{"entity":{"id":"idea-tr1-factorial-dose-finding-for-combinations","kind":"idea","name":"Factorial dose finding for drug combinations instead of full dose of everything","aka":[],"tldr":"When two cancer drugs are combined, each is usually given at its full single-agent dose, which often proves too toxic. Testing a grid of dose pairs would find combinations that work with tolerable side effects.","summary":"Combination phase 1/2 studies use model-based two-agent dose-finding (partial-order CRM, BOIN-COMB) or factorial randomised designs to explore dose pairs, with efficacy and tolerability read-outs at each pair, rather than fixing one agent at its label dose and escalating the other. Regulators expect a justification for each agent's dose in combination labels.","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":["checkpoint-inhibitor","kinase-inhibitors"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-dose-optimisation","b-combination-space"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Combination programmes using two-dimensional dose finding will select regimens with lower total dose intensity and substantially lower discontinuation than full-dose combinations, with equal or better efficacy.","rationale":"Many combination failures (and several withdrawals) were driven by intolerability at full doses of each component; synergy, where present, implies that less of each is needed.","test":"Apply two-dimensional dose finding to three new combination programmes and compare discontinuation and efficacy in subsequent trials with combinations developed conventionally.","maturity":"speculative","actor":"industry","cost":"medium","horizonYears":3},"route":"/ideas/idea-tr1-factorial-dose-finding-for-combinations/","neighbours":{"technology":[{"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/"}],"bottleneck":[{"id":"b-combination-space","kind":"bottleneck","name":"Too many combinations to test","route":"/bottlenecks/b-combination-space/"},{"id":"b-dose-optimisation","kind":"bottleneck","name":"Wrong doses","route":"/bottlenecks/b-dose-optimisation/"}]}}