Study of Tazemetostat in Newly Diagnosed Diffuse Large B Cell and Follicular Lymphoma Patients Treated by Chemiotherapy

* INCLUSION CRITERIA

  * for Cohort DLBCL ONLY

    * 1-Patients with an untreated DLBCL de novo or transformed from indolent lymphoma (CD 20 positive) with

      * Phase Ib aaIPI ≥ 2
      * Phase II: aaIPI ≥ 1ONLY
    * 2\. Age between 60 and 80 years included
  * for Cohort FOLLICULAR ONLY

    * 1-High Tumor Burden (as defined by GELF criteria \> 0) frontline follicular lymphoma (FL) with high risk FLIPI 3-5
    * 2\. Aged between 18 years and 80 years included
    * 11bis. Females of childbearing potential (FCBP) must agree to use one reliable form of contraception or to practice complete abstinence from heterosexual contact during the following time periods related to this study: 1) for at least 28 days before starting study drug; 2) while participating in the study; 3) dose interruptions; and 4) for at least 12 months after discontinuation of any study treatments (R-CHOP, tazemetostat, Rituximab)
  * For both Cohorts

    * 1bis- For phase II patients: Bi-dimensionally measurable disease defined by at least one single node or tumor lesion \> 1.5 cm assessed by CT scan and/or clinical examination AND a FDG avid disease by PETscan
    * 3.ECOG performance status of 0, 1 or 2 (0 or 1 only for phase Ib)
    * 4.Signed informed consent
    * 5.Life expectancy of ≥ 90 days (3 months) before starting tazemetostat
    * 6.Adequate renal function as calculated by a creatinine clearance \> 40 mL/min by local institutional formula
    * 7\. Adequate bone marrow function as defined as:

      * ANC ≥ 1500/mm3 (≥ 1.5 X 109/L)
      * Platelets ≥ 75,000/mm3 (≥ 75 X 109/L) without platelet transfusion dependency during the last 7 days
      * Hemoglobin ≥ 9 g/dL (may receive transfusion)
    * 8\. Adequate liver function as defined as:

      * Total bilirubin ≤ 1.5 × the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome
      * Alkaline phosphatase (in absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 X ULN (or ≤ 5 X ULN if related to lymphoma involvement)
      * Patients with prior Hepatitis B and C are eligible if, for Hepatitis B detection, surface antigen is negative and/or HBV DNA is undetectable, and for Hepatitis C detection, if HCV RNA is undetectable.
    * 9\. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
    * 10\. Adequate tissue (surgical excision is recommended) for central pathology review and biological caracterisation (see appendix 11
    * 11\. Males with partners of childbearing potential must agree to use reliable forms of contraception during 12 months after last treatment administration
    * 12\. Patient covered by any social security system (for France only)
    * 13\. Patient who understands and speaks one of the country official languages
* EXCLUSION CRITERIA

  * for Cohort DLBCL

    \_\_\_15-Previous treatment for B cell lymphoma, except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)
  * for Cohort FOLLICULAR ONLY

    * 14bis. Prior therapy for lymphoma including radiotherapy except glucocorticoids (no more than 7 days before inclusion, 1 mg/kg/day max)
    * 17-Pregnant or lactating females
  * For both Cohorts

    * 1-Central nervous system or meningeal involvement
    * 2-Contraindication to any drug contained in the chemotherapy regimen
    * 3-Prior treatment with tazemetostat or other inhibitor of EZH2
    * 4-Patients who are undergoing active treatment for another malignancy, exceptions include: A patient who has been disease free for 2 years, or a patient with a history of a completely resected non-melanoma skin cancer or successfully treated in situ carcinoma is eligible Patients with prior history of myeloid malignancies, including myelodysplastic syndrome (MDS) or Acute Myeloid Leukemia(AML) or prior history of T-LBL/T-ALL are excluded whatever receiving treatment or not and whatever date of diagnosis of these pathologies
    * 5-Patients taking medications that are known potent CYP3A4 inducers/inhibitors (including St. John's wort)
    * 6-Patients unwilling to exclude St. John's wort, Seville oranges, grapefruit juice and/or grapefruit from diet
    * 7-Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted within 2 weeks of enrollment)
    * 8-Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impare ability to take tazemetostat
    * 9-Significant cardiovascular impairment: congestive heart failure greater than New York Heart Association (NYHA) Class II, unstable angina, myocardial infarction or stroke within 6 months of first dose of tazemetostat or ventricular arrhythmia
    * 10-Not applicable
    * 11-Active uncontrolled infection requiring systemic therapy
    * 12-Congenital immunodeficiency or known HIV (human immunodeficiency virus infection)
    * 13-Any other major illness, that in the investigator's judgement, will substantially increase the risk associated with the patient's participation in the study
    * 14-Patients who have undergone a solid organ transplant
    * 16-Treatment with any investigational drug or device within 30 days before planned first cycle of chemotherapy
    * 18-Person deprived of his/her liberty by a judicial or administrative decision
    * 19-Adult person under legal protection
    * 20-Person hospitalized without consent
    * 21-Adult person unabled to provide informed consent because of intellectual impairment, any serious medical condition, laboratory abnormality or psychiatric illness