Copanlisib is a pan-Class I phosphatidylinositol 3-kinase (PI3K) inhibitor with predominant activity against PI3K-α and PI3K-δ isoforms. Recently, the CHRONOS-1 study demonstrated efficacy of copanlisib monotherapy in patients with relapsed or refractory iNHL with an acceptable safety profile (Dreyling et al., AACR 2017). Two randomized phase III studies are ongoing to evaluate the efficacy and safety of copanlisib in combination with standard therapy: Rituximab [R] either alone or in combination with chemotherapy including an alkylating agent (e.g. bendamustine [R-B] or CHOP [R-CHOP]) in ≥ 2nd line iNHL patients who are relapsed but non-refractory to R or R-based chemotherapy.
Both studies include iNHL patients (including follicular lymphoma, marginal zone lymphoma, small lymphocytic lymphoma, or lymphoplasmacytic lymphoma/Waldenström macroglobulinemia) who have relapsed but are non-refractory after at least 1 prior line of therapy including R. The primary efficacy variable is progression-free survival. In CHRONOS-3, 567 patients unfit/unwilling to receive chemotherapy or who have progressed or relapsed ≥12 months after the last R-based regimen will be randomized 2:1 to copanlisib (60 mg) or placebo administered intravenously on days 1, 8 and 15 of a 28-day cycle until progression in combination with 375 mg/m2 of R days 1, 8, 15 and 22 followed by R bi-monthly up to cycle 9. For CHRONOS-4, a safety run-in phase will be conducted with 45 mg and 60 mg copanlisib with R-B or R-CHOP. Copanlisib will be admnistered (as above) with either B iv 90 mg/m2 days 1 and 2 each 28 days, or on days 1 and 8 of a 21-day cycle with CHOP per standard dosing. After the run-in phase, 520 patients eligible to receive R-B or R-CHOP will be randomized 1:1 to either copanlisib or placebo and receive up to 6 cycles followed by copanlisib or placebo monotherapy. Safety run-in of RB plus copanlisib was assessed by the Data Monitoring Committee and 60 mg was deemed as the copanlisib phase III dose (Gerecitano et al. ICML 2017). The phase III portion of the trial with copanlisib/placebo plus RB is ongoing.
Clinical trial identification
Legal entity responsible for the study
H. Zheng, R. Ito, C. Lu, J. Shen, B.H. Childs, L. Mongay Soler: Employment: Bayer HealthCare Pharmaceuticals Inc. D. Reis: Employment: Bayer SA. All other authors have declared no conflicts of interest.