Study of Ibrutinib in Combination With Rituximab-CHOP in Epstein-Barr Virus-positive Diffuse Large B-cell Lymphoma

1. Newly diagnosed, histologically proven EBV-positive Diffuse large B-cell lymphoma A.EBV positivity: The presence of EBER-positive tumor cells ≥ 20% B.DLBCL based on the WHO classification 2008

2. Hematology values must be within the following limits:

   A.Absolute neutrophil count 1000/mm3 independent of growth factor support B.Platelets 100,000/mm3 or 50,000/mm3 if bone marrow involvement independent of transfusion support in either situation C.Hemoglobin ≥ 10.0 g/dL (may be transfused or erythropoietin treated)

3. Biochemical values within the following limits:

   A.Alanine aminotransferase and aspartate aminotransferase≤ 3 x upper limit of normal B.Total bilirubin ≤ 1.5 x ULN unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin C.Serum creatinine ≤ 2 x ULN or estimated Glomerular Filtration Rate (Cockroft Gault) ≥ 40 mL/min/1.73m2 D.Serum calcium ≤ 12.0 mg/dL

4. Women of childbearing potential and men who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials. Men must agree to not donate sperm during and after the study. For females, these restrictions apply for 1 month after the last dose of study drug. For males, these restrictions apply for 3 months after the last dose of study drug
5. Women of childbearing potential must have a negative serum (beta-human chorionic gonadotropin)or urine pregnancy test at Screening. Women who are pregnant or breastfeeding are ineligible for this study.
6. Sign (or their legally-acceptable representatives must sign) an informed consent document indicating that they understand the purpose of and procedures required for the study, including biomarkers, and are willing to participate in the study.
7. At least one measurable lesion
8. ECOG PS 0-2
9. Informed consent
10. Age ≥ 19 years

Exclusion Criteria:

1. Previous treatment history for EBV-positive DLBCL including any kinds of chemotherapy

   •Exception: a) Prednisolone 100mg or equivalent dosage of any types of steroid is allowed (Maximum 7 days); b) Radiation for reducing symptom related with mass effect is allowed

2. History of or known carcinomatous meningitis, or evidence of symptomatic leptomeningeal disease or secondary CNS involvement on CT or MRI scan.
3. Pregnancy or breastfeeding
4. Major surgery within 4 weeks of enrollment
5. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
6. Requires anticoagulation with warfarin or equivalent vitamin K antagonists (eg, phenprocoumon).
7. Requires treatment with strong CYP3A inhibitors.
8. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of Screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification.
9. Vaccinated with live, attenuated vaccines within 4 weeks of enrollment.
10. Known history of human immunodeficiency virus (HIV) or active Hepatitis C Virus or active Hepatitis B Virus infection or any uncontrolled active systemic infection requiring intravenous (IV) antibiotics.
11. Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk.