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Losartan to loosen the stroma of pancreatic cancer before chemotherapy: a phase 3

A cheap blood pressure drug may soften the dense scar tissue around pancreatic tumours so chemotherapy and immune cells can get in. Early trials look encouraging.

Losartan inhibits angiotensin II and TGF-beta-driven fibrosis and, in mouse models, decompresses tumour vessels and improves drug delivery. A single-arm phase 2 (Massachusetts General Hospital) adding losartan to FOLFIRINOX and chemoradiation in locally advanced pancreatic cancer reported a high R0 resection rate, and a randomised phase 2 with added immunotherapy has followed. Losartan is off patent and costs a few dollars a month. The proposal is a publicly funded randomised phase 3 of losartan plus standard neoadjuvant therapy versus standard therapy alone in borderline resectable and locally advanced pancreatic cancer.

Hypothesis
Adding losartan to neoadjuvant chemotherapy increases the R0 resection rate by at least 15 absolute percentage points and improves overall survival in locally advanced pancreatic cancer.
Rationale
Stromal desmoplasia is the defining obstacle in pancreatic cancer and many expensive stroma-targeting agents have failed; losartan's mechanism is supported by imaging and tissue data in patients, and its safety is well known.
What would test it
Randomised phase 3 of roughly 400 patients with R0 resection rate and OS endpoints, with imaging biomarkers of tumour perfusion in a sub-study.
Maturity
early clinical
Who has to act
research
Cost to try
Medium ($1M to $50M)
Years to first evidence
5
Bottlenecks it attacks

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