A Phase Ib Trial of Copanlisib in Combination with Venetoclax in Patients with Relapsed or Refractory B-Cell Non-Hodgkin Lymphoma-SAKK 66/18 Trial.

Background: This phase I trial aimed to assess the safety and preliminary activity of the combination of copanlisib with venetoclax in previously treated patients with B-cell non-Hodgkin lymphoma, excluding mantle-cell lymphoma patients. Methods: Intravenous copanlisib on days 1, 8, and 15 and oral venetoclax once daily (starting on day 2 of cycle 1, continuously) were administered in 28-day cycles up to a maximum of 12 cycles. Starting doses were 600 mg of venetoclax and 60 mg of copanlisib. Results: A total of seven patients were enrolled. The first two presented dose-limiting toxicities, five additional patients were treated at a lower dose level (45 mg of copanlisib and 400 mg of venetoclax), with no dose-limiting toxicities observed among three evaluable patients. The most frequent treatment-related adverse event of grade 3 or higher was neutropenia (n = 3), followed by thrombocytopenia (n = 2) and hypertension (n = 2). Four treatment-related serious adverse events occurred, including grade 3 febrile neutropenia in one patient and respiratory infections in three patients. Two patients had complete responses, and two had partial responses. Transcriptomic analysis of lymphoma samples showed enrichment of genes coding for proteins involved in B-cell receptor signaling in responding patients. The study was terminated prematurely due to a decision by the pharmaceutical company. Conclusions: Due to the limited sample size, no definite conclusions regarding safety or activity of the combination can be drawn. The two drugs could not be combined at their respective single-agent doses. Responses were observed in heavily pretreated patients. Transcriptomic analyses suggested a possible association between response and B-cell receptor signaling, which warrants further investigation.