Phase 1b/2 capivasertib AKT (PKB) inhibitor plus immune checkpoint inhibitor in urothelial cancer

This VA Office of Research and Development Phase 1b/2 study tests whether adding capivasertib—an oral small‑molecule AKT (protein kinase B) inhibitor from AstraZeneca—to a patient’s ongoing immune checkpoint inhibitor (ICI) can recapture or deepen anti-tumor activity after ICI resistance in advanced/metastatic/recurrent urothelial carcinoma. The design is open-label with a safety-focused Phase 1b lead-in followed by Phase 2 expansion, with patients continuing their current ICI while capivasertib is added as the investigational intervention. The scientific premise is pathway “re-wiring”: PI3K/AKT signaling can support tumor survival and immune evasion, so AKT blockade may make ICI-resistant disease more immunologically vulnerable. This is particularly relevant because only a minority of patients have durable benefit from PD-1/PD-L1 therapy alone, and many progress after an initial response. Today’s treatment after progression depends heavily on what a patient has already received and on tumor biomarkers, with platinum chemotherapy and targeted options available in selected patients. This study instead asks whether adding AKT blockade can restore activity to ongoing checkpoint inhibition.