Background: The histone transferase EZH2 is the catalytic subunit of the polycomb repressive complex 2 (PRC2) responsible for methylating lysine 27 of histone H3, a mark associated with repressed transcription when trimethylated. Aberrant EZH2 activity has been implicated as an oncogenic driver in NHL. In line with preclinical observations of cell line sensitivity to EPZ-6438 exposure, objective responses have been observed in phase 1 in patients with both wild-type and mutated EZH2 tumors. This phase 2 study is enrolling subjects with either EZH2 mutated or EZH2 wild-type relapsed/refractory diffuse large B-cell lymphoma (DLBCL) or follicular lymphoma (FL) to determine efficacy and safety in 5 separate cohorts determined by centrally confirmed histology, cell of origin (COO) and EZH2 mutation status. Methods: Tazemetostat 800 mg is administered orally twice daily to 5 cohorts: DLBCL with GCB subtype and EZH2 mutations; DLBCL with GCB subtype and wild-type EZH2; DLBCL with non-GCB subtype (including PMBCL); FL with EZH2 mutations; and FL with wild-type EZH2. Archival tumor tissue is analyzed prospectively for EZH2 hot spot mutations Y646X, A682G and A692V using a cobas EZH2 mutation test (in development) and COO as determined by immunohistochemistry using the Hans’ algorithm. Next generation sequencing will be used retrospectively to analyze somatic mutations in a panel of 60 genes commonly mutated in NHL (including EZH2). Key inclusion criteria include: ≥ 18 yrs of age; histologically confirmed DLBCL or FL; relapsed/refractory disease following at least 2 prior treatment regimens including at least 1 alkylator and anti-CD20-based regimen; unable to benefit from autologous hematopoietic stem cell transplantation (DLBCL only); measurable disease; and adequate organ function. The primary endpoint is objective response rate with response assessments performed every 8 weeks. This trial is open to enrollment in France, UK and Australia with additional sites to be opened in Canada, US and EU. (NCT01897571) Clinical trial information: NCT01897571