Despite advances in targeted and cellular therapies, outcomes for patients with Richter's transformation (RT) and transformed non-Hodgkin lymphoma (tNHL) remain dismal. In this study we report safety and efficacy of the combination of the selective, small molecule inhibitor of phosphoinositide-3-kinase copanlisib, with the anti-PD-1 antibody nivolumab from a phase 1 multicenter investigator-sponsored study. Twenty-seven adult patients with relapsed and/or refractory RT or tNHL were treated with escalating doses of copanlisib IV on days 1, 8, and 15 (dose level [DL] 1-45 mg, DL2-60 mg) combined with nivolumab 240 mg IV on days 1 and 15 of a 28-day cycle. Three dose limiting toxicities occurred in 2 patients treated at DL2, hence 45 mg was determined the maximum tolerated dose and utilized in the expansion cohort. The most common treatment-related adverse events were diarrhea and anemia. All patients went off protocol, predominantly due to progressive disease and adverse events (67% and 26% of patients, respectively). Overall response rate (ORR) was 46%. Patients with transformed follicular lymphoma had ORR 67% (2 complete responses), with median progression free survival (PFS) 4.4 months (95% CI: 1.4-12.2). Patients with RT had ORR 31% (2 complete responses) with median PFS 2.0 months (95% CI: 0.7-4.9). Treatment resulted in downregulation of MYC and NFκB pathways in malignant B cells. Responding RT patients exhibited sustained activation of IFN-α and IFN-γ signaling pathways in CD4+ and CD8+ T cells. Overall, treatment with copanlisib and nivolumab demonstrated manageable toxicity and promising clinical efficacy in tNHL patients.