This study is evaluating the efficacy of acalabrutinib in combination with rituximab (Arm 1) versus ibrutinib (Arm 2) versus acalabrutinib (Arm 3) for the treatment of relapsed or refractory (R/R) mantle cell lymphoma (MCL).

Inclusion Criteria:

• Men and women ≥ 18 years of age.
• Pathologically confirmed mantle cell lymphoma (MCL).
• Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2.
• Agreement to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib or ibrutinib or 12 months after the last dose of rituximab (whichever is longest).
• Disease that has relapsed, or been refractory to, ≥ 1 prior treatment regimen for mantle cell lymphoma (MCL).
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information (in accordance with national and local patient privacy regulations).

Exclusion Criteria:

• Any history of central nervous system (CNS) lymphoma or leptomeningeal disease.
• Prior exposure to ibrutinib or to a B-cell receptor (BCR) inhibitor.
• Significant cardiovascular disease.
• Malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or gastric restrictions and bariatric surgery, such as gastric bypass.
• Uncontrolled active systemic fungal, bacterial, viral, or other infection.
• Known history of infection with human immunodeficiency virus (HIV).
• History of hepatitis B (HBV) infection or active infection with hepatitis C (HCV).
• Breastfeeding or pregnant.