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.

Eligibility Criteria

• 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 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
• * 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:
• 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
• 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:
• * Without growth factor support (filgrastim or pegfilgrastim) for at least 14 days.
• * Evaluated at least 7 days after last platelet transfusion.
• * 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:
• * 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).
• * Male latex or synthetic condom,
• * Diaphragm,
• * Cervical Cap
• 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, RevAid in Canada) 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.
• 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.
• 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 diffuse large B-cell lymphoma (DLBCL) (subjects transformed from DLBCL to FL may be enrolled).
• 4. Has thrombocytopenia, neutropenia, or anemia of Grade ≥3 (per CTCAE Version 5.0 criteria) or any prior history of myeloid malignancies, including myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML) or myeloproliferative neoplasm (MPN).
• 5. Has a prior history of T-cell lymphoblastic lymphoma (T-LBL)/T-cell acute lymphoblastic leukemia (T-ALL) or B-cell acute lymphoblastic leukemia (B-ALL).
• 6. Subjects with uncontrolled leptomeningeal metastases or brain metastases or history of previously treated brain metastases.
• 7. Subjects 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 the first dose of study drug and for the duration of the study.
• 9. Major surgery within 4 weeks before the first dose of study drug.
• 10. Are unable to take oral medication OR have malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, vomiting) that might impair the bioavailability of tazemetostat.
• 11. Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction, or stroke within 6 months of the first dose of study drug; or cardiac ventricular arrhythmia.
• 12. Prolongation of corrected QT interval using Fridericia's formula (QTcF) to ≥480 msec at screening or history of long QT syndrome.
• 13. Venous thrombosis or pulmonary embolism within the 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.
• 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 with detectable HBV DNA.
• 17. Active viral infection with hepatitis C virus (as measured by positive HCV antibody and detectable viral RNA, HIV), or known active infection with human T-cell lymphotropic virus.
• 18. Any other medical or social condition that, in the Investigator's judgment, will interfere with a participant's ability to provide informed consent, to receive study drugs, or meet study demands, or that substantially increases the risk associated with the subject's participation in the study, or that may interfere with interpretation 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 another malignancy who have been disease-free for 3 years, or subjects with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma are eligible.