Abstract CT085: Phase III randomized, double-blind, controlled studies of the PI3K inhibitor copanlisib in combination with rituximab or rituximab-based chemotherapy in subjects with relapsed indolent B-cell non-Hodgkin's lymphoma (iNHL): CHRONOS-3 and CHRONOS-4
Authors: Gerecitano John F. , Zinzani Pier L. , Zheng HongXia , Ito Rodrigo , Tanaka Paula Y. , Mueller Katharina , Yuan Jason , Childs Barrett H. 
Published: July 2016

Abstract
Background: Patients with newly diagnosed iNHL generally receive rituximab (R) either alone or given with an alkylating agent (bendamustine, ie R-B) or a chemotherapy combination containing an alkylating agent (CHOP, ie R-CHOP). Patients progressing after 6 months or more from last treatment are considered to be R-sensitive and candidates for re-treatment, whether with R treatment alone if ineligible for treatment with an alkylating agent or with a different R-chemotherapy treatment compared to initial treatment. Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. Copanlisib has activity as monotherapy in patients with relapsed or refractory iNHL (Dreyling et al., ASH 2014). Therefore, in two separate phase III studies in the second line setting, we seek to evaluate the efficacy and safety of copanlisib in combination with R or R-based chemotherapy; namely CHRONOS-3, copanlisib plus R versus placebo plus R; and CHRONOS-4, copanlisib plus chemotherapy (R-B or R-CHOP) versus chemotherapy alone. The primary endpoints are progression-free survival.
Methods: Patients must have histologically confirmed diagnosis of iNHL (including follicular lymphoma, marginal zone lymphoma (splenic, nodal, or extra-nodal), small lymphocytic lymphoma, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia) and have previously received at least one line of therapy including rituximab and alkylating agents. Patients must be not refractory to rituximab during any prior line of therapy (response &lt;6 months). Patients contraindicated for chemotherapy in the second line setting or with a treatment-free interval after the last rituximab-based treatment of ?12 months are eligible for CHRONOS-3, whereas patients able to receive chemotherapy are eligible for CHRONOS-4.
For CHRONOS-3, patients will be randomized 2:1 to copanlisib (60 mg) or placebo administered intravenously on days 1, 8 and 15 of a 28-day cycle in combination with 375 mg/m2 of rituximab administered on days 1, 8, 15 and 22. Radiologic tumor assessment will be performed every 8, 12, or 24 weeks for years 1, 2, and 3, respectively.
For CHRONOS-4, there will be an initial safety run-in with 45 mg copanlisib with either R-B or R-CHOP and if well tolerated, 60 mg, on days 1, 8, and 15 of a 28-day cycle with B iv 90 mg/m2 days 1 and 2, or on days 1 and 8 of a 21-day cycle with CHOP per standard dosing. After the run-in phase, 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 of R-B or R-CHOP after which they will receive either copanlisib or placebo as monotherapy. Radiologic tumor assessment will be performed every 12 weeks for years 1 and 2, and every 24 weeks years 3-5.
Citation Format: John F. Gerecitano, Pier L. Zinzani, HongXia Zheng, Rodrigo Ito, Paula Y. Tanaka, Katharina Mueller, Jason Yuan, Barrett H. Childs. Phase III randomized, double-blind, controlled studies of the PI3K inhibitor copanlisib in combination with rituximab or rituximab-based chemotherapy in subjects with relapsed indolent B-cell non-Hodgkin's lymphoma (iNHL): CHRONOS-3 and CHRONOS-4. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT085.