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Dreyling, M.; Morschhauser, F.; Bouabdallah, K.; Bron, D.; Cunningham, D.; Assouline, S. E.; Verhoef, G.; Linton, K.; Thieblemont, C.; Vitolo, U.; Hiemeyer, F.; Giurescu, M.; Garcia-Vargas, J.; Gorbatchevsky, I.; Liu, L.; Koechert, K.; Pena, C.; Neves, M.; Childs, B. H.; Zinzani, P. L. (2017): Phase II study of copanlisib, a PI3K inhibitor, in relapsed or refractory, indolent or aggressive lymphoma. In: Annals of Oncology, Vol. 28, No. 9: pp. 2169-2178
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Background: Copanlisib is a pan-class I phosphatidylinositol 3-kinase inhibitor with predominant activity against the a-and delta-isoforms. Patients and methods: This phase II study evaluated the response rate of copanlisib administered intravenously on days 1, 8, and 15 of a 28-day cycle, in patients with indolent or aggressive malignant lymphoma. Archival tumor tissues were used for immunohistochemistry, gene-expression profiling, and mutation analysis. Results: Thirty-three patients with indolent lymphoma and 51 with aggressive lymphoma received copanlisib. Follicular lymphoma (48.5%) and peripheral T-cell lymphoma (33.3%) were the most common histologic subtypes. Most patients (78.6%) had received prior rituximab and 54.8% were rituximab-refractory. Median duration of treatment was 23 and 8 weeks in the indolent and aggressive cohorts, respectively (overall range 2-138). Eighty patients were evaluated for efficacy. The objective response rate was 43.7% (14/32) in the indolent cohort and 27.1% (13/48) in the aggressive cohort;median progression-free survival was 294 days (range 0-874) and 70 days (range 0-897), respectively;median duration of response was 390 days (range 0-825) and 166 days (range 0-786), respectively. Common adverse events included hyperglycemia (57.1%;grade >= 3, 23.8%), hypertension (54.8%;grade >= 3, 40.5%), and diarrhea (40.5%;grade >= 3, 4.8%), all generally manageable. Neutropenia occurred in 28.6% of patients (grade 4, 11.9%). Molecular analyses showed enhanced antitumor activity in tumors with upregulated phosphatidylinositol 3-kinase pathway gene expression. Conclusion: Intravenous copanlisib demonstrated promising efficacy and manageable toxicity in heavily pretreated patients with various subtypes of indolent and aggressive malignant lymphoma. Subtype-specific studies of copanlisib in patients with follicular, peripheral T-cell, and mantle cell lymphomas are ongoing.