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.

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, 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 as follows

* Negative serologic or polymerase chain reaction (PCR) test results for acute or chronic hepatitis B virus (HBV) infection Note: Participants 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. Participants seropositive for HBV with undetectable HBV DNA by PCR are permitted with appropriate antiviral prophylaxis.

* Negative test results for hepatitis C virus (HCV) Note: Participants who are positive for HCV antibody must be negative for HCV RNA by PCR to be eligible for study participation

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 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 PR or disease progression \<6 months after last 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 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 subjects to allow for stratification

a. If EZH2 mutation status is known from site-specific testing, subjects can be enrolled. Tumor tissue will be required for confirmatory testing of EZH2 status at study-specific laboratories. If the archival tumor sample was collected more than 24 months 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 for procedures deemed to result in unacceptable risk because of the anatomical location including brain, lung/mediastinum, pancreas, or endoscopic procedures extending beyond the esophagus, stomach, or bowel. Archival tumor biopsy sections mounted on slides are also acceptable.

NOTE: Confirmatory testing will also be performed for Stage 1, if local EZH2 testing is conducted, unless there is insufficient tumor tissue to perform testing after discussion with the Sponsor's or Designee Medical Monitor.

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

1. Cytotoxic chemotherapy - At least 21 days.

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

3. Nitrosoureas - At least 6 weeks.

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

5. 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. Absolute neutrophil count (ANC) ≥1000/mm3 (≥1.0 × 10\^9/L) if no lymphoma infiltration of bone marrow OR ANC ≥750/mm3 (≥75 × 10\^9/L) with bone marrow infiltration

* 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:

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

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

16. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastin time (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0). In subjects with thromboembolism risk, prophylactic anticoagulation, or antiplatelet therapy at investigator discretion is recommended.

17. Females of childbearing potential (FCBP) must have a negative urine or serum pregnancy tests (beta-human chorionic gonadotropin \[β-hCG\] tests with a minimum sensitivity of 25 mIU/mL or equivalent units of β-hCG) at screening within 10 to 14 days prior to first dose of study drug. The subject may not receive study drug until the study doctor has verified that the results of pregnancy tests are negative. All females will be considered to be of childbearing potential unless they are naturally postmenopausal (at least 24 months consecutively amenorrhoeic \[amenorrhea following cancer therapy does not rule out childbearing potential\] and without other known or suspected cause) or have been sterilized surgically (ie, total hysterectomy and/or bilateral oophorectomy, with surgery completed at least 1 month before dosing).

18. Females of childbearing potential (FCBP) enrolled must either practice complete abstinence or agree to use two reliable methods of contraception simultaneously. This includes ONE highly effective method of contraception and ONE additional effective contraceptive method. Contraception must begin at least 28 days prior to first dose of study drug, continue during study treatment (including during dose interruptions), and for 12 months after study drug discontinuation. Female subjects must 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 must be referred to a qualified contraception provider to determine the medically effective contraception method appropriate for the subject. The following are examples of highly effective and additional effective methods of contraception:

Examples of highly effective methods:

* Intrauterine device (IUD)

* Hormonal (ovulation inhibitory combined \[estrogen and progesterone\] birth control pills or intravaginal/transdermal system, injections, implants, levonorgestrel-releasing intrauterine system \[IUS\], medroxyprogesterone acetate depot injections, ovulation inhibitory progesterone-only pills \[e.g. desogestrel\]) NOTE: There is a potential for tazemetostat interference with hormonal contraception methods due to enzymatic induction.

* Bilateral tubal ligation

* Partner's vasectomy (if medically confirmed \[azoospermia\] and sole sexual partner).

Examples of additional effective methods:

* Male latex or synthetic condom,

* Diaphragm,

* Cervical Cap

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

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

a. Female subjects of childbearing potential (FCBP) must adhere to the scheduled pregnancy testing as required in theapplicable pregnancy prevention program. During study treatment, FCBP must agree to have pregnancy testing weekly for the first 28 days of study participation and then every 28 days for FCBP with regular or no menstrual cycles OR every 14 days for FCBP with irregular menstrual cycles. FCBP must also have a pregnancy test at end of lenalidomide treatment, at day 14 (for FCBP with irregular menstrual cycles) and day 28 following the last dose of lenalidomide and at overall treatment discontinuation (at the End-of-Treatment/30-day safety Follow-up visit). Female subjects exempt from this requirement are subjects who have been naturally postmenopausal for at least 24 consecutive months OR are surgically sterilized (ie, total hysterectomy or bilateral oophorectomy) with surgery at least 1 month before the first dose of study treatment.

20. Male subjects must either practice complete abstinence or agree to use a latex or synthetic condom, even with a successful vasectomy (medically confirmed azoospermia), during sexual contact with a pregnant female or FCBP from first dose of 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.

What this study is about