Study of Entospletinib (ENTO) in Newly Diagnosed DLBCL Patients With aaIPI>=1 Treated by Chemiotherapy

Inclusion Criteria:

1. Patients with histologically confirmed de novo DLBCL (CD20 positive) (cf section 20.6 - Appendix 4)
2. Age between 60 and 80 years included, on the day of the informed consent document signature
3. Age adjusted International Prognosis Index (aaIPI) score ≥ 1
4. No prior treatment for DLBCL. However prephase treatment with 1mg/kg/day prednisone or equivalent, for a maximum of 14 days, is permitted prior to begin the treatment
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1 or 2 (0 or 1 only for phase 1b)
6. Life expectancy of ≥ 90 days (3 months) before starting Entospletinib
7. Signed informed consent
8. At least one bi-dimensionally measurable lesion defined as at least one node or tumor lesion on CT scan ≥ 1.5 cm
9. fluorodeoxyglucose (FDG) positron emission tomography (PET-CT) performed at baseline with a FDG positive result
10. Adequate hematologic functions defined as follows (unless secondary to bone marrow involvement by lymphoma):

    * Absolute neutrophil count (ANC) \> 1.5 X 10\^9 G/l and
    * Platelets count ≥ 75 X 10\^9/l without platelet transfusion dependency during the last 7 days and
    * Haemoglobin level \> 9 g/dl (may receive transfusion)
11. Adequate liver function defined as follows:

    * Total bilirubin \<1.5 upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome and
    * Alkaline phosphatase (in absence of bone disease), alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 3 X ULN
12. Adequate renal function as calculated by a creatinine clearance \> 40 ml/min by local institutional formula
13. Patients with prior Hepatitis B must be given antiviral prophylaxis and hepatitis B virus (HBV) DNA monitored; Patients with prior Hepatitis C are eligible if, hepatitis C virus (HCV) RNA is undetectable.
14. Left ventricular ejection fraction (LVEF) ≥ 50% of echocardiography or multiple gated acquisition (MUGA) scan
15. Adequate tissue for central retrospective testing for cell of origin (10-15 slides of tumor biopsy must be available at baseline)
16. Heterosexually active females of childbearing potential (as defined in the protocol) must:

    * have a negative serum pregnancy test at baseline and prior to the first study drug administration (C1D-4)
    * have practiced at least 1 reliable method of contraception for at least 2 months prior to the first study drug administration (C1D-4)
    * agree to utilize highly effective methods of contraception (as defined in the protocol) from Cycle 1 Day -4 until 12 months following the last treatment administration
17. Heterosexually active males with partners of childbearing potential must agree to use reliable forms of contraception during treatment and up to 12 months after last treatment administration
18. Male subjects must agree to avoid sperm donation from Cycle 1 Day -4 until 12 months following the last treatment administration

Exclusion Criteria:

1. Central nervous system or meningeal involvement with DLBCL
2. Contraindication to any drug contained in the chemotherapy regimen
3. Prior treatment with Entospletinib or other spleen tyrosine kinase (SYK ) inhibitor
4. Patients with a prior history of other malignancy, exceptions include:

   * a subject who has been disease-free after curative local treatment (surgical resection) for at least 3 years,
   * a subject with a history of a completely resected non-melanoma skin cancer or in situ carcinoma with surgical complete excision.
5. Patients taking current therapy with proton pump inhibitors and current therapy with medicines that are strong Cytochrome P450 3A (CYP3A) or CYP2C9 inducers, or moderate CYP2C9 inducers.
6. Ongoing active pneumonitis
7. Peripheral sensory or motor neuropathy grade \> 1.
8. Major surgery within 4 weeks before first dose of study drug (minor procedures including transcutaneous biopsy, central line placement are permitted at any time)
9. Inability to take oral medication or malabsorption syndrome or any other uncontrolled gastrointestinal condition that would impair ability to take entospletinib
10. 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 entospletinib or ventricular arrhythmia
11. Active infection as judged by the investigator
12. Known hypersensitivity to ENTO
13. Congenital immunodeficiency or known HIV (human immunodeficiency virus infection) or active viral hepatitis B or C
14. Any other major illness that in the investigator's judgement, will substantially increase the risk associated with the subject's participation in the study
15. Subjects who have undergone a solid organ transplant and stem cell transplant
16. Previous treatment for B cell lymphoma or Richter's transformation
17. Primary Mediastinal B Cell Lymphoma