Phase 1 dose escalation study of copanlisib (BAY 80-6946) in combination with gemcitabine or gemcitabine-cisplatin in advanced cancer patients.

2610 Background: Copanlisib (BAY 80–6946) is a potent and reversible pan-class I PI3K inhibitor with significant activity against PI3K-δ and PI3K-α isoforms. We report the results of an open-label, Phase 1 study of copanlisib in combination with gemcitabine alone and with gemcitabine plus cisplatin in advanced cancer patients. Methods: On Treatment A, patients received gemcitabine at 1000 mg/m2 IV and 2 dose levels of copanlisib 0.6 mg /kg or 0.8 mg/kg IV on days 1, 8 and 15 of a 28-day cycle to determine whether the single agent maximum tolerated dose (MTD) of copanlisib (0.8mg/kg) was tolerable with the chemotherapy. On Treatment B, patients received cisplatin at 25 mg/m2 IV, gemcitabine 1000 mg/m2 IV and copanlisib IV on days 1 and 8 of a 21-day cycle at the MTD determined in Treatment A. The primary objective was to determine the safety, tolerability, and MTD of copanlisib in combination with gemcitabine and gemcitabine-cisplatin. Results: A total of 29 patients were treated with copanlisib. In Treatment A, 8 patients received copanlisib at 0.6 mg/kg and 8 at 0.8 mg/kg in combination with gemcitabine. There were no reported dose-limiting toxicities (DLTs) and the 0.8 mg/kg dose was the maximum tested dose. In Treatment B, 13 patients received copanlisib at 0.8 mg/kg with gemcitabine-cisplatin and no DLTs were observed. The most frequently observed drug-related adverse events reported in >20% of the patients were hyperglycemia, nausea, diarrhea, anemia, and fatigue. There were no treatment-related deaths. Pharmacokinetic evaluations showed comparable results across treatment groups indicating the absence of relevant PK interactions. Of the 2 patients enrolled in treatment schedule B with biliary tract cancer (BTC), one achieved a complete response (CR) and one a partial response (PR) according to RECIST criteria. An expansion cohort in patients with BTC with treatment schedule B is now ongoing, and one PR has been observed to date. Conclusions: The combination of copanlisib with gemcitabine alone or with gemcitabine plus cisplatin is generally well tolerated, with an early efficacy signal seen in patients with BTC. Clinical trial information: NCT01460537.