Zanubrutinib Plus Rituximab for Patients With Indolent Mantle Cell Lymphoma

Inclusion Criteria:

1. 18 years of age or over.

2. Life expectancy ≥ 6 months.

3. Pathologically confirmed MCL, with documentation of monoclonal B cells that have achromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1, D2 or D3.

4. Stage II-IV MCL measurable by CT imaging or by white cell count (WCC)/BMinfiltration.

5. 'Indolent' MCL, defined as 1 or more of the following:

• Observation with no treatment for a minimum of 6 months after the initialdiagnosis

• Leukaemic non-nodal variant (lymphocytosis/splenomegaly only without nodalinvolvement)

• Low tumour volume (largest lymph node ≤ 3cm in maximal diameter), proliferationfraction (Ki67 or equivalent) ≤30% and classical morphology (non-blastoid/pleomorphic)

6. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.

7. Absolute neutrophil count ≥1.0 x 109/L and platelets ≥75 x 109/L independent ofgrowth factor support.

8. AST and/or ALT ≤3 x upper limit of normal (ULN).

9. Total Bilirubin ≤1.5 x ULN unless due to Gilberts syndrome or of non-hepatic originunless directly attributable to the patient's MCL.

10. Calculated creatinine clearance ≥30 mL/min. Glomerular filtration rate (GFR) ≥30mL/min directly measured with 24 hour urine collection, or creatinine clearancecalculated according to the modified formula of Cockcroft and Gault (for men: GFR ≈ ((140 - age) x bodyweight)/ (72 x creatinine), for women x 0, 85).

11. Able to give voluntary written informed consent.

12. Willing and able to participate in all required evaluations and procedures in thisstudy protocol including swallowing capsules without difficulty.

13. Negative serum or urine pregnancy test for women of childbearing potential (WOCBP).

14. Willing to comply with the contraceptive requirements of the trial.

Exclusion Criteria:

1. Any prior therapy for MCL, including prior radiotherapy.

2. Central nervous system (CNS) involvement of MCL.

3. Uncontrolled infection with HIV or any uncontrolled active systemic infection (e.g.,bacterial, viral or fungal). Patients with well-controlled HIV status (undetectableviral load) will not be excluded.

4. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HB core) positive and who are surface antigen (HBsAg) negative will need tohave a negative polymerase chain reaction (PCR) test. Those who are hepatitis BHbsAg positive or hepatitis B PCR positive will be excluded. Those who are hepatitisC antibody and PCR positive will be excluded (those who are hepatitis C antibodypositive and PCR negative will not be excluded).

5. No progression requiring treatment since initial diagnosis.

6. Vaccinated with live vaccines (not including messenger ribonucleic acid (mRNA),viral vector or other non-live COVID19 vaccines) within four weeks prior torandomisation.

7. Major surgical procedure within 28 days prior to randomisation. Note: If a subjecthad major surgery, they must have recovered adequately from any toxicity and/orcomplications from the intervention before the first dose of study drug.

8. 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.

9. Requirement for moderate or strong CYP3A inducers. Moderate and strong CYP3Ainhibitors are allowed although these should be switched to agents causing lessCYP3A inhibition where possible.

10. Requirement for vitamin K antagonists (alternative anticoagulation is allowed (e.g.DOACs), but patients must be properly informed about the potential risk of bleedingalongside zanubrutinib). Requires ongoing treatment with warfarin or warfarinderivatives

11. Active bleeding or history of bleeding diathesis (e.g. haemophilia or von Willebranddisease) or history of spontaneous bleeding requiring blood transfusion or othermedical intervention.

12. Clinically significant cardiovascular disease such as uncontrolled arrhythmias, orhistory of ventricular tachycardia, ventricular fibrillation, torsades de points ormyocardial infarction within 6 months of randomisation, or any Class 3 or 4 cardiacdisease as defined by the New York Heart Association (NYHA) FunctionalClassification, or corrected QT interval (QTc) > 480 msec, second-degreeatrioventricular block Type II, third-degree atrioventricular block atrandomisation, unstable angina within 3 months prior to randomisation.

13. History of stroke or intracranial haemorrhage within 6 months prior torandomisation.

14. Any other severe medical or psychiatric illness that in the opinion of theinvestigator would interfere with participation in this clinical study.

15. Malabsorption syndrome, unable to swallow capsules, disease significantly affectinggastrointestinal function, or resection of the stomach or small bowel that is likelyto affect absorption, symptomatic inflammatory bowel disease, partial or completebowel obstruction, or gastric restrictions and bariatric surgery, such as gastricbypass.

16. Women who are pregnant or breastfeeding.

17. Male participants with female partners of childbearing potential who are unwillingto use appropriate contraception methods.

18. Concurrent treatment with another investigational agent.

19. History of severe allergic or anaphylactic reactions to humanized or murinemonoclonal antibodies, known sensitivity or allergy to murine products.

20. Known hypersensitivity to any active substance or to any of the excipients of one ofthe drugs used in the trial.

21. Severe or debilitating pulmonary disease.

22. Underlying medical conditions that, in the investigator's opinion, will render theadministration of study drug hazardous or obscure the interpretation of toxicity orAEs

23. Concurrent participation in another therapeutic clinical trial.

24. Active and/or ongoing autoimmune anaemia and/or autoimmune thrombocytopenia (eg.idiopathic thrombocytopenia purpura).