Abstract CT221: CHRONOS-3: A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of phosphatidylinositol-3 kinase (PI3K) alpha/delta inhibitor copanlisib in combination with rituximab in patients with relapsed indolent B-c
Authors: Zinzani Pier Luigi , Gerecitano John F. , Giurescu Marius , Ito Rodrigo , Mueller Katharina , Childs Barrett H. 
Published: August 2015

Abstract
Background: Copanlisib is a novel pan-Class I PI3K inhibitor with potent preclinical inhibitory activity against both PI3K-δ and PI3K-α isoforms. In a phase II study of copanlisib monotherapy in patients with relapsed/refractory indolent or aggressive lymphoma, an overall response rate of 53% was seen in patients with iNHL (Dreyling et al., ENA 2014). Rituximab in combination with chemotherapy is standard first-line therapy for indolent iNHL and is a therapeutic option for relapsed patients who cannot tolerate chemotherapy or who had a long response following the last rituximab-based therapy. The objective of this study is to evaluate the efficacy and safety of copanlisib in combination with rituximab versus placebo plus rituximab in patients with iNHL who relapsed after one or more lines of therapy, including rituximab and alkylating agents, and who are either unfit for chemotherapy or had a treatment-free interval of at least 12 months following last rituximab-based therapy.
Methods: Patients must meet the following criteria: histologically confirmed diagnosis of iNHL, with follicular lymphoma (FL) grade 1-2-3a, marginal zone lymphoma (splenic, nodal, or extra-nodal), small lymphocytic lymphoma, or lymphoplasmacytoid lymphoma/Waldenström macroglobulinemia, and who 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). Approximately 567 patients (435 FL patients and 132 other iNHL patients) will be randomized 2:1 and stratified according to the four factors: NHL histology (FL vs. other iNHL), treatment-free interval after rituximab treatment vs. contraindication for chemotherapy, bulky disease (yes vs. no), and previous treatment with PI3K inhibitors (yes vs. no). Patients will receive 60 mg of copanlisib 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. The primary endpoint will be progression-free survival (PFS) as assessed by central review. Secondary objectives include objective tumor response rate, duration of response, complete response rate, time to progression, overall survival, 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. The study is planned to detect a 50% increase in median PFS in copanlisib plus rituximab arm versus the placebo plus rituximab arm (hazard ratio of 0.6667) within the FL patients, using a stratified log-rank test.
Citation Format: Pier Luigi Zinzani, John F. Gerecitano, Marius Giurescu, Rodrigo Ito, Katharina Mueller, Barrett H. Childs. CHRONOS-3: A phase III, randomized, double-blind, placebo-controlled study evaluating the efficacy and safety of phosphatidylinositol-3 kinase (PI3K) alpha/delta inhibitor copanlisib in combination with rituximab in patients with relapsed indolent B-c [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT221. doi:10.1158/1538-7445.AM2015-CT221