Background: Tazemetostat is a potent and selective inhibitor of the histone methyltransferase enhancer of zeste-homolog 2 (EZH2), the catalytic subunit of the polycomb repressive complex 2 (PRC2). EZH2 is responsible for trimethylation of lysine 27 on histone H3, which results in chromatin remodelling and repressed transcription. Aberrant EZH2 activity has been implicated as an oncogenic driver in non-Hodgkin lymphoma and other malignancies. The SWI/SNF complex also remodels chromatin, activates transcription and acts in opposition to PRC2. Oncogenesis from mutation and/or loss of the SWI/SNF subunit INI1 in cancers such as malignant rhabdoid tumor (MRT) or SMARCA4 loss in ovarian “small cell carcinoma, hypercalcemic type” is associated with anticancer activity of EZH2 inhibition in preclinical models. This has translated into objective responses of promising durability in subjects (subjs) whose solid tumors exhibited either INI1 or SMARCA4 loss in the tazemetostat phase I adult study. Methods: This is a phase II, multi-center, open-label, single arm study of tazemetostat (800 mg dosed orally twice daily) in subjs whose tumors harbor mutation and/or loss of INI1 or SMARCA4. Subjs ≥ 16 years of age who have measurable disease enroll into 1 of 3 cohorts: Cohort 1 -INI1 or SMARCA4 negative rhabdoid tumors (MRT, atypical teratoid rhabdoid tumor, rhabdoid tumor of the kidney, MRT of ovary), Cohort 2 - relapsed/refractory synovial sarcoma, and Cohort 3 -other INI1 negative tumors including epithelioid sarcoma, renal medullary carcinoma, myoepithelial carcinoma, and others. Each cohort will enroll up to 30 subjs using a 2-stage Green-Dahlberg design. Tumor response is evaluated every 8 weeks using RANO or RECIST 1.1. Primary endpoints include overall response rate (ORR) (Cohorts 1 and 3) and progression-free survival (PFS) at Week 16 (Cohort 2). Secondary endpoints include ORR (Cohort 2), PFS and overall survival, duration of response, safety/tolerability, population PK and biomarkers of response. The first subj was dosed in December 2015 in the US with additional sites to be opened in Canada, the EU and Australia (NCT02601950). Clinical trial information: NCT02601950