A phase II multicenter study evaluating combination immunotherapy with pembrolizumab and peginterferon alfa-2b for advanced cholangiocarcinoma

TPS507 Background: No effective therapy is available for patients (pts) with advanced cholangiocarcinoma (CC) after disease progression on first-line chemotherapy. In Phase I studies, pembrolizumab (pem) showed activity in pts with advanced CC. Interferon alpha-2b was shown to increase tumor immune infiltrates. In order to improve the response rate (RR) of pts with CC to pem, we propose to combine sylatron with pem in an open-label, single-arm, multicenter Phase II study. Methods: To be eligible for study, pts must have CC, manifesting as either intrahepatic, extrahepatic or gallbladder cancer that is unresectable, metastatic, and has either failed to respond to or demonstrated progression on frontline chemotherapy. Forty-four pts will be enrolled on study to receive SC sylatron (200 mg) weekly for 12 weeks, and IV pem (200mg) once every 3 weeks, starting on week 4 (at the same time as the 4th dose of sylatron), until pts experience disease progression or unacceptable toxicity, or withdraw consent. CT scans will be performed every 9 weeks. The primary endpoints are overall RR (ORR) and the safety and tolerability of combined pem and sylatron therapy. Secondary endpoints include OS, PFS, and ORR by irRECIST. An initial 3-week window will exist in which to evaluate the effect of sylatron alone (following prior chemotherapy) on the tumor microenvironment: one biopsy (biopsy 1) will be obtained before the start of sylatron therapy, and another (biopsy 2) after the third but before the fourth injection of sylatron (and the initiation of pem plus sylatron combination therapy). The effect of sylatron on the CC immune microenvironment will be studied by comparing biopsies 1 and 2. Immune microenvironment in pem + sylatron responders will be compared with non-responders. The study will assess whether the addition of sylatron improves the RR of pem from 17% to 35% in pts with advanced CC. Simon’s two-stage optimum design will be used to test the null hypothesis that P ≤ 0.17 vs. the alternative hypothesis that P ≥ 0.350. This study design provides 80% power (one-sided significance level of 0.05). The time-to-event endpoints (PFS, OS) will be estimated using Kaplan-Meier methodology.