ideasIdea
Two-week pre-operative windows to compare combination biology head to head
Give patients a short course of one of several drug pairs in the gap before surgery and compare what happened inside the tumours. It is the fastest human test of whether a combination does anything.
Window-of-opportunity studies give a drug for 1 to 4 weeks between diagnosis and surgery and compare pre- and post-treatment tissue. Multi-arm windows randomising to several combinations with pharmacodynamic endpoints (proliferation, immune infiltration, target pathway suppression) can rank combinations by biological effect in under a year, before any efficacy trial.
Hypothesis
Combinations ranked highest by pharmacodynamic effect in a multi-arm window study will have higher pathological response rates when taken forward into neoadjuvant trials than lower-ranked ones.
Rationale
Window studies with Ki67 changed endocrine therapy development in breast cancer (POETIC). Multi-arm windows with modern spatial and single-cell readouts can compare combinations mechanistically.
What would test it
A four-arm window study in resectable colorectal or head and neck cancer with paired biopsies, spatial transcriptomics and a pre-specified pharmacodynamic ranking; follow the top arm into a neoadjuvant trial.
Maturity
early clinical
Who has to act
research
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.
- Preclinical models that do not predict people · Nine in ten cancer drugs that work in mice fail in humans. Our models are the reason.