Inclusion Criteria:
1. Willing and able to participate in all required evaluations and procedures in this study protocol, including swallowing capsules and tablets without difficulty.
2. 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).
3. Age ≥18 years at the time of consent.
4. Subject has adequate performance status as defined by The Eastern Cooperative Oncology Group (ECOG) of ≤ 2
5. Subject has histological confirmation of biopsy-proven central nervous system (CNS) lymphoma or magnetic resonance imaging (MRI) findings consistent with CNS lymphoma if biopsy is not possible (due to inaccessible location). Subjects with intra-ocular lymphoma will not be excluded as long as there is also parenchymal disease.
6. Subject has B-cell Non-Hodgkin Lymphoma.
7. Subject has no evidence of systemic involvement of lymphoma confirmed by computerized tomography (CT) or positron emission tomography (PET)-CT imaging within 28 days prior to first dosing in the study.
8. Subject must have received at least one prior line of chemotherapy for primary or secondary CNS lymphoma.
9. Subject has adequate organ function as demonstrated by: System Laboratory Value Hematological\* Absolute Neutrophil Count (ANC) ≥ 1 x 109/L Platelets ≥ 75 x 109/L Renal\* Calculated creatinine clearance ≥ 30 mL/min using the Cockcroft-Gault formula (Appendix B) Hepatic\* Bilirubin ≤ 1.5 × upper limit of normal (ULN). Subjects with Gilbert's syndrome may be enrolled despite a total bilirubin level \>1.5 mg/dL if their conjugated bilirubin is \<1.5× ULN) Aspartate aminotransferase (AST) ≤ 2.5 × ULN Alanine aminotransferase (ALT) ≤ 2.5 × ULN Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤ 2 × ULN (in the absence of lupus anticoagulant)
Exclusion Criteria:
Subjects meeting any of the following exclusion criteria will not be able to participate in this study.
1. Prior cancer treatment that was completed less than 14 days prior to Day 1 of study dosing or if subject has not recovered from all reversible acute toxic effects of the regimen to grade ≤1 or baseline.
2. Prior brain radiotherapy under the following conditions:
* Whole-brain radiotherapy (WBRT) that was completed less than 28 days prior to Day 1 of study dosing
* Stereotactic radiosurgery (SRS) that was competed less than 14 days prior to Day 1 of study dosing.
3. Currently participating in or has participated in a study of an investigational agent within 28 days of first dosing with study treatment.
4. Subject is pregnant or breastfeeding.
5. Subject has active cerebrospinal fluid (CSF) involvement that requires ongoing intrathecal chemotherapy
6. Previous exposure to a Bruton Tyrosine Kinase (BTK) inhibitor.
7. Subjects with severe hepatic insufficiency, as defined by Child-Pugh Score \> 6.
8. Subject is receiving prohibited medications or treatments as listed in the protocol that cannot be discontinued/replaced by an alternative therapy.
9. Subject requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists within 14 days of first dose of study drug. Subjects requires or is taking direct oral anticoagulants within 7 days of first dose of study drug.
10. Subject requires treatment with proton pump inhibitors. Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrollment to this study.
11. Subject is currently receiving any chemotherapy, anticancer immunotherapy.
12. Subject has clinically significant cardiovascular disease such as ventricular dysfunction, symptomatic coronary artery disease, uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association (NYHA) Functional Classification at screening. Subjects with controlled, asymptomatic atrial fibrillation during screening can enroll on study.
13. Subject has familial short QT syndrome.
14. Subject has a history of 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 that is likely to affect absorption.
15. Subject has a known history of infection with HIV or any uncontrolled active significant infection.
16. Subject has a known history of drug-specific hypersensitivity or anaphylaxis to acalabrutinib (including active ingredient or excipient components).
17. Subject has active bleeding or history of bleeding diathesis.
18. Subject has a history of uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP).
19. Subject has a history of significant cerebrovascular disease/event, including stroke or intracranial hemorrhage, within 6 months before the first dose of acalabrutinib.
20. Subject had major surgical procedure within 28 days of first dose of acalabrutinib.
21. Subject who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative PCR result before randomization and must be willing to undergo DNA PCR testing during the study. Subjects who are core antibody positive and viral load negative must receive entecavir Those who are HbsAg-positive, or hepatitis B PCR positive will be excluded.
22. Subjects who are hepatitis C antibody positive must have a negative polymerase chain reaction (PCR) result. Those who are hepatitis C PCR positive will be excluded.
23. Subjects with evidence of disease that investigator decides that is not suitable to enroll in the study.
24. History of or ongoing confirmed progressive multifocal leukoencephalopathy (PML).
25. Received a live virus vaccination within 28 days of first dose of study drug.
26. Any active significant infection.
27. Concurrent participation in another therapeutic clinical trial.
28. Current life-threatening illness, medical condition, or organ system dysfunction which, in the Investigator's opinion, could compromise the subject's safety or put the study at risk.
