Background: DKK1 is a secreted modulator of Wnt signaling often expressed in tumors, including BTC. DKK1 expression in BTC is associated with advanced stage and shorter survival. Depletion of DKK1 has efficacy in BTC xenograft models, inhibits cell invasion, and decreases MMP9 and VEGF-C expression, known promoters of metastasis and angiogenesis. D is a humanized monoclonal antibody against DKK1. This study evaluated the safety and efficacy of D in combination with GC in pts with advanced BTC. Methods: In Part A, pts received D at either 150 or 300 mg (and 300 mg D in Part B expansion) with 1000 mg/m2 G and 25 mg/m2 C on days 1 and 8 of each 21-day cycle. Response assessed every 2 cycles using RECISTv1.1. Results: 27 pts were enrolled; 4 dosed at 150 mg and 23 dosed at 300 mg. Median age: 65; Female: 74%; White: 85%. Gallbladder cancer 37%, intrahepatic cholangiocarcinoma 59%. 3 pts had prior G: 2 pts with adjuvant G; 1 pt with 2 prior regimens. Median number of cycles with D: 8 (range 1, 17). Median duration on study 6.8 mos; 8 pts still on therapy. No dose limiting toxicities or D-related serious adverse events have been observed. 24 pts (89%) had grade 3/4 treatment emergent adverse events (TEAEs); events in ≥ 3 pts include: neutropenia (n = 19), leukopenia (n = 9), thrombocytopenia (n = 9), hyperbilirubinemia (n = 6), anemia (n = 5), AST/ALT elevation (n = 4), and ALP elevation, bacteremia, hypertension, and hyponatremia (n = 3 each). The MTD of D + GC was 300 mg. At the MTD; 7 pts had a confirmed partial response (PR), 14 pts had stable disease > 6 weeks, and 1 pt had progressive disease. Both overall and MTD median PFS were 9.4 mos (95% CI 4.6, NE); median overall survival and duration of response were not reached. Conclusions: The addition of D (300 mg) to GC demonstrated a preliminary PFS of 9.4 mos and disease control rate of 96% with a 32% PR rate in pts with BTC. D + GC is well tolerated with no new emerging safety trends. Clinical trial information: NCT02375880