Efficacy and Safety of CAP7.1 as Second-Line Treatment for Advanced Biliary Tract Cancers: Data from a Randomised Phase II Study

SIMPLE SUMMARY: Advanced biliary tract cancer is difficult to treat, and 5-year survival is less than 5% for tumours that cannot be removed by surgery. CAP7.1 is a drug being investigated for biliary tract cancer. This study assessed treatment with CAP7.1 in patients with advanced biliary tract cancer whose disease had progressed despite receiving other treatments. One group of patients received CAP7.1 together with best supportive care (BSC) and another group received BSC from their physician. The patients receiving BSC were subsequently given CAP7.1 if their disease was seen to progress. Disease control in those receiving CAP7.1 was better than that observed in patients who received BSC, with an associated greater time to disease progression. Side effects were as expected for this type of anti-cancer drug, related to dose of CAP7.1, and manageable. CAP7.1 may offer a new treatment option for biliary tract cancer and should undergo further clinical investigation. ABSTRACT: CAP7.1 is a novel topoisomerase II inhibitor, converted to active etoposide via carboxylesterase 2 (CES2), with signals of efficacy in treatment-refractory solid tumours. In a Phase II trial, 27 patients with advanced biliary tract cancers (BTC) were randomised 1:1 to CAP7.1 plus best supportive care (BSC), or BSC alone, with crossover to CAP7.1 upon disease progression. The primary objective was disease control rate (DCR) following 28-day cycles of CAP7.1 (200/150 mg/m(2); iv), or BSC until progression. Secondary objectives included progression-free survival (PFS), time-to-treatment failure (TTF), overall survival (OS) and safety. Fourteen patients received CAP7.1 and 13 BSC. DCR favoured CAP7.1 vs. BSC (50% vs. 20%; treatment difference: 30%, 95%CI −18.44, 69.22, full analysis set [FAS]), with disease progression in 40% vs. 70%, respectively. Significantly longer median PFS was achieved for CAP7.1 vs. BSC: 66 vs. 39 days, respectively (hazard ratio [HR] 0.31; 95%CI 0.11, 0.86; p = 0.009; FAS). Similar trends were observed for TTF and OS. CES2-positive patients had longer median PFS (158 vs. 56 days) and OS (228 vs. 82 days) vs. CES2-negative patients. Adverse events were predictable, dose-dependent and consistent with those previously observed with etoposide. These efficacy and safety findings in second-line BTC warrant further clinical investigation of CAP7.1.