Background: The current standard of treatment for cholangiocarcinoma (CCA) is gemcitabine and cisplatin that favored both overall survival (OS) and progression free survival (PFS) when compared to gemcitabine alone. The survival however remains less than than 1 year. Predominant activation of PI3K/AKT signaling pathway is seen in cell line and human tumors of CCA promoting tumorigenesis and increased resistance to radiation and chemotherapy. Inhibition of this pathway sensitizes CCA cells to therapies. Copanlisib is a selective and reversible pan-class I PI3K inhibitor. In preclinical studies, copanlisib demonstrated anti-tumor activity in PIK3CA mutated cells particularly in BC. In a Phase I study, 4 treatment naïve patients with CCA showed response, including 1 complete response. The maximum tolerated dose of copanlisib was determined to be 0.8 mg/kg in this study. We hypothesize that the addition of copanlisib to gemcitabine + cisplatin will enhance the efficacy of the current standard regimen in advanced CCA. Tumor tissue will be collected on every patient for PTEN immunohistochemical staining and NGS analysis using a 26-genes panel. Methods: This is a single institution phase II single arm two-stage design trial using copanlisib in combination with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients include those diagnosed with advanced, unresectable CCA that are treatment naïve or should have received adjuvant treatment more than 6 months prior to initiating the trial. Patients will be treated with Cisplatin (25 mg/m²) plus Gemcitabine (1000 mg/m²) and Copanlisib (60 mg) on days 1 and 8 on a 21 days cycle. Primary objective of the study is PFS at 6 months with secondary objectives being response rate, median PFS, OS, safety and tolerability. Accrual began on June 28, 2016, with planned enrollment for 25 patients. 14 eligible patients will be enrolled in the first stage. If 8 or more patients (≥57%) are alive and progression free at 6 months, an additional 11 patients will be enrolled in the second stage. 11 patients have been enrolled until now. After 3 cycles, response and progression will be evaluated using RECIST v1.1. Clinical trial information: NCT02631590