SYMPHONY-2, A Trial to Examine Combination of Tazemetostat With Rituximab in Subjects With Relapsed/Refractory Follicular Lymphoma

Inclusion Criteria: 1. Men and women of 18 years of age and older 2. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol 3. Eastern Cooperative Oncology Group (ECOG) score of 0 \</=, 1 or 2 4. Life expectancy (in the opinion of the investigator) of \>3 months before enrollment 5. Have histologically confirmed FL, Grade 1 to 3a. Subjects may have R/R disease following at least 2 standard prior systemic treatment regimens where at least 1 anti- CD20-based regimen was used 6. Treatment recommended in accordance with the Groupe d'Etude des Lymphomes b Folliculaires (GELF) criteria 7. Meet the following laboratory parameters: 1. Absolute neutrophil count (ANC) ≥ 750 cells/μL (0.75 x 109/L), or ≥ 500 cells/μL (0.50 x 109/L) in subjects with documented bone marrow involvement 2. Platelet count ≥ 50,000 cells/μL (50 x 109/L), or ≥ 30,000 cells/μL (30 x 109/L) in subjects with documented bone marrow involvement, and without transfusion dependence 3. Hemoglobin ≥ 8 g/dL 4. Serum alanine aminotransferase (AST) and aspartate aminotransferase (ALT) ≤ Incl3.0 x ULN, unless related to disease involvement 5. Total bilirubin ≤ 1.5 x ULN, unless due to disease involvement, Gilbert's syndrome, or hemolytic anemia 6. Estimated creatinine clearance (ie, estimated glomerular filtration rate \[eGFR\] using Cockcroft-Gault) ≥ 40 mL/min 8. At least one bi-dimensionally measurable nodal lesion \> 1.5 cm in its longest diameter by computed tomography (CT) scan or magnetic resonance imaging (MRI) 9. Any clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy), except for alopecia, either resolved to ≤ Grade 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 or is clinically stable and no longer clinically significant 10. Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection 11. Negative test results for hepatitis C virus (HCV) and human immunodeficiency virus (HIV). 12. Females of childbearing potential (FCBP) must have a negative serum pregnancy test (beta-human chorionic gonadotropin \[β-hCG\] test with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening and within 24 hours prior to the first dose of study drug. 13. FCBP must either practice complete abstinence or agree to use a highly effective method of contraception beginning at least 28 days prior to the first dose of study drug, during study treatment (including during dose interruptions), for 6 months after tazemetostat discontinuation, and for 12 months after rituximab discontinuation. . 14. Male subjects must have had a successful vasectomy (with medically confirmed azoospermia) OR must either practice complete abstinence or agree to use a latex or synthetic condom during sexual contact with a FCBP from the first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation. Exclusion Criteria: 1. Prior exposure to Tazemetostat or other inhibitor(s) of EZH2 2. Grade 2b, mixed histology, or transformed FL 3. Treatment with any of the following anticancer therapies within the timeframe of a specific treatment prior to first dose of study drug: 1. Cytotoxic chemotherapy within 21 days 2. Noncytotoxic chemotherapy (e.g. small molecule inhibitor) within 14 days 3. Nitrosoureas within 6 weeks 4. Prior immunotherapy within 4 weeks 5. Radiotherapy- within 6 weeks from prior radioisotope therapy; within 12 weeks from 50% pelvic or total body irradiation 6. Any investigational treatment within 4 weeks or at least 5 half lives, whichever is shorter 4. History of solid organ transplant 5. Major surgery within 4 weeks of the start of study treatment 6. Thrombocytopenia, neutropenia, or anemia of Grade \> 3 (per CTCAE v5.0 criteria) or any prior history of myeloid malignancies, including MDS/AML or MPN 7. Prior history of T-LBL/T-ALL 8. Unwillingness to exclude grapefruit juice-containing products, Seville oranges, and grapefruits from the diet and/ or consumed within 1 week of the first dose of study drug 9. Subjects taking medications that are known strong cytochrome P450 (CYP)3A inhibitors and strong or moderate CYP3A inducers (including St. John's wort) 10. Any uncontrolled illness 11. History of clinically significant cardiovascular abnormalities 12. History of clinically significant gastrointestinal (GI) conditions 13. Other diagnosis of cancer that is likely to require treatment in the next 2 years 14. Females who are pregnant or lactating/breastfeeding 15. Received a live virus vaccination within 28 days of first dose of rituximab 16. Concurrent participation in a separate investigational therapeutic study 17. Psychiatric illness/social situations that would interfere with study compliance