# Find the lowest effective doses of both drugs in a combination, not the highest tolerated

Source: https://onco.cc/ideas/idea-tr2-combo-dose-matrix/  
OnCo record `idea-tr2-combo-dose-matrix` (Idea). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Idea
- Last checked: 2026-09-08
- 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.
- Proposed 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

## Sources

- FDA Project Optimus: https://www.fda.gov/about-fda/oncology-center-excellence/project-optimus

## Connected records

- pairings: [Caution: DXd ADC + agents with pneumonitis risk](https://onco.cc/pairings/ild-overlap-caution/)
- technologies: [Antibody-drug conjugate (ADC)](https://onco.cc/technologies/adc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- bottlenecks: [Too many combinations to test](https://onco.cc/bottlenecks/b-combination-space/), [Wrong doses](https://onco.cc/bottlenecks/b-dose-optimisation/)
- ideas: [Mechanistic computer models to pick combination doses before dosing patients](https://onco.cc/ideas/idea-tr2-qsp-combo-dosing/)

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