Copanlisib Plus Venetoclax in R/R DLBCL

Inclusion Criteria: * A confirmed diagnosis of DLBCL according to the 2016 WHO classification. Patients with high-grade B-cell lymphoma with translocations of MYC and BCL-2 and/or BCL-6 are eligible * Relapsed after autologous stem cell transplantation or chimeric antigen receptor (CAR) T-cell therapy or not a candidate for these therapies * Willingness to undergo a pre-treatment biopsy. If considered unsafe to proceed with biopsy, archival tissue samples may be utilized after discussion with the PI. Archival samples performed within 90 days and without intervening therapy are also acceptable if they meet the criteria as specified in the laboratory manual. * ECOG performance status \< 2 * Age ≥ 18 years * Patients must meet the following hematologic criteria at screening: * Absolute neutrophil count ≥1000 cells/mm3 (0.5 x 109/L), with no white-blood cell growth factor use for at least 7 days prior to screening. * Platelet count ≥75,000 cells/mm3 (75 x 109/L) or ≥50,000 cells/mm3 (50 x 109/L if documented disease involvement of the bone marrow), without platelet transfusion within 7 days of screening * Hemoglobin (Hb) ≥ 8 g/dL, without blood transfusion within 7 days of screening * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN (≤ 5 x ULN for patients with liver involvement by lymphoma) * Lipase ≤ 1.5 x ULN * Total bilirubin ≤ 1.5 x ULN (\< 3 x ULN for patients with Gilbert's syndrome, patients with cholestasis due to compressive adenopathies of the hepatic hilum or documented liver involvement or with biliary obstruction due to lymphoma) * Adequate renal function defined by serum creatinine ≤1.5 x ULN or creatinine clearance (by Cockroft-Gault) ≥ 50 ml/min * Women of childbearing potential (WOCBP) 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 for WOCBP and for men 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, e.g. intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner, use of two forms of birth control, and sexual abstinence. The use of condoms by male patients is required unless the female partner is permanently sterile. * Ability to understand and the willingness to sign a written informed consent document Exclusion Criteria: * Patients receiving cancer therapy (i.e., chemotherapy, radiation therapy, immunotherapy, biologic therapy, hormonal therapy, surgery and/or tumor embolization) within 2 weeks of Cycle 1/Day 1 with the following exceptions: * Limited palliative radiation is allowed if completed \> 1 week of C1D1 * Systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone is allowed until C1D1. * Chronic systemic corticosteroid therapy at a daily dose higher than 15 mg prednisone or equivalent. * History of other malignancies, except: * Malignancy treated medically or surgically with curative intent and with no known active disease present for ≥2 years before the first dose of study drug * Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease * Adequately treated carcinoma in situ without evidence of disease. * Localized prostate cancer and low-risk prostate cancer on active surveillance * Within three months of autologous stem cell transplantation at time of starting study treatment * Within six months of allogeneic stem cell transplantation at time of starting study treatment or active graft vs. host disease requiring systemic treatment or prophylaxis within 6 weeks of starting study treatment * Vaccinated with live, attenuated vaccines of any kind \<4 weeks before first dose of study drug * History of or active autoimmune disease requiring systemic immunosuppression * Recent infection requiring intravenous antibiotics that was completed ≤7 days before the first dose of study drug, or any uncontrolled active systemic infection * Patients with ongoing use of prophylactic antibiotics are eligible as long as there is no evidence of active infection and the antibiotic is not included on the list of prohibited medications * Known bleeding disorders (eg, von Willebrand's disease) or hemophilia * History of stroke or intracranial hemorrhage within 3 months prior to enrollment * Known history of Human Immunodeficiency Virus (HIV) infection. All patients must be screened for HIV up to 28 days prior to study drug start using a blood test for HIV according to local regulations. * Hepatitis B (HBV) or hepatitis C (HCV). All patients must be screened for HBV and HCV up to 28 days prior to study drug start. Patients positive for HBsAg or HBcAb will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA. * CMV PCR positive at baseline * Major surgery within 4 weeks of first dose of study drug * Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety at undue risk * Uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization * Unable to swallow capsules or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel currently affecting absorption, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction * History of or concurrent condition of interstitial lung disease of any severity and/or severely impaired lung function (as judged by the investigator) * Concurrent diagnosis of pheochromocytoma * Lactating or pregnant. Women of child bearing potential must have a pregnancy test prior performed a maximum of 7 days before the start of treatment, and a negative result must be documented * Patients receiving any other anti-cancer study agents * Known lymphomatous involvement of the central nervous system * Seizure disorder requiring medication * Patients who require warfarin or other vitamin K antagonists for anticoagulation (other anticoagulants are allowed after consultation with the overall study chair). * Concurrent administration of medications or foods that are strong inhibitors or inducers of CYP3A, CYP3A substrates with NTI, and P-gp inhibitors taken within 7 days of starting study treatment. * Herbal medications excluded within 7 days of starting study treatment * Uncontrolled arterial hypertension despite optimal medical management * Type 1 or type 2 diabetes mellitus with a HbA1c \> 8.5% * Known hypersensitivity to any of the test drugs, test drug classes, or excipients in the formulation