Background: Follicular lymphoma (FL) is the second most common non-Hodgkin lymphoma (NHL) and comprises approximately 22% of all NHL cases. Most patients treated eventually relapse and subsequent responses and duration of responses become shorter. Patients ultimately become resistant to chemoimmunotherapy and repeated treatment-related toxicity commonly outweighs the benefit of treatment. Ibrutinib is a potent inhibitor of BTK (downstream of the B-cell receptor, BCR) that binds covalently to Cys-481 in the active site, abrogating intrinsic survival pathways (eg, ERK1/2, NF-kB, AKT) as well as survival signals from the microenvironment (eg, TNF family members: BAFF, CD40L; cytokines from T-cells: IL4, IL6, IL10, TNFα). Irish et al (2010) have also shown that up to 60% of FL patients display BCR signaling addiction. Early indications from study PCYC-04753 suggest activity of the BTK inhibitor ibrutinib in FL. Three CR and 3 PR were observed in 11 patients at a dose of 2.5 mg/kg or higher that achieved full BTK occupancy (Fowler, ASH 2012). Methods: The DAWN study, PCI-32765FLR2002, is a phase II, single-arm study of ibrutinib in refractory FL. The study aims to enroll 110 patients with chemoimmunotherapy-resistant FL. Patients will receive an oral daily dose of 560 mg ibrutinib. Patients must have been treated with at least 2 prior lines of therapy, at least 1 rituximab-containing combination chemotherapy regimen, and the last prior line of therapy included an anti-CD20 monoclonal antibody-containing chemotherapy regimen. The primary objective of the study is to evaluate the ORR (CR + PR), with secondary objectives of duration of response, progression-free survival, overall survival, and safety. To better understand the mechanism of action of ibrutinib, blood and tumor samples will be collected and, where feasible, characterized by GEP, SMA, IHC, or other technology as applicable. These evaluations aim to identify biomarkers associated with response or resistance to ibrutinib in subjects with FL and results may assist in the development of this drug in this and potentially other indications. Approximately 64 sites in the US and Europe will enroll patients. Enrollment began in 1Q of 2013. Clinical trial information: NCT01779791.