Patients are eligible to be included in the study only if all of the following inclusion criteria and none of the exclusion criteria apply: Informed consent 1 Ability to understand the purpose and risks of the study and capable of giving signed informed consent which includes: (a) Compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol (b) Authorization to use protected health information (in accordance with national and local patient privacy regulations) 2 Provision of signed and dated, written ICF prior to any mandatory study specific procedures, sampling, and analyses The informed consent process is described in Appendix A 3. Age, sex 3 Age e"18 and d"65 years at the time of screening 4 Male or female Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. (a) Male participants: " Male participants: For genotoxic IMPs, the male participant should use a condom from enrolment, throughout the study and until the last dose of acalabrutinib, prednisone, or rituximab, or 3 months after the last dose of vincristine, cyclophosphamide, or doxorubicin, whichever is longer. For non-pregnant potentially childbearing partners, contraception recommendations should also be considered. (b) Female participants: " Women not of childbearing potential are defined either permanently sterilized (hysterectomy, bilateral oophorectomy, or bilateral salpingectomy), or postmenopausal. Women will be considered postmenopausal if for 12 months prior to the planned date of randomisation (without an alternative medical cause) the following apply: " Women < 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatment and follicle stimulating hormone levels in the postmenopausal range. " Women e" 50 years old would be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatment. " Women of childbearing potential who are sexually active with a nonsterilized male partner must agree to use one highly effective form of birth control from enrolment, throughout the study and 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is the longer. A highly effective method of contraception is defined as one with a failure rate of less than 1% per year when used consistently and correctly. Cessation of contraception after this point should be discussed with a responsible physician. Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea are not acceptable methods of contraception. A female condom and male condom should not be used together. All women of child bearing potential must have a negative serum pregnancy test result at Visit 1. " Highly effective birth control methods include: sexual abstinence (periodic abstinence, e.g., calendar, ovulation, symptothermal, post-ovulation methods), declaration of abstinence for the duration of exposure to IMP, and withdrawal are not acceptable methods of contraception], a vasectomised partner, Implanon®, bilateral tubal occlusion, intrauterine device/levonorgestrel intrauterine system, Depo-Provera"! injections, oral contraceptive, and Evra Patch"!, Xulane"!, or NuvaRing®. Women of childbearing potential must agree to use one highly effective methods of birth control, as defined above, from enrolment throughout the study and 12 months after the last dose of rituximab or cyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after the last dose of vincristine, and 2 days after the last dose of acalabrutinib, whichever is the longer. Type of patient and disease characteristics 5 Histologically documented DLBCL (a) Verification of DLBCL based on central review of local pathology report (b) FFPE tumor tissue sample sent to the central laboratory prior to first cycle of R-CHOP (Cycle 1 Day 1) (c) Central laboratory confirmation of non-GCB subtype of DLBCL by GEP (using the investigational LymphMark assay) prior to first cycle of investigational study treatment (Cycle 2 Day 1) 6 No prior treatment for DLBCL 7 Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2 with no deterioration over the previous 2 weeks prior to baseline or day of first dosing 8 International Prognostic Index (IPI) score of 2 to 5 (see Appendix L) 9 Disease Stage II, III, or IV by the Ann Arbor Classification (see Appendix K) 10 Measurable disease (e"1 lesion defined as e"1.5 cm in the longest dimension for nodal lesions, or e"1 cm in the longest dimension for extranodal lesions, as measured using CT with contrast [or MRI] per 2014 Lugano Classification [Cheson et al 2014], see Appendix J) 11 Adequate organ and marrow function as follows: (a) Adequate peripheral blood counts independent of growth factor or transfusion support during the screening period and at baseline, as follows: (i) Absolute neutrophil count (ANC) e"1.0×109/L (e"1,000/¼L), except in the case of bone marrow involvement (ii) Platelet count e"75×109/L (e"75,000/¼L), except in the case of bone marrow involvement when platelet count may be e"50×109/L (e"50,000/¼L) (b) Serum aspartate aminotransferase (AST) and alanine aminotransferase (ALT) d"3×upper limit of normal (ULN) (c) Total bilirubin d"1.5×ULN, unless directly attributable to Gilbert syndrome (d) Estimated creatinine clearance of e"40 mL/min, calculated by Cockcroft-Gault (using actual body weight), or serum creatinine d"2×ULN (i) Cockcroft-Gault equation for males: CrCL (mL/min) = Weight (kg) × (140 - Age) / 72 × serum creatinine (mg/dL) (ii) Cockcroft-Gault equation for females: CrCL (mL/min) = Weight (kg) × (140 - Age) × 0.85 / 72 × serum creatinine (mg/dL) 12 Left ventricular ejection fraction (LVEF) within institutional normal limits as determined by cardiac echocardiogram (ECHO) or multiple-uptake gated acquisition (MUGA) scan 13 Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty

Medical conditions 1 Evidence of disease (such as severe uncontrolled systemic diseases, including uncontrolled hypertension and renal transplant) that, in the investigator s opinion, make it undesirable for the patient to participate in the study or that would jeopardize compliance with the protocol 2 Known history of a bleeding diathesis (i.e., hemophilia, von Willebrand disease) 3 Refractory nausea and vomiting, inability to swallow the formulated product, or malabsorption syndrome, chronic gastrointestinal disease, gastric restrictions, or bariatric surgery such as gastric bypass, partial or complete bowel obstruction, or previous significant bowel resection that would preclude adequate absorption, distribution, metabolism, or excretion of study treatment 4 Known CNS lymphoma or leptomeningeal disease 5 Known primary mediastinal lymphoma 6 Known High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma [DHL or THL]) 7 Prior history of indolent lymphoma 8 History of or ongoing confirmed progressive multifocal leukoencephalopathy 9 History of prior malignancy that could affect compliance with the protocol or interpretation of results, except for the following: (a) Curatively treated basal cell carcinoma or squamous cell carcinoma of the skin or carcinoma in situ at any time prior to study (b) Malignancy treated with curative intent and with no known active disease present for e"3 years before randomization 10 Significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months before screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification at screening Note: Subjects with controlled, asymptomatic atrial fibrillation during screening are allowed to enroll in the study 11 Known history of infection with HIV 12 Active tuberculosis infection (clinical evaluation may include clinical history, physical examination and radiographic findings, or tuberculosis testing in line with local practice) 13 Any active uncontrolled systemic infection 14 Serologic status reflecting active hepatitis B or C infection (a) Subjects who are hepatitis B core antibody (anti-HBc) positive and hepatitis B surface antigen (HBsAg) negative are required to have a negative hepatitis B DNA PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Subjects who are HbsAg-positive or hepatitis B DNA PCR-positive will be excluded. (b) Subjects who are hepatitis C antibody positive are required to have a negative hepatitis C RNA PCR result before randomization. Subjects who are hepatitis C RNA PCR-positive will be excluded. 15 History of stroke or intracranial hemorrhage within 6 months before first dose of R-CHOP Prior/concomitant therapy 16 Any concurrent anticancer treatment, concurrent use of hormonal therapy for non-cancer-related conditions (e.g., hormone replacement therapy) is allowed 17 Prior anthracycline use e"150 mg/m2 18 Requiring or receiving anticoagulation with warfarin or equivalent vitamin K antagonists 19 Requiring continued treatment with a strong cytochrome P450 3A (CYP3A) inhibitor or use within 2 weeks of first study treatment (Cycle 1 Day 1), see details in Section 6.5.3.1 20 Use of a potent CYP3A inducer (e.g., St. John s wort) within 3 weeks of first study treatment (Cycle 1 Day 1), see details in Section 6.5.3.1 21 Requiring treatment with proton pump inhibitors (i.e., omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole), subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study 22 Receiving a live virus vaccination within 28 days before the first dose of study treatment (Cycle 1 Day 1) or during study treatment 23 Major surgical procedure (excluding placement of vascular access) or significant traumatic injury within 30 days of the first dose of study treatment (Cycle 1 Day 1), or anticipated need for major surgery during the study Prior/concurrent clinical study experience 24 Involvement in the planning or conduct of this study (applies to sponsor staff and staff at any study site) 25 Concurrent participation in another therapeutic clinical trial or participation in another clinical study with an investigational product or investigational medicinal device within 30 days prior to first dose of study treatment (Cycle 1 Day 1) 26 History of known hypersensitivity or anaphylactic reactions to study treatments or any product excipients Other exclusions 27 Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements 28 Females currently pregnant (confirmed with positive pregnancy test) or breastfeeding