A Study of Acalabrutinib Plus Venetoclax and Rituximab in Participants With Treatment Naïve Mantle Cell Lymphoma

Inclusion Criteria: Age 1. Participant must be ≥ 18 years or the legal age of consent in the jurisdiction in which the study is taking place, whichever is greater, at the time of signing the informed consent. Type of Participant and Disease Characteristics 2. Histologically documented MCL based on criteria established by the World Health Organization with documentation of chromosomal translocation t(11;14) (q13;q32) and/or overexpression of cyclin D1 in association with other relevant markers (e.g., CD5, CD19, CD20 or PAX5). 3. Clinical Stage II, III, or IV by Ann Arbor Classification and requiring systemic treatment in the opinion of the treating clinician. 4. At least 1 measurable site of disease per Lugano Classification for NHL (Appendix K). The site of disease must be \> 1.5 cm in the long axis regardless of short axis measurement or \> 1.0 cm in the short axis regardless of long axis measurement, and clearly measurable in 2 perpendicular dimensions, as assessed by diagnostic quality CT (MRI may be used for participants who are either allergic to CT contrast media or have renal insufficiency that per institutional guidelines restricts the use of CT contrast media). OR Participant with leukemic non-nodal MCL presentation with splenomegaly (spleen \>13 cm in length cranial to caudal) and Bone Marrow (BM) involvement. 5. Eastern Cooperative Oncology Group PS of 0, 1, or 2 and ECOG PS of 3 if poor PS is due to lymphoma. 6. Confirmed availability of sufficient FFPE tumour samples for central laboratory genomic profiling, including TP53 and clone identification for MRD testing per clonoSEQ® assay. Participants with leukemic non-nodal MCL may be enrolled with available BM tissue. For non-nodal leukaemic MCL participants and when nodal or extranodal tissue is not easily accessible and an invasive biopsy will cause a significant risk to the participant, the participant can be enrolled without a tissue biopsy if MCL BM involvement is confirmed by a BM biopsy and sufficient BM biopsy and aspirate provided for TP53 testing, tumour profiling and clone identification for MRD testing. 7. Adequate organ and bone marrow function. Sex and Contraceptive/Barrier Requirements 8 Male and/or female Contraceptive use by males or females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. 1. Male participants: \- Male participants with a female partner of child-bearing potential should use a condom from enrolment, throughout the study until 90 days following the last dose of venetoclax or rituximab, whichever is longer. * For non-pregnant potentially childbearing partners, contraception recommendations should also be considered. A male participant must agree to refrain from sperm donation throughout the study until 90 days following the last dose of venetoclax or rituximab, whichever is longer. 2. Female participants: * Women of childbearing potential must have negative serum pregnancy test result prior to the start of study intervention (Cycle 1 Day 1) and agree to abstain from breastfeeding during study participation and at least 12 months after the last drug administration. * Female participants of childbearing potential who are sexually active with a nonsterilized male partner must agree to use at least one highly effective form of birth control from enrolment, throughout the study and at least 2 days after the last dose of acalabrutinib, at least 6 months after the last dose of venetoclax, and at least 12 months after the last dose of rituximab, whichever is longer. Informed Consent 9 Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the ICF and in this protocol. Informed consent may be given either by the participant or their legally authorised representative. 10 Provision of signed and dated written Optional Genetic Research Information informed consent prior to collection of samples for optional genetic research that supports the Genomic Initiative. Exclusion Criteria: Medical Conditions 1. Active CNS involvement by lymphoma or leptomeningeal disease 2. Current or previous active malignancies requiring anticancer therapy except: \- adequately treated basal cell or squamous cell skin cancer \- in situ cancer \- history of cancer with no evidence of recurrence for ≥ 2 years before enrolment \- local radiotherapy with a field that does not overlap with sites of current MCL disease and given at least 3 months prior to the screening PET-CT scan and the participant had recovered from any associated toxicity. \- anti-hormonal therapies are permitted after discussion with the sponsor's medical monitor 3. Participants for whom the goal of therapy is tumour debulking before ASCT 4. Any severe or life-threatening illness, medical condition (e.g., uncontrolled hypertension, bleeding diathesis), or organ system dysfunction which, in the investigator' opinion, could compromise the participant safety, interfere with the absorption or metabolism of study intervention (acalabrutinib, rituximab, venetoclax) or put the study outcomes at undue risk 5. Clinically significant cardiovascular disease such as uncontrolled or untreated symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 (moderate) or Class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification, or QTc \> 480 msec at screening. Exception: Participants with controlled, asymptomatic atrial fibrillation during screening may enroll. 6. Any active uncontrolled infection (bacterial, viral, fungal, or other infection including tuberculosis), defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment, which in the investigator's opinion makes it undesirable or pose a safety risk for the participant to participate in the study. 7. HIV infection. As per standard of care, results of HIV serology should be known prior to start of study intervention. In the acute situation, registration may occur without the results of the HIV serology but must be available prior to start of study intervention Excluded Participants: Participants with active HIV infection (i.e., with detectable viral load by PCR) are excluded. Included Participants: HIV-positive participants receiving anti-retroviral treatment with undetectable viral load by PCR may be enrolled following discussion with the participant's HIV physician and the sponsor medical monitor. Potential interactions between anti-retroviral medications and study interventions should be considered. 8. Serologic status reflecting active hepatitis B or C. As per standard of care, results of hepatitis serology should be known prior to start of study intervention. In the acute situation, enrolment may occur without the results of the hepatitis serology but must be available prior to start of study intervention. 1. Participants who are HBsAg positive or HBV-DNA PCR positive will not be eligible. Participants who are anti-HBc IgG antibody positive and who are HBsAg negative will need to have a negative PCR result before enrolment. Participants who have protective titres of HBsAb after vaccination will be eligible. 2. Participants who are hepatitis C antibody positive and are HCV-PCR positive will not be eligible. 9. History or ongoing confirmed progressive multifocal leukoencephalopathy. 10. History of stroke or intracranial haemorrhage within 6 months prior to the first dose of study intervention (Cycle 1 Day 1). 11. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura. 12. Active bleeding from a gastrointestinal ulcer, except incidental finding identified on endoscopy that is attributable to MCL 13. Participants with a known hypersensitivity to acalabrutinib, venetoclax, or rituximab or any of the excipients of the product. 14. Known allergy to uric acid lowering agents (e.g., xanthine oxidase inhibitors or rasburicase) 15. Severe prior reactions to monoclonal antibodies 16. Known glucose-6-phosphate dehydrogenase deficiency 17. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach, extensive small bowel resection 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 or inability to swallow the formulated product (tablets). 18. Currently pregnant (confirmed with positive pregnancy test) or breast feeding Prior/Concomitant Therapy 19. Any prior therapies for the treatment of MCL with the exception of involved site radiotherapy given at least 3 months prior to screening PET-CT scan and where the radiotherapy field does not overlap areas of current disease activity. 20. Requiring continued treatment with a strong CYP3A4 inhibitor/inducer or its use within 7 days prior to the first dose (Cycle 1 Day 1) of acalabrutinib or venetoclax 21 Requiring continued anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon). Exceptions are DOACs rivaroxaban, apixaban, edoxaban and dabigatran 22 Requiring ongoing immunosuppressive therapy, including systemic or enteric corticosteroids except: * Topical or inhaled corticosteroids or low-dose oral steroids (≤ 20 mg of prednisone or equivalent per day) as a therapy for comorbid conditions * Short courses of glucocorticoids in excess of 20 mg prednisone for no more than 14 days for comorbid conditions. * Systemic use of corticosteroids as a pre-phase to control MCL manifestations (up to approximately 100 mg prednisolone or equivalent daily) for up to 10 days. 23 Received major surgery (excluding placement of vascular access or for diagnosis) within 28 days of first dose of study intervention (Cycle 1 Day 1) 24 Receipt of live, attenuated vaccine within 28 days before the first dose of study intervention (Cycle 1 Day 1). See Section 6.9, for lists of prohibited (Table 15) and restricted (Table 16) concomitant medications. Prior/Concurrent Clinical Study Experience 25 Concurrent participation in another therapeutic clinical trial or participation in another clinical study with an investigational product or investigational medicinal device within 30 days prior to first dose of study treatment (Cycle 1 Day 1). Other Exclusions 26 Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site). 27 Judgement by the investigator that the participant should not participate in the study if the participant is unlikely to comply with study procedures, restrictions, and requirements. 28 Previous enrolment in the present study.