Background: The standard regimen for frontline treatment of DLBCL is R-CHOP, which results in a complete response (CR) in 76% of patients and a 10-year overall survival (OS) rate of 44%. DLBCL can be classified by immunohistochemistry (IHC) into 2 subgroups: germinal center B-cell-like (GCB) or non-GCB (including the activated B-cell-like and some intermediate molecular subtypes). Prognosis is suggested to be least favorable for non-GCB DLBCL, the subgroup associated with NF-κB pathway activation and chronic active B-cell receptor (BCR) signaling. Ibrutinib inhibits BCR signaling by covalently binding to Bruton's tyrosine kinase. A phase 2 monotherapy study in relapsed/refractory DLBCL showed a 41% overall response rate (ORR) in the non-GCB subgroup (ASH 2012). A phase 1 study combining ibrutinib with R-CHOP showed an ORR of 100% in DLBCL and a favorable safety profile (ASH 2013), suggesting that ibrutinib can be safely combined with R-CHOP. Methods: The PHOENIX study, PCI32765DBL3001, is a phase 3 randomized, placebo-controlled, double-blind study of ibrutinib in combination with R-CHOP versus R-CHOP for the treatment of newly diagnosed non-GCB DLBCL. The study aims to enroll 800 patients (≈400 per arm). All patients will receive standard doses of R-CHOP therapy for 6 or 8 cycles (according to local practice), with ibrutinib 560 mg daily or placebo. The primary objective is to evaluate if the addition of ibrutinib to R-CHOP will result in prolongation of event-free survival. Secondary objectives include progression-free survival, OS, ORR (CR + PR), CR rate, and safety. The study will enroll previously untreated adult patients with the non-GCB subgroup of DLBCL determined by central IHC (Hans algorithm). Key exclusion criteria include central nervous system involvement or primary mediastinal lymphoma, diagnosis or treatment for malignancy other than DLBCL, or history of indolent lymphoma. Approximately 280 sites globally will enroll patients. Enrollment began in Q4 of 2013. Clinical trial information: NCT01855750.