{"entity":{"id":"idea-tr1-model-based-dose-finding-with-late-toxicity","kind":"idea","name":"Retire the 3+3: model-based dose finding that counts late and chronic side effects","aka":[],"tldr":"The traditional way of finding a dose looks only at severe side effects in the first month. Modern statistical designs can use all patients' data and count the grumbling, long-lasting problems that make people quit months later.","summary":"Phase 1 designs (BOIN, CRM, TITE variants) that incorporate late-onset toxicity, cumulative low-grade toxicity over multiple cycles, patient-reported tolerability and pharmacokinetics into dose selection, with a target of the 'optimal biological dose' rather than the MTD, and with backfill cohorts at lower doses. Regulators expect a model-based design; the 3+3 becomes the exception requiring justification.","asOf":"2026-09-08","links":[{"label":"Bottleneck evidence (Wrong doses): FDA Oncology Center of Excellence, Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"}],"tags":[],"related":[],"cancers":[],"sections":[],"technologies":["kinase-inhibitors","adc","checkpoint-inhibitor"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":["ruth-plummer"],"bottlenecks":["b-dose-optimisation","b-trial-design"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Model-based designs incorporating late toxicity will recommend lower doses than 3+3 for the same agents in a substantial fraction of cases, and those doses will show lower real-world discontinuation.","rationale":"For chronic oral therapies and immunotherapies, the toxicities that matter appear after cycle 1 and are often grade 2 but persistent; 3+3 is statistically inefficient and structurally blind to them.","test":"Re-analyse completed phase 1 datasets under TITE-BOIN with cumulative toxicity and compare recommended doses to the original; prospectively adopt in a sponsor's early-phase portfolio and track later dose changes.","maturity":"early-clinical","actor":"industry","cost":"small","horizonYears":2},"route":"/ideas/idea-tr1-model-based-dose-finding-with-late-toxicity/","neighbours":{"technology":[{"id":"adc","kind":"technology","name":"Antibody-drug conjugate (ADC)","route":"/technologies/adc/"},{"id":"checkpoint-inhibitor","kind":"technology","name":"Immune checkpoint inhibitors","route":"/technologies/checkpoint-inhibitor/"},{"id":"kinase-inhibitors","kind":"technology","name":"Small-molecule kinase inhibitors","route":"/technologies/kinase-inhibitors/"}],"person":[{"id":"ruth-plummer","kind":"person","name":"Ruth Plummer","route":"/people/ruth-plummer/"}],"bottleneck":[{"id":"b-trial-design","kind":"bottleneck","name":"Trial design, endpoints and cost","route":"/bottlenecks/b-trial-design/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}]}}