Assessing a ctDNA and PET-oriented Therapy in Patients With DLBCL A Multicenter, Open-label, Phase II Trial.

Inclusion Criteria: * Written informed consent according to ICH GCP E6(R2) regulations before registration and prior to any trial specific procedures. * Histologically confirmed, treatment-naïve DLBCL, NOS that fulfill all the following: * Patient eligible for 6 cycles of R-CHOP * Ann Arbor stage I-IV * Metabolically active measurable disease by 18FDG PET-CT * No previous treatment with systemic chemotherapy or radiotherapy (a pre-phase treatment with steroids for up to a total of 10 days is allowed; baseline PET/CT, liquid biopsy and bone marrow biopsy and aspirate must be collected either before or within a maximum of 5 days after steroid pre-phase treatment starts. If a patient receives steroids, glucose levels must be checked and be normal on the day of PET/CT before the exam. * At least 1 measurable site of disease according to Revised Response Criteria for Malignant Lymphoma. The site of disease must be greater than 1.5 cm in the long axis regardless of short axis measurement or greater than 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions. * Quantifiable and qualifiable circulating tumor DNA * Patients with a prior malignancy and treated with curative intention are eligible if all treatment of that malignancy was completed at least 2 years before registration and the patient has no evidence of disease at registration. Less than 2 years is acceptable for malignancies with low risk of recurrence and/or no late recurrence. * Age ≥ 18 years * EGOG performance status 0-2 (or 3 if due to disease) * Adequate bone marrow function: neutrophil count ≥ 1.0 x 109/L, platelet count ≥ 75 x 109/L (unless due to bone marrow involvement: in this case the permitted limit is ≥ 50 x 109/L) with allowed premedication or supportive medication. * Adequate hepatic function: total bilirubin ≤ 1.5 x ULN (except for patients with Gilbert's disease ≤ 3.0 x ULN), AST, ALT ≤ 2.5 x ULN, or ≤ 5 x ULN under the assumption that abnormal values are a result of liver involvement by lymphoma * Adequate renal function: estimated glomerular filtration rate (eGFR) ≥ 30 mL/min/1.73 m2 (according to CKD-EPI formula) * Adequate cardiac function: Left ventricular Ejection Fraction (LVEF) ≥ 50% as determined by echocardiography (ECHO) * Adequate coagulation function: INR ≤ 1.5 x ULN (the ULN for INR is defined with the value 1.2 for all sites, in case no ULN is documented in the lab certificates/sheets), aPTT ≤ 1.5 x ULN. * Women of childbearing potential must use highly effective contraception, are not pregnant or lactating and agree not to become pregnant during trial treatment and until 12 months after the last dose of investigational drug. A negative pregnancy test before inclusion into the trial is required for all women of childbearing potential. (www.swissmedicinfo.ch). * Men agree not to donate sperm or to father a child during trial treatment and until 12 months after the last dose of investigational drug * Patient is able and willing to swallow trial drug as whole capsule or tablet. * Patient is willing to participate in translational research projects Exclusion criteria: * CNS lymphoma involvement * Stage I disease that has been completely surgically excised (not measurable) * Specific diagnostic categories of large B-cell lymphoma such as high grade B-cell lymphoma, primary mediastinal large B-cell lymphoma, primary central nervous system lymphoma, T-cell/histiocyte-rich large B-cell lymphoma, intravascular large B-cell lymphoma, plasmablastic lymphoma, lymphomatoid granulomatosis, primary effusion lymphoma or transformed lymphoma etc. * Concomitant treatment with any other experimental drug * Severe or uncontrolled cardiovascular disease (congestive heart failure NYHA III or IV; unstable angina pectoris, history of myocardial infarction within the last six months, serious arrhythmias requiring medication (with exception of asymptomatic or rate controlled atrial fibrillation or paroxysmal supraventricular tachycardia), significant QT-prolongation, uncontrolled hypertension. * Uncontrolled systemic infection. * History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML). * History of cerebrovascular accident or intracranial hemorrhage within 6 months prior to registration * History of bleeding diathesis (eg, haemophilia, von Willebrand disease). * Major surgery in the preceding 4 weeks of first dose of study drug. If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug. * Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass. * History or presence of clinically relevant central nervous system (CNS) pathology as epilepsy, seizure, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome, psychosis. * Known history of human immunodeficiency virus (HIV) or active chronic hepatitis C or hepatitis B virus infection or any uncontrolled active systemic infection requiring intravenous (iv) antimicrobial treatment. 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. All patients must be screened for hepatitis up to 28 days prior to study drug start using the routine hepatitis virus laboratory panel. Patients positive for hepatitis B surface antigen (HBsAg) or hepatitis B core antibody (HBcAb) will be eligible if they are negative for HBV-DNA, these patients should receive prophylactic antiviral therapy and have HBV-DNA testing every 4 months. Patients positive for anti-HCV antibody will be eligible if they are negative for HCV-RNA. * Active, uncontrolled autoimmune phenomenon (autoimmune hemolytic anemia or immune thrombocytopenia) requiring steroid therapy with \> 20 mg daily of prednisone dose or equivalent. * Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg, phenprocoumon), 'dual' antiplatelet therapy (DAPT), such as aspirin and clopidogrel. However, use of therapeutic low molecule weight heparin, direct oral anticoagulants, or low dose anti-platelet agents is allowed. * Concomitant treatment to acalabrutinib capsules or tablets with strong CYP3A inducers or strong CYP3A inhibitors. The use of strong CYP3A inhibitors within 1 week or strong CYP3A inducers within 3 weeks of the first dose of acalabrutinib is prohibited. * Co-administration of acalabrutinib capsules with proton pump inhibitors (PPIs). * Any concomitant drugs contraindicated for use with the trial drugs according to the approved product information * Known hypersensitivity to trial drug(s) or to any component of the trial drug(s) * Any other serious underlying medical, psychiatric, psychological, familial or geographical condition, which in the judgment of the investigator may interfere with the planned staging, treatment and follow-up, affect patient compliance or place the patient at high risk from treatment-related complications.