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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 a large share of 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.
Shares Dose-limiting toxicity (DLT), Maximum tolerated dose (MTD), Project Optimus.
Shares First-in-human (FIH) trial, Low-dose nivolumab plus metronomic chemotherapy (Tata Memorial), Phase 1, 2 and 3 trials.
Shares Bayesian trial design, Seamless, adaptive and Bayesian trial designs, Phase 1, 2 and 3 trials.
Shares First-in-human (FIH) trial, Seamless, adaptive and Bayesian trial designs.
Shares Maximum tolerated dose (MTD), Recommended phase 2 dose (RP2D), Project Optimus.
Shares Bayesian trial design, Seamless, adaptive and Bayesian trial designs, Phase 1, 2 and 3 trials.
Shares Reverse swing-M, phase 1 study of repurposing mebendazole in recurrent high-grade glioma, Recommended phase 2 dose (RP2D).