Current treatment options for peripheral T-cell lymphomas (PTCLs) in the relapsed/refractory setting are limited and demonstrate modest response rates with rare achievement of complete response (CR).This phase 1/2 study (NCT03052933) investigated the safety and efficacy of copanlisib, a phosphatidylinositol 3-kinase (PI3K)-α/-δ inhibitor, in combination with gemcitabine in 28 patients with relapsed/refractory PTCL. Patients received escalating doses of intravenous copanlisib on days 1, 8, and 15, administered concomitantly with fixed-dose gemcitabine (1,000 mg/m2 on days 1 and 8) in a 28-day cycles.Dose-limiting toxicity was not observed in the dose-escalation phase and 60 mg copanlisib was selected for phase 2 evaluation. Twenty-five patients were enrolled in phase 2 of the study. Frequent grade ≥3 adverse events (AEs) included transient hyperglycemia (57%), neutropenia (45%), thrombocytopenia, (37%), and transient hypertension (19%). However, AEs were manageable, and none were fatal. The overall response rate was 72% with a CR rate of 32%. Median duration of response was 8.2 months, progression-free survival 6.9 months, and median overall survival was not reached. Combination treatment produced a greater CR rate in patients with angioimmunoblastic T-cell lymphoma (AITL) than those with PTCL-not otherwise specified (55.6% vs 15.4%, respectively, P=0.074) and progression-free survival was significantly longer (13.0 vs 5.1 months, respectively, P=0.024). In an exploratory gene mutation analysis of 24 tumor samples, TSC2 mutation was present in 25% of patients and occurred exclusively in responders.Combination copanlisib and gemcitabine is a safe and effective treatment option in relapsed/refractory PTCLs and represents an important new option for therapy in this rare group of patients.