A Study to Assess the Efficacy, Safety, Pharmacodynamics, and Pharmacokinetics of Tazemetostat in Combination With Lenalidomide Plus Rituximab Versus Placebo in Combination With Lenalidomide Plus Rituximab in Adult Patients at Least 18 Years of Age With Relapsed/Refractory Follicular Lymphoma.

Inclusion Criteria:

1. Have voluntarily agreed to provide written informed consent and demonstratedwillingness and ability to comply with all aspects of the protocol.

2. Males or females are ≥18 years of age, or per country adult legal age regulations,at the time of providing voluntary written informed consent.

3. Life expectancy ≥3 months before enrollment.

4. Meet requirement for hepatitis and human immunodeficiency virus (HIV) infection asfollows

• Negative serologic or polymerase chain reaction (PCR) test results for acute orchronic hepatitis B virus (HBV) infection Note: Participants whose HBVinfection status could not be determined by serologic test results have to benegative for HBV-DNA by PCR to be eligible for study participation.Participants seropositive for HBV with undetectable HBV DNA by PCR arepermitted with appropriate antiviral prophylaxis.

• Negative test results for hepatitis C virus (HCV) Note: Participants who arepositive for HCV antibody must be negative for HCV RNA by PCR to be eligiblefor study participation

• If HIV positive, HIV infection is controlled. Based on Cancer Clinical TrialEligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis CVirus Infections - Guidance for Industry (https://www.fda.gov/media/121319/download), patients with HIV should beconsidered eligible if they have CD4+ T-cell counts ≥ 350 cells/uL and ingeneral, if they have not had an opportunistic infection within the past 12months. Other exclusion criteria should be considered regarding the drug-druginteraction if antiviral drugs are used. Therefore, in case of controlled HIVinfection, since antiviral drugs are used, trial patients should be onestablished ART for at least 4 weeks and have an HIV viral load less than 400copies/mL prior to enrolment.

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 subject has receivedat least 1 prior systemic therapy as discussed in Inclusion Criterion #6a.

d. Prior autologous/allogeneic hematopoietic stem cell transplant (HSCT) will beallowed.

e. Prior chimeric antigen receptor T-cell therapy (CAR T) will be allowed.

7. Must have documented relapsed, refractory, or PD after treatment with systemictherapy (refractory defined as less than PR or disease progression <6 months afterlast dose).

8. Have measurable disease as defined by the Lugano Classification (Cheson, 2014;Appendix 5).

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 toa prior anticancer treatment (ie, chemotherapy, immunotherapy, and/or radiotherapymust have either resolved to Grade 1 per NCI CTCAE Version 5.0 OR are clinicallystable and no longer clinically significant.

11. Have provided sufficient tumor tissue block or unstained slides for EZH2 mutationtesting in all subjects to allow for stratification

a. If EZH2 mutation status is known from site-specific testing, subjects can beenrolled. Tumor tissue will be required for confirmatory testing of EZH2 status atstudy-specific laboratories. If the archival tumor sample was collected more than 24months prior to the anticipated administration of the first dose (cycle 1 day 1),then a fresh biopsy must be provided. Fresh tumor biopsy is appropriate except forprocedures deemed to result in unacceptable risk because of the anatomical locationincluding brain, lung/mediastinum, pancreas, or endoscopic procedures extendingbeyond the esophagus, stomach, or bowel. Archival tumor biopsy sections mounted onslides are also acceptable. NOTE: Confirmatory testing will also be performed for Stage 1, if local EZH2 testingis conducted, unless there is insufficient tumor tissue to perform testing afterdiscussion with the Sponsor's or Designee Medical Monitor.

12. Time between prior anticancer therapy and first dose of tazemetostat as follows:

13. Cytotoxic chemotherapy - At least 21 days.

14. Noncytotoxic chemotherapy (eg, small molecule inhibitor) - At least 14 days.

15. Nitrosoureas - At least 6 weeks.

16. Monoclonal and/or bispecific antibodies or CAR T - At least 28 days.

17. Radiotherapy - At least 6 weeks from prior radioisotope therapy; at least 12weeks from 50% pelvic or total body irradiation.

18. Adequate renal function defined as calculated creatinine clearance ≥30 mL/minute perthe Cockcroft and Gault formula.

19. Adequate bone marrow function:

a. Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 × 10^9/L) if no lymphomainfiltration of bone marrow OR ANC ≥750/mm3 (≥75 × 10^9/L) with bone marrowinfiltration

• Without growth factor support (filgrastim or pegfilgrastim) 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

• May receive transfusion

15. Adequate liver function:

16. Total bilirubin ≤1.5 × the upper limit of normal (ULN) except for unconjugatedhyperbilirubinemia of Gilbert's syndrome.

17. Alkaline phosphatase (ALP) (in the absence of bone disease), alanineaminotransferase (ALT), and aspartate aminotransferase (AST) ≤3 × ULN (≤5 × ULNif subject has liver infilration).

18. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastintime (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). In subjects withthromboembolism risk, prophylactic anticoagulation, or antiplatelet therapy atinvestigator discretion is recommended.

19. Females of childbearing potential (FCBP) must have a negative urine or serumpregnancy tests (beta-human chorionic gonadotropin [β-hCG] tests with a minimumsensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening within 10 to 14days prior to first dose of study drug. The subject may not receive study drug untilthe study doctor has verified that the results of pregnancy tests are negative. Allfemales will be considered to be of childbearing potential unless they are naturallypostmenopausal (at least 24 months consecutively amenorrhoeic [amenorrhea followingcancer therapy does not rule out childbearing potential] and without other known orsuspected cause) or have been sterilized surgically (ie, total hysterectomy and/orbilateral oophorectomy, with surgery completed at least 1 month before dosing).

20. Females of childbearing potential (FCBP) enrolled must either practice completeabstinence or agree to use two reliable methods of contraception simultaneously.This includes ONE highly effective method of contraception and ONE additionaleffective contraceptive method. Contraception must begin at least 28 days prior tofirst dose of study drug, continue during study treatment (including during doseinterruptions), and for 12 months after study drug discontinuation. Female subjectsmust also refrain from breastfeeding for 12 months following last dose of study drug. If the below contraception methods are not appropriate for the FCBP, she mustbe referred to a qualified contraception provider to determine the medicallyeffective contraception method appropriate for the subject. The following areexamples of highly effective and additional effective methods of contraception: Examples of highly effective methods:

• Intrauterine device (IUD)

• Hormonal (ovulation inhibitory combined [estrogen and progesterone] birthcontrol pills or intravaginal/transdermal system, injections, implants,levonorgestrel-releasing intrauterine system [IUS], medroxyprogesterone acetatedepot injections, ovulation inhibitory progesterone-only pills [e.g.desogestrel]) NOTE: There is a potential for tazemetostat interference withhormonal contraception methods due to enzymatic induction.

• Bilateral tubal ligation

• Partner's vasectomy (if medically confirmed [azoospermia] and sole sexualpartner). Examples of additional effective methods:

• Male latex or synthetic condom,

• Diaphragm,

• Cervical Cap NOTE: Female subjects of childbearing potential exempt from these contraceptionrequirements are subjects who practice complete abstinence from heterosexual sexualcontact. True abstinence is acceptable when this is in line with the preferred andusual lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation,symptothermal, or post ovulation methods) and withdrawal are not acceptable methodsof contraception.

19. All study participants enrolled must be registered into the applicable pregnancyprevention program (e.g. REVLIMID REMS in the US, Pregnancy Prevention Programme [PPP] in Europe) for lenalidomide to be administered and be willing and able tocomply with the requirements of the applicable program as appropriate for thecountry in which the drug is being used.

a. Female subjects of childbearing potential (FCBP) must adhere to the scheduledpregnancy testing as required in theapplicable pregnancy prevention program. Duringstudy treatment, FCBP must agree to have pregnancy testing weekly for the first 28days of study participation and then every 28 days for FCBP with regular or nomenstrual cycles OR every 14 days for FCBP with irregular menstrual cycles. FCBPmust also have a pregnancy test at end of lenalidomide treatment, at day 14 (forFCBP with irregular menstrual cycles) and day 28 following the last dose oflenalidomide and at overall treatment discontinuation (at theEnd-of-Treatment/30-day safety Follow-up visit). Female subjects exempt from thisrequirement are subjects who have been naturally postmenopausal for at least 24consecutive months OR are surgically sterilized (ie, total hysterectomy or bilateraloophorectomy) with surgery at least 1 month before the first dose of studytreatment.

20. Male subjects must either practice complete abstinence or agree to use a latex orsynthetic condom, even with a successful vasectomy (medically confirmedazoospermia), during sexual contact with a pregnant female or FCBP from first doseof study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.

NOTE: Male subjects must not donate semen or sperm from first dose of study drug, during study treatment (including during dose interruptions), and for 3 months after study drug discontinuation.

Exclusion Criteria:

All Subjects

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 diffuselarge B-cell lymphoma (DLBCL) (subjects transformed from DLBCL to FL may beenrolled).

4. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE Version 5.0criteria) or any prior history of myeloid malignancies, including myelodysplasticsyndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).

5. Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acutelymphoblastic leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL).

6. Subjects with uncontrolled leptomeningeal metastases or brain metastases or historyof previously treated brain metastases.

7. Subjects taking medications that are known strong CYP3A inhibitors and strong ormoderate CYP3A inducers (including St. John's wort).

8. Are unwilling to exclude grapefruit juice, Seville oranges, and grapefruits from thediet and/or consumed within 1 week of the first dose of study drug and for theduration of the study.

9. Major surgery within 4 weeks before the first dose of study drug. a. Note: Minor surgery (eg, minor biopsy of extracranial site, central venouscatheter placement, shunt revision) is permitted within 3 weeks prior to enrollment.

10. Are unable to take oral medication OR have malabsorption syndrome or any otheruncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that mightimpair the bioavailability of tazemetostat.

11. Significant cardiovascular impairment: history of congestive heart failure greaterthan New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension,unstable angina, myocardial infarction, or stroke within 6 months of the first doseof study drug; or cardiac ventricular arrhythmia.

12. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to ≥480 msecat screening or history of long QT syndrome.

13. Venous thrombosis or pulmonary embolism within the last 3 months before startingtazemetostat. a. Note: Participants who have experienced deep vein thrombosis/pulmonary embolismmore than 3 months before enrollment are eligible but are recommended to receiveprophylaxis.

14. Have an active infection requiring systemic therapy.

15. Known hypersensitivity to any component of tazemetostat or lenalidomide; knownsevere hypersensitivity to any component of rituximab requiring hospitalization orresuscitation.

16. Active viral infection with or seropositive for HBV: HBV surface antigen (HBsAg)positive OR HBsAg negative, anti-HBs positive and/or anti-HBc positive withdetectable HBV DNA. NOTE: Subjects who are HBsAg negative, anti-HBs positive and/or anti-HBc positive,but with undetectable viral DNA and normal ALT are eligible. Subjects who areseropositive due to HBV vaccination (HBsAg negative, HBV surface antibody [anti-HBs]positive, and HBV core antibody [anti-HBc] negative) are eligible.

17. Active viral infection with hepatitis C virus (as measured by positive HCV antibodyand detectable viral RNA, HIV), or known active infection with human T-celllymphotropic virus. NOTE: Subjects with a history of hepatitis C infection (HCV antibody reactive) whohave normal ALT and undetectable HCV RNA are eligible.

18. Any other medical or social condition that, in the Investigator's judgment, willinterfere with a participant's ability to provide informed consent, to receive studydrugs, or meet study demands, or that substantially increases the risk associatedwith the subject's participation in the study, or that may interfere withinterpretation of results.

19. Female subjects who are pregnant or lactating/breastfeeding.

20. Subjects who have undergone a solid organ transplant.

21. Subjects with malignancies other than FL. a. Exception: Subjects with anothermalignancy who have been disease-free for 3 years, or subjects with a history of acompletely resected non-melanoma skin cancer or successfully treated in situcarcinoma are eligible.