Shares Recommended phase 2 dose (RP2D), Dose-escalation designs (3+3, BOIN, dose-expansion).
Shares Therapeutic index (therapeutic window), Dose reduction, interruption and discontinuation.
Shares Dose-escalation designs (3+3, BOIN, dose-expansion), Project Optimus.
Shares Therapeutic index (therapeutic window), Dose reduction, interruption and discontinuation.
Shares Dose-escalation designs (3+3, BOIN, dose-expansion), Project Optimus.
Shares Pharmacokinetics (PK), half-life and exposure, Dose reduction, interruption and discontinuation.
Shares Dose-escalation designs (3+3, BOIN, dose-expansion), Project Optimus.