{"entity":{"id":"idea-tr2-combo-dose-matrix","kind":"idea","name":"Find the lowest effective doses of both drugs in a combination, not the highest tolerated","aka":[],"tldr":"Combination trials usually keep one drug at full dose and push the other as high as patients can bear. Testing a grid of dose pairs would find combinations that work at lower, safer doses.","summary":"Project Optimus asks for dose optimisation of single agents; combinations remain largely dosed by escalating the new agent onto a fixed backbone. Model-based combination designs (BOIN-COMB, Bayesian optimal interval for drug combinations, and exposure-response modelling) can explore a two-dimensional dose grid and pick the pair with the best benefit-to-toxicity ratio. The proposal is regulatory expectation that registrational combination trials justify both doses with such data.","asOf":"2026-09-08","links":[{"label":"FDA Project Optimus","url":"https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus"}],"tags":[],"related":["ild-overlap-caution"],"cancers":[],"sections":[],"technologies":["adc","checkpoint-inhibitor"],"targets":[],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":[],"trials":[],"people":[],"bottlenecks":["b-combination-space","b-dose-optimisation"],"keyPapers":[],"journals":[],"dependsOn":[],"notes":[],"hypothesis":"Combinations dosed from a two-dimensional optimisation will have at least 30% lower grade 3 or worse toxicity and non-inferior response rates compared with combinations dosed by conventional escalation on a fixed backbone.","rationale":"Many targeted-agent combinations (PI3K plus endocrine, MEK plus BRAF plus PD-1) failed on toxicity rather than efficacy. Overlapping toxicity is a dose problem that a matrix design can solve.","test":"Re-run dose selection for one toxic doublet (for example an ADC plus a checkpoint inhibitor) using a dose-matrix design in 60 patients and compare tolerability and response against the registrational dose.","maturity":"early-clinical","actor":"regulator","cost":"medium","horizonYears":3},"route":"/ideas/idea-tr2-combo-dose-matrix/","neighbours":{"pairing":[{"id":"ild-overlap-caution","kind":"pairing","name":"Caution: DXd ADC + agents with pneumonitis risk","route":"/pairings/ild-overlap-caution/"}],"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/"}],"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/"}],"idea":[{"id":"idea-tr2-qsp-combo-dosing","kind":"idea","name":"Mechanistic computer models to pick combination doses before dosing patients","route":"/ideas/idea-tr2-qsp-combo-dosing/"}]}}