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Dose-escalation designs (3+3, BOIN, dose-expansion)

aka 3+3, 3 + 3, 3+3 design, rule-based design, BOIN, Bayesian optimal interval, CRM, continual reassessment method, mTPI, TITE-CRM, model-based dose finding, model-based design, dose-finding, dose finding, dose-finding study, dose escalation cohort, dose escalation, dose-escalation, dose escalation phase, dose-expansion, dose expansion, expansion phase, accelerated titration, backfill cohort, dose level, dose levels, cohort of 3

How a phase 1 trial climbs from a tiny starting dose to a useful one: the old 3+3 design treats three patients at a time and moves up if none has serious toxicity; newer statistical designs (BOIN, CRM) use all the data to pick doses more accurately with fewer patients on ineffective levels.

The 3+3 design (still the most used) is simple but imprecise, treats many patients at sub-therapeutic doses and identifies the MTD poorly; model-based designs such as the continual reassessment method and the Bayesian optimal interval design estimate the toxicity curve continuously and are recommended by the FDA and methodologists, with time-to-event versions handling late toxicities. After escalation, dose-expansion cohorts (often 20-40 patients per tumour type) gather efficacy signals and may be randomised between two doses under Project Optimus. Accelerated titration and single-patient cohorts speed the early low-dose levels, and backfill cohorts add patients at lower doses to inform dose optimisation.

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Dose-limiting toxicity (DLT)First-in-human (FIH) trial Maximum tolerated dose (MTD)Project Optimus Recommended phase 2 dose (RP2D)