Copanlisib in Combination With Rituximab and CHOP Chemotherapy in Patients With Previously Untreated DLBCL

Inclusion Criteria: 1. Histologically confirmed 1. DLBCL (NOS) or 2. High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements or 3. High-grade B-cell lymphoma (NOS) 4. Follicular lymphoma Grade 3B (primary diagnosis without history of indolent lymphoma) with a diagnostic biopsy performed within 3 months before study entry and with material available for central review and complimentary scientific analyses 2. 18-80 years of age 3. International Prognostic Index (IPI) 2-5 4. Eastern Cooperative Oncology Group Performance status (ECOG) 0-2 5. Life expectancy of at least 3 months 6. Women of childbearing potential and men must agree to use effective contraception when sexually active. This applies for the time period between signing of the informed consent form and 6 months after the last administration of study treatment. A woman is considered of childbearing potential, i.e. fertile, following menarche and until becoming post-menopausal unless permanently sterile. Permanent sterilization methods include but are not limited to hysterectomy, bilateral salpingectomy, and bilateral oophorectomy. A postmenopausal state is defined as no menses for continuous 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. The investigator or a designated associate is requested to advise the patient how to achieve highly effective birth control (failure rate of less than 1%), e.g. intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomized partner and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile. Adequate baseline laboratory values collected no more than 7 days before starting study treatment: 7. Total bilirubin ≤ 1.5 x ULN (\< 3 x ULN for patients with Gilbert syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or documented liver involvement or with biliary obstruction due to lymphoma) 8. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement by lymphoma) 9. Lipase ≤ 1.5 x ULN 10. Glomerular filtration rate (GFR) ≥ 40 mL/min/1.73 m2 according to the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula. If not on target, this evaluation may be repeated once after at least 24 hours either according to the CKD-EPI formula or by 24-hour sampling. If the later result is within acceptable range, it may be used to fulfill the inclusion criteria instead. 11. INR and PTT ≤ 1.5 x ULN 12. Platelet count ≥ 75,000 /mm3. 13. Hemoglobin (Hb) ≥ 8 g/dL 14. Absolute neutrophil count (ANC) ≥ 1,500/mm3 15. Left ventricular ejection fraction ≥ 50% 16. No prior lymphoma therapy 17. Ability to understand and willingness to sign written informed consent. Signed informed consent must be obtained before any study specific procedure. Exclusion Criteria: Patients who meet any of the following criteria at the time of screening will be excluded. 1. Previous assignment to treatment during this study. Patients permanently withdrawn from study participation will not be allowed to re-enter the study. 2. Previous (within 28 days or less than 5 half-lives of the drug before start of study treatment) or concomitant participation in another clinical study with investigational medicinal product(s). 3. Close affiliation with the investigational site; e.g. a close relative of the investigator, dependent persons (e.g. employee or student of the investigational site). Excluded medical conditions: 4. Type I or II diabetes mellitus with HbA1c \> 8.5% at screening or fasting plasma glucose \> 160 mg/dL at screening 5. History or concurrent condition of interstitial lung disease and/or severely impaired lung function (as judged by the investigator) 6. Known lymphoma involvement of the central nervous system 7. Human immunodeficiency virus (HIV) infection 8. Hepatitis B (HBV) and C (HCV) infection. Patients with serologic markers of HBV immunization due to vaccination (HBsAg negative, Anti-HBc negative and Anti-HBs positive) will be eligible 9. CMV-PCR positive at baseline 10. Previous or concurrent history of malignancies within 5 years prior to study treatment except for curatively treated: 1. Cervical carcinoma in situ 2. Non-melanoma skin cancer 3. Superficial bladder cancer (Ta \[non-invasive tumor\], Tis \[carcinoma in situ\] and T1 \[tumor invades lamina propria\]) 4. Localized prostate cancer 11. Patients with evidence or history of bleeding diathesis. Any hemorrhage or bleeding event ≥ CTCAE Grade 3 within 4 weeks prior to the start of study medication 12. Patients with seizure disorder requiring medication 13. Proteinuria of ≥ CTCAE Grade 3 as assessed by a 24h protein quantification or estimated by urine protein: creatinine ratio \> 3.5 on a random urine sample 14. Concurrent diagnosis of pheochromocytoma 15. Congestive heart failure \> New York Heart Association (NYHA) class 2 16. Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months) 17. Myocardial infarction less than 6 months before start of test drug 18. Arterial or venous thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), deep vein thrombosis or pulmonary embolism within 3 months before the start of study medication 19. Non-healing wound, ulcer, or bone fracture 20. Active, clinically serious infections \> CTCAE Grade 2 21. Uncontrolled hypertension (systolic blood pressure \> 150 mmHg or diastolic pressure \> 90 mmHg despite optimal medical management) 22. Known history of drug induced liver injury, alcoholic liver disease, non-alcoholic steatohepatitis, primary biliary cirrhosis, on-going extra-hepatic obstruction caused by cholelithiasis, cirrhosis of the liver or portal hypertension 23. Ongoing inflammatory bowel disease 24. History of, or current autoimmune disease 25. Prior treatment with PI3K inhibitors 26. Any other co-existing medical or psychological condition that will preclude participation in the study or compromise ability to give informed consent 27. Patient is pregnant (β-HCG positive) or breast-feeding 28. Known hypersensitivity to copanlisib or to any of the excipients of rituximab, cyclophosphamide, doxorubicine, vincristine, and/or prednisone