Background: Follicular lymphoma (FL) and marginal zone lymphoma (MZL) are indolent non-Hodgkin lymphomas (iNHL) and account for approximately 22% and 10%, respectively, of all NHLs. Although patients (pts) often respond to initial therapy, most relapse and suffer substantial morbidity and mortality related to persistence/recurrence of disease. For pts with relapsed iNHL, the most common chemoimmunotherapy regimens are BR and R-CHOP; however, outcomes in the relapsed setting remain suboptimal. Ibrutinib is an oral Bruton’s tyrosine kinase (BTK) inhibitor that has demonstrated activity in a phase 1 study in pts with various B-cell malignancies, including iNHL. A phase 2 monotherapy study in chemoimmunotherapy-resistant FL is ongoing. Other studies have demonstrated that ibrutinib can be safely combined with BR or R-CHOP. Based on these observations, this phase 3 trial has been designed to investigate the combination of ibrutinib with BR or R-CHOP in pts with iNHL. Methods: The SELENE study, PCI32765FLR3001, is a randomized, double-blind, placebo-controlled, multicenter phase 3 study of ibrutinib combined with either BR or R-CHOP for previously treated FL or MZL. The study aims to enroll approximately 400 pts with disease that has relapsed, or was refractory to, prior chemoimmunotherapy. All pts will receive 6 cycles of BR or R-CHOP (based on prior treatment) and either daily oral 560 mg ibrutinib or placebo continued up to progression. The primary objective is to evaluate whether the addition of ibrutinib to BR or R-CHOP will prolong progression-free survival; secondary objectives were evaluation of OS, CR rate, ORR, patient-reported lymphoma symptoms, and safety. Exploratory objectives include minimal residual disease negative rate in FL pts, patient-reported outcomes related to general health status, and the pharmacokinetics of ibrutinib. Approximately 145 sites in Europe, Asia, Australia, USA and South America will participate. Enrollment began in Q1 2014. As of January 8, 2015, 163 pts have been randomized across 76 sites in 16 countries. Clinical trial information: NCT01974440