Acalabrutinib and Rituximab in Previously Untreated Mantle Cell Lymphoma

Inclusion criteria:

1. Men and women ≥ 60 years of age.

2. Pathologically confirmed MCL, with documentation of monoclonal B cells that have achromosome 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 assessedby echocardiogram

• Significant co-morbidities or cardiac risk factors makinganthracycline-containing chemotherapy inadvisable

• Heart failure clinically determined by the presence of New York HeartAssociation (NYHA) failure grade II due to a cause other than MCL

• Impaired respiratory function with DLCO and/or FVC/FEV1 ratio less than 75% ofpredicted due to a cause other than MCL

• Significant respiratory illness e.g. moderate chronic obstructive pulmonarydisease (COPD) bronchiectasis

• Other co-morbidities that in the Investigator's opinion which would precludethe use of standard full dose immuno-chemotherapy (to be discussed on acase-by-case basis with the TMG, via UCL CTC)

6. Willing and able to participate in all required evaluations and procedures in thisstudy protocol including swallowing capsules/tablets 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.

Exclusion criteria:

1. Any prior therapy (including targeted inhibitors) for MCL (other than priorlocalised radiotherapy, a 10-day pulse of high dose steroids or continuousprednisolone above 20mg od or equivalent for symptom control).

2. Patients considered by the investigator fit enough to receive standard, full dosecytotoxic immunochemotherapy as treatment for non-transplant eligible MCL e.g., fulldose R-CHOP, VR-CAP, R-Bendamustine, R-FC.

3. Prior malignancy (or any other malignancy requiring active treatment), except foradequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,localised prostate cancer or other cancer from which the subject has been diseasefree for ≥ 2 years or which will not limit survival to < 5 years.

4. Clinically significant cardiovascular disease such as uncontrolled arrhythmias, ormyocardial infarction within 6 months of screening, or any Class 3 or 4 cardiacdisease as defined by the New York Heart Association (NYHA) FunctionalClassification (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, orgastric 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 Willebranddisease).

9. Uncontrolled AIHA (autoimmune haemolytic anaemia) or ITP (idiopathicthrombocytopenic purpura).

10. Known presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 monthsbefore screening.

11. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.

12. Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists (e.g. phenprocoumon) within 7 days prior to the first dose of studydrug.

13. Prothrombin time (PT)/INR or aPTT (in the absence of lupus anticoagulant) > 2 xupper limit of normal (ULN).

14. Requires treatment with proton pump inhibitors (e.g. omeprazole, esomeprazole,lansoprazole, rabeprazole, or pantoprazole). Subjects receiving proton pumpinhibitors who switch to H2-receptor antagonists or antacids are eligible forenrolment to this study.

15. History of significant cerebrovascular disease/event, including stroke orintracranial 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 anytoxicity and/or complications from the intervention before the first dose of studydrug.

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 anegative polymerase chain reaction (PCR) test. Those who are hepatitis B surfaceantigen (HbsAg) positive or hepatitis B PCR positive will be excluded. Those who arehepatitis C antibody or PCR positive will be excluded (those who are hepatitis Cantibody positive but PCR negative will not be excluded). Note, if a patient withknown HBV or HCV infection who is on current antiviral treatment meets serologycriteria for trial eligibility then the case must be discussed with the TMG prior toregistering the patient.

18. Absolute neutrophil count <1.0 x 109/L (or requires growth factor support tomaintain absolute neutrophil count >1.0 x 109/L) and/or platelets <75 x109/L unlessrelated to bone marrow infiltration or splenomegaly due to underlying MCL (whereplatelets between 50-75 x109/L are acceptable)

19. Total bilirubin > 1.5 x ULN, unless due to Gilbert's syndrome or of non-hepaticorigin.

20. AST and/or ALT > 3 x ULN.

21. Calculated creatinine clearance <30 mL/min.

22. History of or ongoing confirmed 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