Background: Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant PI3K-α and PI3K-δ activity recently approved in the US for treatment of relapsed follicular lymphoma. In the CHRONOS-1 trial, treatment of patients with relapsed or refractory indolent lymphoma resulted in an objective response rate of 59% (JCO 35:2169-2178, 2017). The most prominent adverse event following intravenous administration of copanlisib is transient hyperglycemia, thought to be due to impaired glucose uptake associated with PI3K-α isoform inhibition. We focus here on the diabetic mellitus (DM) patients enrolled in the phase II study. Methods: Indolent B-cell lymphoma patients with well-controlled DM were eligible and required to have fasting glucose < 160 mg/dL prior to each infusion. Patients received copanlisib 60 mg as a 1-hour infusion on days 1, 8, and 15 of a 28-day cycle. On C1D1, glucose was measured at pre-dose, and 3, 5, 6 and 8 hours after infusion. DM patients were instructed to check blood glucose at home 3x per day for 72 hrs after infusion until fasting glucose was < 160 mg/dL or non-fasting glucose was < 200 mg/dL. Results: Twenty patients with DM out of a total of 142 patients were enrolled; 17 patients with a history of DM, 1 with history of impaired glucose tolerance, and 2 diagnosed at screening. Comparing non-DM patients (n = 122) to DM patients, all-grade (G) hyperglycemia was 43% vs 85%, G3 31% vs 40%, and G4 2% vs 35%. In routine laboratory glucose assessments, G3 events were reported in 39% vs 70% and G4 in 2% vs 30%, non-DM vs DM respectively. Objective responses were observed in 9 of 20 patients (45%; 2 non-evaluable), including one complete response and stable disease in 8 patients (40%). Of note, 6 responders were on treatment > 300 days (or > 30 infusions), with 5 of these patients remaining on treatment at data cut-off. Conclusions: These results strongly suggest that the transient hyperglycemia seen with IV administration of copanlisib is also manageable in indolent lymphoma patients with DM as a comorbidity and should thus not preclude treatment of such patients. Clinical trial information: NCT01660451