A randomised Phase II Evaluation of Molecular Guided Therapy for Diffuse Large B-Cell Lymphoma with Acalabrutinib

1.Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to HMDS for gene expression profiling and central pathology review. The following diagnoses by 2016 WHO classification of lymphoid neoplasms may be included: • DLBCL, not otherwise specified (NOS) • T-cell/histiocyte-rich large B-cell lymphoma • Epstein-Barr virus positive DLBCL, NOS • ALK-positive large B-cell lymphoma • HHV8-positive DLBCL, NOS • High-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (double-hit or triple-hit lymphoma) • High-grade B-cell lymphoma, NOS 2. At least one bi-dimensionally measurable lesion, defined as > 1.5 cm in its longest dimension as measured by CT 3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent 4. Stage IAX (bulk defined as lymph node mass [either single or conglomerate] diameter > 7.5cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be eligible. 5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma. 6. Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at study entry, unless lower figures are attributable to lymphoma. 7. Measured or calculated creatinine clearance > 30mls/min, (calculated using the formula of Cockcroft and Gault [(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for men))/Serum Creatinine (µmolL)]). 8. Serum bilirubin < 35μmol/L and transaminases < 1.5x upper limit of normal at time of study entry. 9. Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than institutional normal range. 10. No concurrent uncontrolled medical condition. 11. Life expectancy > 3 months. 12. Aged 16 years or above. 13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent.

1. Previous history of treated or untreated indolent lymphoma. Newly diagnosed patients with DLBCL found to have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible. 2. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible. 3. Diagnosis of primary mediastinal lymphoma. 4. Diagnosis of primary Central Nervous System lymphoma or secondary CNS involvement. 5. History of stroke or intracranial haemorrhage in preceding 6 months. 6. History of bleeding diathesis (e.g.haemophilia, von Willebrand disease). 7. History of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Requires or receiving anticoagulation with warfarin or equivalent antagonists (e.g. phenprocoumon) within 7 days of first dose of acalabrutinib. Patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible, as will those receiving direct oral anticoagulants. 9. Prior exposure to an inhibitor in the BCR pathway (e.g. Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (e.g. ABT-199). 10. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 11. Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). 12. Active significant infection (e.g. progressive multifocal leukoencephalopathy (PML)). 13. Uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP). 14. Major surgery in the preceding 4 weeks of first dose of study drug. 15. Corticosteroid use > 30 mg/day of prednisone or equivalent, for purposes other than for lymphoma symptom control. Patients receiving corticosteroid treatment with < 30 mg/day of prednisone or equivalent must be documented to be on a stable dose of at least 4 weeks’ duration prior to the start of Cycle 1. If glucocorticoid treatment is urgently required for lymphoma symptom control prior to the start of study treatment, prednisone 100 mg or equivalent could be given for a maximum of 14 days as a prephase. A dose of upto 30mg or prenisolone or equivalent may be used during the screening phase to control symptoms. 16. Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification. 17. Serological positivity for Hepatitis B, C, or known HIV infection. a. Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. b. Patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. 18. Women who can bear children must agree to use two highly effective forms of contraception or abstinence during the study and for 12 months after the last treatment dose. 19. Breastfeeding or pregnant women. 20. Men who can father children must agree to use two highly effective forms of contraception with additional barrier or abstinence during the study and for 12 months after the last treatment dose. 21. Men must agree to refrain from sperm donation during the study and for 12 months after the last treatment dose. 22. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent. 23. Prior malignancy (other than DLBCL), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for > = 2 years or which will not limit survival to < 2 years. 24. Has difficulty with or is unable to swallow oral medication, or has significant gastrointestinal disease, resection of the stomach or small bowel, partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass that would limit absorption of oral medication. 25. Any immunotherapy within 4 weeks of 1st dose. 26. Concurrent participation in another therapeutic clinical trial.