A Study to Evaluate Acalabrutinib, in Combination With the R-CHOP Standard of Care, for Previously Untreated Mantle Cell Lymphoma in Spain

INCLUSION CRITERIA:

1. Adult men or women.

2. Pathologically confirmed MCL, with documentation of chromosome translocationt(11;14)(q13;q32) and/or overexpression of cyclin D1 in association with otherrelevant markers.

3. MCL requiring treatment and for which no prior systemic anticancer therapies havebeen received.

4. Unsuitable for autologous stem cell transplantation.

5. Presence of radiologically measurable lymphadenopathy, splenomegaly and/orextranodal lymphoid malignancy.

6. Eastern Cooperative Oncology Group (ECOG) performance status of ≤2.

7. Men who are sexually active and can beget children must agree to use highlyeffective forms of contraception during the study treatment and for 12 months afterthe last dose of rituximab or cyclophosphamide, 6 months after the last dose ofdoxorubicin, 30 days after the last dose of vincristine, and 2 days after the lastdose of acalabrutinib, whichever is longest.

8. Men must agree to refrain from sperm donation during the study treatment and for 12months after the last dose of rituximab or cyclophosphamide, 6 months after the lastdose of doxorubicin, 30 days after the last dose of vincristine, and 2 days afterthe last dose of acalabrutinib, whichever is longest.

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

10. Ability to understand the purpose and risks of the study and provide signed anddated informed consent and authorization to use protected health information (inaccordance with national and local patient privacy regulations).

11. WOCBP who are sexually active must use highly effective methods of contraceptionduring the study treatment and for 12 months after the last dose of rituximab orcyclophosphamide, 6 months after the last dose of doxorubicin, 30 days after thelast dose of vincristine, and 2 days after the last dose of acalabrutinib, whicheveris the longest.

12. Male patients should use barrier contraception from the time of screening until 12months after the last dose of rituximab or cyclophosphamide, 6 months after the lastdose of doxorubicin, 30 days after the last dose of vincristine, and 2 days afterthe last dose of acalabrutinib, whichever is longest. Male patients wishing tofather children in the future should be advised to arrange for the freezing of spermprior to the start of study treatment.

EXCLUSION CRITERIA:

1. History of prior malignancy except for the following:

2. Malignancy treated with curative intent and with no evidence of active diseasepresent for more than 2 years before screening and felt to be at low risk forrecurrence by treating physician.

3. Adequately treated lentigo maligna melanoma without current evidence of diseaseor adequately controlled nonmelanomatous skin cancer.

4. Adequately treated carcinoma in situ without current evidence of disease.

5. Subjects for whom the goal of therapy is tumor debulking before stem celltransplant.

6. Subjects who are deemed by the treating physician to be unfit to tolerate the R-CHOPregimen.

7. Any history of central nervous system (CNS) lymphoma or leptomeningeal disease.

8. Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenicpurpura (ITP).

9. Major surgical procedure within 28 days before first dose of study drug.

10. Significant cardiovascular disease such as uncontrolled or untreated symptomaticarrhythmias, congestive heart failure, or myocardial infarction within 6 months offirst dose of study drug, or any Class 3 or 4 cardiac disease as defined by the NewYork Heart Association Functional Classification at screening. Exception: Subjectswith controlled, asymptomatic atrial fibrillation during screening are allowed toenroll on study.

11. Absolute neutrophil count (ANC) <1.0 x 109/L or platelet count <75 x 109/L; forsubjects with disease involvement in the bone marrow, ANC <0.75 x 109/L or plateletcount <50 x 109/L. Subjects will only be considered eligible if peripheral bloodcounts can be maintained independent of growth factors or transfusions during thescreening period.

12. Total bilirubin >1.5 x upper limit normal (ULN) unless other reason known; oraspartate aminotransferase (AST) or alanine transaminase (ALT) >2.5 x ULN.

13. Estimated creatinine clearance of <30 mL/min, calculated using the formula ofCockcroft and Gault [(140-age) • mass (kg)/(72 • creatinine mg/dL) • multiply by 0.85 if female].

14. Prothrombin time/international normalized ratio (INR) or activated partialthromboplastin time (aPTT) (in the absence of a lupus anticoagulant) >2.0 x ULN.Exception: Subjects receiving a vitamin K antagonist are excluded; however, thosereceiving other anticoagulant therapy who have a higher INR/aPTT may be permitted toenroll to this study after discussion with the medical monitor.

15. Malabsorption syndrome, disease significantly affecting gastrointestinal function,resection of the stomach, extensive small bowel resection that is likely to affectabsorption, symptomatic inflammatory bowel disease, partial or complete bowelobstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.

16. Uncontrolled active systemic fungal, bacterial, viral, or other infection (definedas exhibiting ongoing signs/symptoms related to the infection and withoutimprovement, despite appropriate antibiotics or other treatment), or intravenousanti-infective treatment within 2 weeks before first dose of study drug.

17. Known history of infection with human immunodeficiency virus (HIV).

18. Ongoing immunosuppressive therapy, including systemic corticosteroids within 2 weeksbefore the first dose of study drug.

19. Known history of anaphylaxis or hypersensitivity to any study drug, or any of theircomponents.

20. Serologic status reflecting active hepatitis B or C infection.

21. Subjects who are anti-HBc positive and who are surface antigen negative willneed to have a negative polymerase chain reaction (PCR) result before the firstdose of study drug. Those who are HbsAg positive or hepatitis B PCR positivewill be excluded.

22. Subjects who are hepatitis C antibody positive will need to have a negative PCRresult before the first dose of study drug. Those who are hepatitis C PCRpositive will be excluded.

23. Received a live virus vaccination within 28 days of first dose of study drug.

24. History of stroke or intracranial hemorrhage within 6 months of first dose of studydrug.

25. History of bleeding diathesis.

26. Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months beforefirst dose of study drug.

27. Requires or receiving anticoagulation with warfarin or equivalent vitamin Kantagonists within 7 days of first dose of study drug.

28. Requires treatment with a strong CYP3A inhibitor/inducer.

29. Concurrent participation in another therapeutic clinical trial.

30. Active cytomegalovirus (CMV) infection (active viremia as evidenced by positive PCRresult for CMV DNA).

31. History of confirmed progressive multifocal leukoencephalopathy (PML).

32. Pregnant or breastfeeding women.