Phase II Study of Acalabrutinib and Rituximab for Elderly or Frail Patients with Previously Untreated Mantle Cell Lymphoma

1. Men and women ≥ 60 years of age. 2. Pathologically confirmed MCL,with documentation of monoclonal B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1. 3. Stage II-IV MCL and requiring treatment in the opinion of the treating clinician. 4. Eastern Cooperative Oncology Group (ECOG) performance status 0-3 5. One or more of the following: - Age 80 years or more - Cumulative Illness Rating Scale for Geriatrics (CIRS-G) score 6 or greater - Left ventricular ejection fraction (LVEF) less than or equal to 50% as assessed by echocardiogram - Significant co-morbidities or cardiac risk factors making anthracycline-containing chemotherapy inadvisable - Heart failure clinically determined by the presence of New York Heart Association (NYHA) failure grade II due to a cause other than MCL - Impaired respiratory function with DLCO and/or FVC/FEV1 ratio less than 75% of predicted due to a cause other than MCL - Significant respiratory illness e.g. moderate chronic obstructive pulmonary disease (COPD) bronchiectasis - Other co-morbidities that in the Investigator’s opinion which would preclude the use of standard full dose immuno-chemotherapy (to be discussed on a case-by-case basis with the TMG,via UCL CTC) 6. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty. 7. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP). 8. Willing to comply with the contraceptive requirements of the trial 9. Written informed consent.

1. Any prior therapy (including targeted inhibitors) for MCL (other than prior localised radiotherapy,a 10-day pulse of high dose steroids or continuous prednisolone above 20mg od or equivalent for symptom control). 2. Patients considered by the investigator fit enough to receive standard,full dose cytotoxic immunochemotherapy as treatment for non-transplant eligible MCL e.g.,full dose R-CHOP,VR-CAP,R-Bendamustine,R-FC. 3. Prior malignancy (or any other malignancy requiring active treatment),except for adequately treated basal cell or squamous cell skin cancer,in situ cervical cancer,localised prostate cancer or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 5 years. 4. Clinically significant cardiovascular disease such as uncontrolled arrhythmias,or myocardial infarction within 6 months of screening,or any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification (33),or corrected QT interval (QTc) > 480 msec at screening. 5. Malabsorption syndrome,disease significantly affecting gastrointestinal function,or resection of the stomach or small bowel that is likely to affect absorption,symptomatic inflammatory bowel disease,partial or complete bowel obstruction,or gastric restrictions and bariatric surgery,such as gastric bypass. 6. Known history of infection with HIV or any uncontrolled active systemic infection (e.g.,bacterial,viral or fungal). 7. Known history of drug-specific hypersensitivity or anaphylaxis to any study drug (including active product or excipient components). 8. Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebrand disease). 9. Uncontrolled AIHA (autoimmune haemolytic anaemia) or ITP (idiopathic thrombocytopenic purpura). 10. Known presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before screening. 11. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer. 12. Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists (e.g. phenprocoumon) within 7 days prior to the first dose of study drug. 13. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) > 2 x upper limit of normal (ULN). 14. Requires treatment with proton pump inhibitors (e.g. omeprazole,esomeprazole,lansoprazole,rabeprazole,or pantoprazole). Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study. 15. History of significant cerebrovascular disease/event,including stroke or intracranial haemorrhage,within 6 months before the first dose of study drug. 16. Major surgical procedure within 28 days prior to the first dose of study drug. Note: 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. 17. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HB core) positive and who are surface antigen negative will need to have a negative polymerase chain reaction (PCR) test. Those who are hepatitis B surface antigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Those who are hepatitis C antibody or PCR positive will be excluded (those who are hepatitis C antibody positive but PCR negative will not be excluded). Note,if a patient with known HBV or HCV infection who is on current antiviral treatment meets serology criteria for trial eligibility then the case must be discussed with the TMG prior to registering the patient. 18. Absolute neutrophil count < 1.0 x 109/L (or requires growth factor support to maintain absolute neutrophil count > 1.0 x 109/L) and/or platelets < 75 x109/L unless related to bone marrow infiltration or splenomegaly due to underlying MCL (where platelets between 50-75 x109/L are acceptable) 19. Total bilirubin > 1.5 x ULN,unless due to Gilbert's syndrome or of non-hepatic origin. 20. AST and/or ALT > 3 x ULN. 21. Calculated creatinine clearance < 30 mL/min. 22. Active central nervous system (CNS) involvement 23. Breastfeeding or pregnant. 24. Concurrent participation in another therapeutic clinical trial. 25. Live vaccine within 28 days prior to the first study drug dose