Phase II study of copanlisib in combination with gemcitabine and cisplatin in advanced cholangiocarcinoma

556 Background: First line therapy for advanced cholangiocarcinoma (CCA) is currently gemcitabine and cisplatin. However, survival rarely exceeds one year with this regimen. PI3K/AKT activation has been shown to increase resistance to chemotherapy in CCA; therefore, inhibiting this pathway may improve chemotherapy’s efficacy. This phase II study evaluated the safety and efficacy of copanlisib, a potent and reversible pan-class I PI3K inhibitor, with gemcitabine and cisplatin in advanced CCA. Methods: Between July 2016 and April 2019, pts with histologically confirmed advanced/unresectable CCA received cisplatin (25 mg/m2), gemcitabine (1000mg/m2), and copanlisib 60mg on day 1 and 8, every 21 days as first line treatment. The primary endpoint was PFS at 6 months. Secondary endpoints were RR, median OS and PFS, and safety profile. A single-arm Simon’s two-stage minimax design with one-sided 10% type I error and 80% power was used. Based on ABC-01 and ABC-02 studies, PFS6 for gemcitabine and cisplatin were 57.1% and 59.3%, respectively. Therefore, PFS6 of 57% was considered not to warrant further study and ≥72% to warrant further investigation. Results: Twenty-four pts received at least one dose of the study drug (62.5% female, median age 64 years), with 70.8% intrahepatic, 16.7% extrahepatic, and 12.5% gallbladder cancer. For all pts, median OS was 13.9 months (95% CI: 6.8-17.9) and median PFS was 6.2 months (95% CI: 1.3-11.1). PFS at 6 and 12 months was 57.0% and 42.2%, and 6 and 12-month OS was 73.9% and 53.2%, respectively. Only 19 pts were considered evaluable for RR. Five pts were either lost to follow up, withdrew consent, or died before a second scan was done. Six pts achieved PR (31.5%) and 11 (57.9%) had SD. Grade 3 or higher adverse events (AE) occurred in 75% of pts. The most common grade 3/4 AEs were decreased neutrophil count (40%) and increased lipase (20%). Treated related AEs led to drug discontinuation for 3 pts (12.5%) and dose modification for 7 pts (29.2%). Conclusions: Gemcitabine, cisplatin, and copanlisib in combination did not meet the primary endpoint of 6-month PFS. However, additional correlative work is ongoing to identify a possible biomarker for copanlisib. Clinical trial information: NCT02631590.