Abstract CT084: A randomized, double-blind phase III study of phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (iNHL): CHRONOS-2

Abstract

Abstract Background: Copanlisib is a novel pan-Class I phosphatidylinositol-3-kinase (PI3K) inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. A phase II study of copanlisib in patients with relapsed/refractory indolent or aggressive lymphoma reported promising activity in the indolent NHL group (Dreyling et al., ENA 2014). The objective of this study is to evaluate the efficacy and safety of copanlisib in patients with indolent B-cell NHL relapsed after or refractory to standard therapy. Methods: Patients meeting the following criteria are eligible for enrollment: histologically confirmed diagnosis of indolent B-cell NHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (MZL; splenic, nodal, or extra-nodal), small lymphocytic lymphoma (SLL) with absolute lymphocyte count < 5 × 109/L at the time of diagnosis and at study entry, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia (LPL/WM), and who have previously received ? 2 prior lines of therapy with rituximab and an alkylating agent and must be refractory to the last treatment with rituximab (refractory defined as progressing or not responding within 6 months of the last course of treatment). Patients will be randomized in 2:1 manner to receive 60 mg of copanlisib administered intravenously on days 1, 8 and 15 of a 28-day cycle or placebo administered on the same schedule until disease progression or intolerable toxicity. Patients in the placebo arm will be allowed to cross-over to receive follow-up treatment with copanlisib, after confirmed disease progression. Dose reductions due to toxicities will be allowed. Radiologic tumor assessment will be performed every 12, 16 or 24 weeks for years 1, 2, and 3, respectively. The primary endpoint will be progression-free survival (PFS). Secondary objectives include overall objective response rate (ORR), duration of response (DOR), time to progression (TTP), complete response rate (CRR), overall survival (OS), time to deterioration as well as time to improvement in disease-related symptoms. Exploratory objectives will include secondary PFS after first progression in placebo-treated patients who cross over to receive copanlisib and time to improvement and the time to deterioration in disease-related symptoms - physical (DRS-P) of at least 3 points as measured by the FLymSI-18 questionnaire. Approximately 189 patients who meet the eligibility criteria will be randomized 2:1, with approximately 126 patients in the copanlisib monotherapy arm and approximately 63 patients in placebo arm. The study is planned to detect a 132% increase in median PFS in copanlisib versus placebo (i.e. to detect a hazard ratio of 0.43), using a stratified log-rank test. This study is currently enrolling patients (NCT02369016). Citation Format: Grzegorz S. Nowakowski, Igor Gorbatchevsky, Florian Hiemeyer, Lisa Cupit, Barrett H. Childs. A randomized, double-blind phase III study of phosphatidylinositol-3 kinase alpha/delta inhibitor copanlisib versus placebo in patients with rituximab-refractory indolent non-Hodgkin's lymphoma (iNHL): CHRONOS-2. [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 CT084.