ideasIdea
Find the lowest effective doses of both drugs in a combination, not the highest tolerated
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.
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.
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.
What would test it
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
Who has to act
regulator
Cost to try
Medium ($1M to $50M)
Years to first evidence
3
Bottlenecks it attacks
- Too many combinations to test · There are thousands of possible drug pairs and sequences. Trials can test a few dozen a year.
- Wrong doses · Most drug doses were chosen as the highest a person can tolerate, which is often more than they need.