A Phase 1/2, Open-label Study of Valemetostat in Combination With Rituximab and Lenalidomide in Relapsed or Refractory Follicular Lymphoma

Inclusion Criteria:

Subjects must meet all of the eligibility criteria to be enrolled on this study.

1. Subjects ≥18 years of age at the time the ICF is signed.

2. Have histologically confirmed FL, grades 1-3A

3. Must have been previously treated with at least 1 prior systemic therapy followed byrelapsed, refractory or progressive disease. a. Systemic therapy includes: i. Anti-CD20 monoclonal antibody in combination withchemotherapy ii. Anti-CD20 monoclonal antibody monotherapy iii. Anti-CD20 monoclonalantibody in combination with lenalidomide iv. Anti-CD20 monoclonal antibody plusinvestigational agent on protocol

4. Requiring systemic therapy as assessed by investigator based on tumor size,location, and/or GELF criteria.

5. Bi-dimensionally measurable disease, with at least one mass lesion ≥ 2 cm in longestdiameter by CT, PET/CT, and/or MRI which was not previously irradiated.

6. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2

7. Adequate renal function defined as calculated creatinine clearance per the Cockcroftand Gault formula

• In phase 1, creatinine clearance must be >60 mL/minute

• In Phase 2, creatinine clearance must be ≥30 mL/minute.

8. Adequate bone marrow function:

9. Absolute neutrophil count (ANC) ≥1,000/mm3 (≥1.0 × 109/L) if no lymphomainfiltration of bone marrow OR ANC ≥750/mm3 (≥0.75 × 109/L) with bone marrowinfiltration, without growth factor support (filgrastim or pegfilgrastim) forat least 14 days.

10. Platelet ≥75,000/mm3 (≥75 × 109/L). Evaluated at least 7 days after platelettransfusion.

11. Hemoglobin > 8.0 g/dL. Evaluated at least 7 days after RBC transfusion.

12. Adequate liver function:

13. Total bilirubin ≤1.5 × the upper limit of normal (ULN) except for unconjugatedhyperbilirubinemia of Gilbert's syndrome (eg, a gene mutation in UGT1A1), whocan have total bilirubin <3.0 mg/dL.

14. ALT and AST ≤3 × ULN.

15. International normalized ratio (INR) ≤1.5 × ULN and activated partial thromboplastintime (aPTT) ≤1.5 × ULN (unless on warfarin, then INR ≤3.0).

16. If the subject is a female of childbearing potential, she must have a negative serumpregnancy test at Screening and must be willing to use 1 highly effective method and 1 additional effective birth control method upon enrollment, during the TreatmentPeriod, and for 3 months, following the last dose of study drug. A female isconsidered of childbearing potential following menarche and until becomingpostmenopausal (no menstrual period for a minimum of 12 months) unless permanentlysterile (undergone a hysterectomy, bilateral salpingectomy or bilateraloophorectomy) with surgery at least 1 month before the first dose of study drug orconfirmed by follicle stimulating hormone (FSH) test >40 mIU/mL and estradiol < 40pg/mL (<140 pmol/L).

17. If the subject is a male, the subject must be surgically sterile or willing to use ahighly effective birth control upon enrollment, during the treatment period, and for 3 months following the last dose of study drug. Male subjects must not freeze ordonate sperm starting at Screening and throughout the study period, and for at least 3 months after the final study drug administration

18. Female subjects must not donate, or retrieve for their own use, ova from the time ofscreening and throughout the study treatment period, and for at least 3 months afterthe final study drug administration. Females of reproductive potential must adhereto the scheduled pregnancy testing as required in the Revlimid REMS® program.

19. All study participants must be registered into the mandatory Revlimid REMS® program,and be willing and able to comply with the requirements of the REMS® program.

20. Able and willing to provide written informed consent and to comply with the studyprotocol

Exclusion Criteria:

Patients who meet any of the following criteria will be excluded from study entry.

1. Transformation to DLBCL at study entry

2. Grade 3B FL

3. Prior systemic therapy (eg, chemotherapy, immunomodulatory therapy, or monoclonalantibody therapy) within 3 weeks prior to the first dose of study drug.

4. Having progressive disease while on prior lenalidomide, discontinuing lenalidomidedue to unacceptable toxicity, or prior lenalidomide therapy within the past 12months prior to the first dose of study drug

5. Had curative radiation therapy or major surgery within 4 weeks or palliativeradiation therapy within 2 weeks prior to the first dose of study drug

6. Systemic treatment with corticosteroids (>10 mg daily prednisone equivalents). Note:Short-course systemic corticosteroids (eg, prevention/treatment for transfusionreaction) or use for a non-cancer indication (eg, adrenal replacement) ispermissible

7. History of autologous stem cell transplant within 60 days prior to first dose ofstudy drug

8. History of allogeneic stem cell transplant within 90 days prior to the first dose ofstudy drug, and clinically significant graft-versus-host disease (GVHD) or GVHDrequiring systemic immunosuppressive prophylaxis or treatment

9. Prior malignancy active within the previous 2 years except for locally curablecancer that is currently considered as cured, such as cutaneous basal or squamouscell carcinoma, superficial bladder cancer, or cervical carcinoma in situ, or anincidental histological finding of prostate cancer

10. Presence or history of central nervous system (CNS) involvement of lymphoma

11. Prior EZH inhibitor therapy

12. Current use of moderate or strong cytochrome P450 (CYP)3A inducers (See Appendix E)or inhibitors, or prior use of moderate or strong CYP3A within the past 2 weeks.

13. Current use of P-gp inducers and on narrow therapeutic index, sensitive P-gpsubstrates.

14. Any life-threatening illness, medical condition, or organ system dysfunction which,in the investigator's opinion, could compromise the subject's safety, interfere withthe absorption or metabolism of lenalidomide capsules, or put the study outcomes atundue risk

15. Human immunodeficiency virus (HIV), active Hepatitis C Virus, active Hepatitis BVirus infection, or any active systemic infection. Patients with inactive hepatitisB infection must adhere to hepatitis B reactivation prophylaxis unlesscontraindicated.

16. Clinically significant cardiovascular disease such asymptomatic arrhythmias,congestive heart failure, or myocardial infarction within 6 months of Screening, orany Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the NewYork Heart Association Functional Classification.

17. Significant screening electrocardiogram (ECG) abnormalities including left bundlebranch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rddegree block. QT prolongation is not a significant ECG abnormality that wouldwarrant exclusion.

18. Lactating or pregnant subjects