A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter's Syndrome

Entry criteria for randomised trial component (standard of care and experimental arms): Inclusion criteria for the randomised trial component: * Suitable for anthracycline-containing chemo-immunotherapy. * Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS. * ECOG performance status of 0, 1, 2 or 3. * Age 16 years and over. * Signed written informed consent prior to performing any study-specific procedures. Exclusion criteria for the randomised trial component: * Prior therapy with CHOP or any anthracycline containing treatment at any time prior to randomisation. (Please note that pre-treatment with prednisolone up to 2mg/kg is allowed for up to 14 days prior to the start of treatment). * Ibrutinib-exposed CLL patients who have been newly diagnosed with RS within four weeks of their last dose of ibrutinib. (Ibrutinib-exposed CLL patients who discontinue ibrutinib due to toxicity or progressive CLL and later (more than four weeks) develop RS are not excluded from the randomised trial component). * Previous acalabrutinib exposure. (Prior exposure to other Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), or BCL-2 inhibitors is permitted, with the exception of patients who have progressed on ibrutinib - see exclusion criterion above). * Known central nervous system (CNS) involvement of CLL or DLBCL. * Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin. * Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, and active hepatitis * Positive serology for Hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg). In addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HBsAb status), a HBV deoxyribonucleic acid (DNA) test will be performed and if positive the patient will be excluded. * Known human immunodeficiency virus (HIV) positive. * Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease). * Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenprocoumon). * Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) \> 2 x the upper limit of normal (ULN). * Major surgery within 30 days prior to randomisation and/or inadequate recovery (at Investigators discretion) from any prior major surgery, toxicity or complications. * Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function. * Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. Stable and controlled atrial fibrillation is not an exclusion. * Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease. * History of significant cerebrovascular disease in the 6 months prior to randomisation, including intracranial haemorrhage. * Known or suspected hypersensitivity to components of the investigational products * Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment unless discussed and approved by the Chief Investigator or Clinical Coordinator via the Trials Office. * Current participation in any other interventional clinical study. * Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder). * Breast feeding women or women with a positive pregnancy test at screening. * Women of childbearing potential and men not willing to use highly effective contraception during study and for 12 months after last dose of study therapy. Highly effective contraception is defined as abstinence, hormonal birth control, intrauterine devices, vasectomy/surgical sterilisation. Entry criteria for single-arm relapsed Cohort 1: Inclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy): * Patients with relapsed/refractory RS who received anthracycline based chemotherapy with anti-CD20 monoclonal antibody If fewer than the expected number of patients from the randomised component enter into Cohort 1, patients from outside STELLAR with relapsed/refractory RS following chemo-immunotherapy (anthracycline based chemotherapy with anti-CD20 monoclonal antibody) will be able to join this cohort if they meet the eligibility criteria. The Trials Office will alert sites by email if any slots are released for patients outside of STELLAR, these must be booked with the Trials Office prior to registration. * ECOG performance status of 0, 1, 2 or 3. * Age 16 years and over. * Signed written informed consent prior to performing any study-specific procedures. Exclusion criteria for Cohort 1 (progressive RS following chemo-immunotherapy): * Previous acalabrutinib exposure. (Prior exposure to other Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), or BCL-2 inhibitors is permitted). * Known central nervous system (CNS) involvement of CLL or DLBCL. * Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin. * Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, and active hepatitis * Positive serology for Hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg). In addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HBsAb status), a HBV deoxyribonucleic acid (DNA) test will be performed and if positive the patient will be excluded. * Known human immunodeficiency virus (HIV) positive. * Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease). * Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenprocoumon). * Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) \> 2 x the upper limit of normal (ULN). * Major surgery within 30 days prior to registration and/or inadequate recovery (at Investigators discretion) from any prior major surgery, toxicity or complications. * Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function. * Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. Stable and controlled atrial fibrillation is not an exclusion. * Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease. * History of significant cerebrovascular disease in the 6 months prior to registration, including intracranial haemorrhage. * Known or suspected hypersensitivity to components of the investigational products * Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment unless discussed and approved by the Chief Investigator or Clinical Coordinator via the Trials Office. * Current participation in any other interventional clinical study. * Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder). * Breast feeding women or women with a positive pregnancy test at screening. * Women of childbearing potential and men not willing to use highly effective contraception during study and for 12 months after last dose of study therapy. Highly effective contraception is defined as abstinence, hormonal birth control, intrauterine devices, vasectomy/surgical sterilisation. Entry criteria for single arm Cohort 2 Inclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib): * Ibrutinib-exposed CLL patients who have developed biopsy-proven DLBCL-type RS within four weeks of last dose of ibrutinib. * No previous anthracycline treatment and suitable for anthracycline-containing chemo-immunotherapy. * Patients with CLL and newly diagnosed biopsy proven DLBCL-type RS. * ECOG performance status of 0, 1, 2 or 3. * Age 16 years and over. * Signed written informed consent prior to performing any study-specific procedures. Exclusion criteria for Cohort 2 (anthracycline-naïve RS patients, diagnosed while on ibrutinib): * Prior therapy with CHOP or any anthracycline containing treatment at any time prior to registration. (Please note that pre-treatment with prednisolone up to 2mg/kg is allowed for up to 14 days prior to the start of treatment). * Previous acalabrutinib exposure. (Prior exposure to other Bruton tyrosine kinase (BTK), phosphoinositide-3-kinase (PI3K), or BCL-2 inhibitors is permitted) * Known central nervous system (CNS) involvement of CLL or DLBCL. * Any other active malignancy that requires active treatment, with the exception of basal cell carcinoma, in-situ cervical cancer, and non-invasive squamous cell carcinoma of the skin. * Chronic or ongoing active infectious disease requiring systemic treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis, tuberculosis, and active hepatitis * Positive serology for Hepatitis B (HB) defined as a positive test for HB surface antigen (HBsAg). In addition, if negative for HBsAg but HB core antibody (HBcAb) positive (regardless of HBsAb status), a HBV deoxyribonucleic acid (DNA) test will be performed and if positive the patient will be excluded. * Known human immunodeficiency virus (HIV) positive. * Patients with active bleeding or history of bleeding diathesis (e.g. haemophilia, von Willebrand disease). * Patients receiving therapeutic anticoagulation with warfarin or equivalent (e.g. phenprocoumon). * Uncorrected prolonged prothrombin time (PT) or an activated partial thromboplastin time (APTT) \> 2 x the upper limit of normal (ULN). * Major surgery within 30 days prior to registration and/or inadequate recovery (at Investigators discretion) from any prior major surgery, toxicity or complications. * Patients with malabsorption syndrome or medical conditions significantly affecting gastrointestinal function. * Clinically significant cardiac disease including unstable angina, uncontrolled congestive heart failure, and unstable arrhythmias requiring therapy, with the exception of extra systoles or minor conduction abnormalities. Stable and controlled atrial fibrillation is not an exclusion. * Significant concurrent, uncontrolled severe medical condition including, but not limited to, renal, hepatic, haematological, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease. * History of significant cerebrovascular disease in the 6 months prior to registration, including intracranial haemorrhage. * Known or suspected hypersensitivity to components of the investigational products * Patients who have received treatment with any non-marketed drug substance or experimental therapy within 4 weeks prior to proposed start of treatment unless discussed and approved by the Chief Investigator or Clinical Coordinator via the Trials Office. * Current participation in any other interventional clinical study. * Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder). * Breast feeding women or women with a positive pregnancy test at screening. * Women of childbearing potential and men not willing to use highly effective contraception during study and for 12 months after last dose of study therapy. Highly effective contraception is defined as abstinence, hormonal birth control, intrauterine devices, vasectomy/surgical sterilisation.