EZH-302 (SYMPHONY-1)

Adults ≥18 with histologically confirmed FL G1-3A, R/R after ≥1 prior systemic therapy, measurable disease, ECOG 0-2, adequate marrow/liver/renal/coagulation function, required virology criteria, and contraception/pregnancy-prevention compliance.

Patients must meet ALL of the following inclusion criteria to be eligible to enroll in this study: 1. Have voluntarily agreed to provide written informed consent and demonstrated willingness and ability to comply with all aspects of the protocol. 2. Males or females are ≥18 years of age at the time of providing voluntary written informed consent. 3. Life expectancy ≥3 months before enrollment. 4. Meet requirements for hepatitis and human immunodeficiency virus (HIV) infection as follows: - Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection. Note: Patients whose HBV infection status could not be determined by serologic test results have to be negative for HBV-DNA by PCR to be eligible for study participation. Patients seropositive for HBV with undetectable HBV-DNA by PCR are permitted with appropriate antiviral prophylaxis. - Negative test results for hepatitis C virus (HCV). Note: Patients who are positive for HCV antibody must be negative for HCV-RNA by PCR to be eligible for study participation. - If HIV positive, HIV infection is controlled. 5. Have histologically confirmed FL, Grades 1 to 3A. 6. Must have been previously treated with at least 1 prior systemic chemotherapy, immunotherapy, or chemoimmunotherapy: a. Systemic therapy includes treatments such as: i. Rituximab monotherapy ii. Chemotherapy given with or without rituximab iii. Radioimmunoconjugates such as 90Y-ibritumomab tiuxetan and 131I-tositumomab. b. Systemic therapy does not include, for example: i. Local involved field radiotherapy for limited stage disease ii. Helicobacter pylori eradication c. Prior investigational therapies will be allowed provided the patient has received at least 1 prior systemic therapy as discussed in Inclusion Criterion #6a. d. Prior autologous/allogeneic hematopoietic stem cell transplant (HSCT) will be allowed. e. Prior chimeric antigen receptor T-cell therapy (CAR-T) will be allowed. 7. Must have documented relapsed, refractory, or PD after treatment with systemic therapy (refractory defined as less than partial response [PR] or disease progression <6 months after last dose). 8. Have measurable disease as defined by the Lugano Classification. 9. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2. 10. Within 7 days prior to randomization, all clinically significant toxicity related to a prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapy) must have either resolved to Grade 1 per NCI CTCAE Version 5.0 OR are clinically stable and no longer clinically significant. 11. Have provided sufficient tumor tissue block or unstained slides for EZH2 mutation testing in all patients to allow for stratification through the IWRS. 12. Time between prior anticancer therapy and first dose of tazemetostat as follows: a. Cytotoxic chemotherapy – At least 21 days. b. Noncytotoxic chemotherapy (eg, small molecule inhibitor) – At least 14 days. c. Nitrosoureas – At least 6 weeks. d. Monoclonal and/or bispecific antibodies or CAR T – At least 28 days. e. Radiotherapy – At least 6 weeks from prior radioisotope therapy; at least 12 weeks from 50% pelvic or total body irradiation. 13. Adequate renal function defined as calculated creatinine clearance ≥30 mL/minute per the Cockcroft and Gault formula. 14. Adequate bone marrow function: a. ANC ≥1,000/mm3 (≥1.0 × 10^9/L) if no lymphoma infiltration OR ANC ≥750/mm3 (≥0.75 × 10^9/L) with bone marrow infiltration; without growth factor support for at least 14 days. b. Platelets ≥75,000/mm3 (≥75 × 10^9/L), evaluated at least 7 days after last platelet transfusion. c. Hemoglobin ≥9.0 g/dL (transfusion allowed). 15. Adequate liver function: a. Total bilirubin ≤1.5 × ULN except unconjugated hyperbilirubinemia of Gilbert’s syndrome. b. ALP (in absence of bone disease), ALT, AST ≤3 × ULN (≤5 × ULN if liver infiltration). 16. INR ≤1.5 × ULN and aPTT ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). 17. Females of childbearing potential (FCBP) must have negative pregnancy testing at screening and pre-dose as specified. 18. FCBP must either practice complete abstinence or agree to two reliable contraceptive methods simultaneously (one highly effective + one additional effective), starting ≥28 days prior to first dose, during treatment, and for 12 months after discontinuation; must refrain from breastfeeding for 12 months after last dose. 19. All enrolled patients must be registered in applicable lenalidomide pregnancy prevention program and comply with required pregnancy testing schedule. 20. Male patients must either practice complete abstinence or agree to condom use during sexual contact with pregnant female or FCBP from first dose, during treatment, and for 3 months after discontinuation; must not donate semen/sperm during this period.

Exclude prior EZH2 inhibitor or lenalidomide exposure, FL grade 3b/transformed disease, severe cytopenias/myeloid malignancy history, CNS disease, major CV risks, active significant infections (HBV/HCV/HIV), recent major surgery, pregnancy/lactation, and other major comorbidity/confounders.

Patients who meet ANY of the following exclusion criteria are NOT eligible to enroll in this study: 1. Prior exposure to tazemetostat or other inhibitor(s) of EZH2. 2. Prior exposure to lenalidomide or drugs of the same class. 3. Grade 3b, mixed histology, or FL that has histologically transformed to DLBCL (patients transformed from DLBCL to FL may be enrolled). 4. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (CTCAE v5.0) or any prior history of myeloid malignancies, including MDS/AML or MPN. 5. Has a prior history of T-LBL/T-ALL or B-ALL. 6. Patients with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases. 7. Patients taking medications that are known strong CYP3A inhibitors and strong or moderate CYP3A inducers (including St. John’s wort). 8. Are unwilling to exclude grapefruit juice, Seville oranges, and grapefruits from the diet and/or consumed within 1 week of first dose and for study duration. 9. Major surgery within 4 weeks before first dose. 10. Are unable to take oral medication or have malabsorption syndrome or other uncontrolled GI condition that might impair tazemetostat bioavailability. 11. Significant cardiovascular impairment: CHF > NYHA Class II, uncontrolled HTN, unstable angina, MI or stroke within 6 months of first dose, or cardiac ventricular arrhythmia. 12. QTcF ≥480 msec at screening or history of long QT syndrome. 13. Venous thrombosis or pulmonary embolism within last 3 months before starting tazemetostat. 14. Have an active infection requiring systemic therapy. 15. Known hypersensitivity to any component of tazemetostat or lenalidomide; known severe hypersensitivity to any component of rituximab requiring hospitalization or resuscitation. 17. Active viral infection with or seropositive for HBV: HBsAg positive OR HBsAg negative/anti-HBs positive and/or anti-HBc positive with detectable HBV DNA. 18. Active viral infection with HCV (positive antibody and detectable RNA), HIV, or known active HTLV-1 infection. 19. Any other medical or social condition that, in Investigator judgment, interferes with consent, study drug receipt, study demands, substantially increases risk, or may interfere with interpretation of results. 20. Female patients who are pregnant or lactating/breastfeeding. 21. Patients who have undergone a solid organ transplant. 22. Patients with malignancies other than FL (except specified eligible exceptions, including disease-free ≥3 years, resected nonmelanoma skin cancer, treated in situ carcinoma).