A Study of Tazemetostat With Rituximab and Abbreviated Bendamustine in the Frontline Treatment of High Tumor Burden Follicular Lymphoma

Inclusion Criteria:

• Written informed consent and HIPAA authorization for release of personal healthinformation. NOTE: HIPAA authorization may be included in the informed consent orobtained separately.

• Age ≥ 18 years at the time of consent.

• ECOG Performance Status of 0-2 within 10 days prior to registration.

• Low grade follicular lymphoma (grade 1-2 or 3A by WHO-HAEM4R and/or cFL byWHO-HAEM5). Specifically, grade 3B or FLBL will not be allowed. Must not haveevidence of transformed lymphoma at the time of study enrollment.

• Stage II, III, or IV by Ann Arbor staging system.

• Meet the definition of high tumor burden follicular lymphoma as defined by Grouped'Etude des Lymphomes Follicularies (GELF) Criteria or be defined as high risk bythe follicular lymphoma international prognostic index (FLIPI) 1 or FLIPI 2.

--GELF Criteria (Must meet ≥ 1 of the following)

• Any nodal or extranodal mass ≥ 7 cm in diameter

• Involvement of ≥ 3 nodal sites ≥ 3 cm

• Systemic or B symptoms

• Presence of serous effusion

• Splenic enlargement

• Risk of compression syndrome (epidural, ureteral, etc)

• Leukemic phase of disease

• Cytopenia deemed due to disease involvement (hemoglobin < 10, granulocyte count < 1.5×10^9/L, or platelet count < 100×10^9/L)

• In addition to meeting GELF criteria, must have at least one FDG-avid site on PETthat measures 1.5 cm in at least one dimension of a nodal site or 1cm in at leastone dimension for extranodal sites.

• Received no prior therapy except local radiation therapy (field did not exceed 2adjacent nodal regions), single agent rituximab (limited to 4 doses), or steroidsfor symptom control in the 28 days preceding trial enrollment.

• Must have prior EZH2 testing already performed or have tissue available to performretrospective EZH2 testing. If prior EZH2 results are not available, tissue must besubmitted. Tissue block is preferred but unstained slides are also acceptable.Patients who have insufficient or suboptimal tissue must be willing to have a biopsyperformed prior to starting study drugs. See Correlative Lab Manual for details.

• Demonstrate adequate organ function as defined below; all screening labs to beobtained within 28 days prior to registration.

• Hematological

• Platelets ≥ 50 K/dL

• Absolute Neutrophil Count (ANC) ≥ 1000 K/mm3

• Hemoglobin (Hgb) ≥ 8 g/dL

• Renal

• Calculated creatinine clearance ≥ 40 mL/min using the Cockcroft-Gaultformula

• or Serum creatinine < 2 mg/dL

• Hepatic

• Bilirubin ≤ 1.5 × upper limit of normal (ULN)

• Aspartate aminotransferase (AST) ≤ 3 × ULN

• Alanine aminotransferase (ALT) ≤ 3 × ULN

• Coagulation ---International Normalized Ratio (INR) or Prothrombin Time (PT)Activated Partial Thromboplastin Time (aPTT) ≤ 2 × ULN

• Females of childbearing potential with a male partner able to father a child musthave a negative serum or urine pregnancy test within 7 days prior to registration.See the protocol for definition of childbearing potential.

• Females of childbearing potential must be willing to abstain from vaginalintercourse or use two effective methods of contraception from the time of informedconsent, during the study and for 6 months after the last dose of study drug(s).Males able to father a child must be willing to abstain from vaginal intercourse orto use an effective method(s) of contraception from initiation of treatment, duringthe study and for 3 months after the last dose of study drug(s). See the protocol.

• As determined by the enrolling physician or protocol designee, ability of thesubject to understand and comply with study procedures for the entire length of thestudy.

Exclusion Criteria:

• Active infection requiring systemic therapy with 4 weeks of study drugadministration.

• Pregnant or breastfeeding (NOTE: breast milk cannot be stored for future use whilethe mother is being treated on study).

• Concurrent malignancy or malignancy within the last 3 years (except for ductalbreast cancer in situ, non-melanoma skin cancer, prostate cancer not requiringtreatment, and cervical carcinoma in situ) whose natural history or treatment hasthe potential to interfere with the safety or efficacy assessment of theinvestigational regimen are not eligible for this trial. Any prior history ofmyeloid malignancies are excluded, regardless of when the subject was diagnosed,including myelodysplastic syndrome (MDS), acute myeloid leukemia (AML),myeloproliferative neoplasm (MPN), prior history of T-cell lymphoblastic lymphoma (T-LBL), T-cell acute lymphoblastic leukemia (T-ALL), or B-cell acute lymphoblasticleukemia (B-ALL).

• Active central nervous system (CNS) metastases or leptomeningeal disease. NOTE:Subjects who are symptomatic and have not undergone prior brain imaging must undergoa head computed tomography (CT) scan or brain MRI within 28 days prior toregistration to exclude brain metastases.

• Treatment with any investigational drug within 4 weeks prior to registration.

• Subjects who require chronic use of moderate or strong CYP3A4/5 inhibitors orinducers within 28 days prior to registration.

• Clinically significant acute infection requiring systemic antibacterial, antifungal,or antiviral therapy.

• Known Uncontrolled Human Immunodeficiency Virus infection. Testing not required.NOTE: If a subject is known to have HIV/AIDS, then they will be allowed on studywith adequate antiviral therapy, no detectable viral load, and stable on antiviraltreatment for ≥ 4 weeks prior to first dose of study drug(s).

• Known hepatitis C infection. Testing not required. NOTE: If hepatitis C antibodytest is known positive, patients are excluded unless a hepatitis C virus ribonucleicacid (HCV RNA) is negative.

• Must be tested for hepatitis B within 28 days of registration: including hepatitis Bsurface antigen, hepatitis B surface antibody, hepatitis B core antibody. A positivehepatitis B core antibody should be followed by hepatitis B DNA PCR testing toconfirm or rule out active infection. Patients with hepatitis B surface antigenand/or detectable hepatitis B DNA PCR are not allowed on study. Patients with apositive hepatitis B core antibody but negative hepatitis B surface antigen andhepatitis B DNA PCR will be allowed on study, but hepatitis B prophylactic treatmentshould be strongly considered.

• Clinically significant cardiovascular disease or cardiac insufficiency (New YorkHeart Association classes III-IV), cardiomyopathy, preexisting clinicallysignificant arrhythmia, acute myocardial infarction within 3 months of enrollment,angina pectoris within 3 months of enrollment.