Inclusion Criteria (Part A)

1. Written informed consent by the patient prior to screening

2. Patients aged ≥ 18 years on the day of consenting to the study

3. Pathologic diagnosis of PCNSL

4. Relapse or refractory PCNSL with at least one prior HD MTX based therapy for PCNSL

5. Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced
magnetic resonance imaging (MRI) performed within 14 days before starting tirabrutinib
treatment

6. ECOG PS of 0, 1 or 2

7. Life expectancy of at least 3 months

8. Adequate bone marrow, renal, and hepatic function

Inclusion Criteria (Part B)

1. Written informed consent by the patient prior to screening

2. Patients aged ≥ 18 years on the day of consenting to the study

3. Pathologic diagnosis of PCNSL within the past 3 months

4. No prior anti-tumor treatments for PCNSL

5. Patients who, in the opinion of the Investigator, are suitable to receive treatment
with a high dose methotrexate containing regimen

6. Measurable brain lesion with a minimum diameter > 1.0 cm in gadolinium enhanced MRI
performed within 14 days before starting study treatment

7. ECOG PS of 0, 1 or 2

8. Life expectancy of at least 6 months

9. Adequate bone marrow, renal, and hepatic function

Exclusion Criteria (Part A)

1. Intraocular PCNSL with no brain lesion

2. Patient who is intolerant of contrast enhanced MRI due to allergic reactions to
contrast agents

3. Patient with non-B cell PCNSL

4. Patient with systemic presence of lymphoma

5. Prior chemotherapy within 21 days, nitrosourea within 42 days, an antibody drug with
anticancer activity (e.g., rituximab) within 28 days, prior radiotherapy within 14
days, prior major invasive surgery within 28 days, or allogeneic stem cell transplant
within 6 months before starting tirabrutinib treatment

6. Prior BTK inhibitor treatment

7. Prior investigational drugs (including treatment in clinical research, unapproved
combination products, and new dosage forms) within 28 days or 5 half-lives, whichever
is shorter, before starting tirabrutinib treatment

8. Concomitant systemic corticosteroid on an ongoing basis within 14 days before starting
tirabrutinib treatment, with the exception of the following:

- Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL

- Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone)
for patients with lesions of the brain or spinal cord or both

9. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before
starting tirabrutinib treatment

10. Concomitant warfarin, any other warfarin derivative anticoagulant, vitamin K
antagonists, novel oral anticoagulants, or antiplatelet therapy on an ongoing basis
within 7 days before starting tirabrutinib treatment

11. Active malignancy, other than PCNSL requiring systemic therapy

12. Poorly controlled comorbidity, severe heart, severe lung disease, clinically
significant liver diseases that could affect protocol compliance or safety or efficacy
assessments

13. Patient with bleeding diathesis

14. Patients with a history of moderate or severe hepatic impairment

15. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant
medications that prolong the QT interval

16. Active infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has
had, within 28 days before starting tirabrutinib treatment, an infection (other than
nail trichophytosis) that requires hospitalization or an intravenous antibiotic

17. Prior history of hypersensitivity or anaphylaxis to tirabrutinib

18. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis

19. Medical history of organ allografts

20. Tests positive for HIV-1 antibody and HIV-2 antibody, human T-lymphotropic virus 1
antibody, HBs antigen, or HCV antibody. Tests positive for HBs antibody or hepatitis B
virus core protein antibody and has a result of at least detectable in a hepatitis B
virus deoxyribonucleic acid assay despite testing negative for HBs antigen.

21. Patient is unable to swallow tablets; has malabsorption, malabsorption syndrome, or a
comorbidity that affects gastric function; has undergone complete resection of the
stomach or small intestine; has ulcerative colitis or symptomatic inflammatory bowel
disease; or has partial or complete intestinal obstruction.

22. Women who are pregnant or lactating

23. Patient is found incapable of giving consent due to dementia or another such condition

24. Patient is found to be otherwise ineligible for the study by the Investigator or
sub-Investigator.

Exclusion Criteria (Part B)

1. Intraocular PCNSL with no brain lesion

2. Patients for whom the selected backbone regimen medications (i.e,
methotrexate/temozolomide/rituximab for MTR and
rituximab/methotrexate/procarbazine/vincristine for R-MPV) are contraindicated

3. Patients with a history of intolerable toxicity, hypersensitivity, anaphylaxis to the
selected backbone regimen medications

4. Patient who is intolerant of contrast enhanced MRI due to allergic reactions to
contrast agents

5. Patient with non-B cell PCNSL

6. Patient with systemic presence of lymphoma

7. Prior chemotherapy within 21 days, nitrosourea within 42 days, an antibody drug with
anticancer activity (e.g., rituximab) within 28 days, prior radiotherapy within 14
days, prior major invasive surgery within 28 days, or allogeneic stem cell transplant
within 6 months before starting tirabrutinib treatment

8. Prior BTK inhibitor treatment

9. Prior investigational drugs (including treatment in clinical research, unapproved
combination products, and new dosage forms) within 28 days or 5 half-lives, whichever
is shorter, before starting tirabrutinib treatment

10. Concomitant systemic corticosteroid on an ongoing basis within 14 days before starting
tirabrutinib treatment, with the exception of the following:

- Equivalent of up to 10 mg/day of prednisone for a disease other than PCNSL

- Equivalent of up to 50 mg/day of prednisone (equal to 8 mg/day of dexamethasone)
for patients with lesions of the brain or spinal cord or both

11. Patient who has received a CYP3A4 inducer or P-gp inducer within 14 days before
starting tirabrutinib treatment

12. Concomitant warfarin, any other warfarin derivative anticoagulant, vitamin K
antagonists, novel oral anticoagulants, or antiplatelet therapy on an ongoing basis
within 7 days before starting tirabrutinib treatment

13. Active malignancy, other than PCNSL requiring systemic therapy

14. Poorly controlled comorbidity, severe heart, severe lung disease, clinically
significant liver diseases that could affect protocol compliance or safety or efficacy
assessments

15. Patient with bleeding diathesis

16. Patients with a history of moderate or severe hepatic impairment

17. QTcF > 480 milliseconds or requirement for ongoing treatment with concomitant
medications that prolong the QT interval

18. Active infection, including a HIV, cytomegalovirus infection or SARS-CoV-2, or has
had, within 28 days before starting tirabrutinib treatment, an infection (other than
nail trichophytosis) that requires hospitalization or an intravenous antibiotic

19. Prior history of hypersensitivity or anaphylaxis to tirabrutinib

20. Prior history of Stevens Johnson Syndrome or Toxic Epidermal Necrolysis

21. Medical history of organ allografts

22. Tests positive for HIV-1 antibody and HIV-2 antibody, human T-lymphotropic virus 1
antibody, HBs antigen, or HCV antibody. Tests positive for HBs antibody or hepatitis B
virus core protein antibody and has a result of at least detectable in a hepatitis B
virus deoxyribonucleic acid assay despite testing negative for HBs antigen.

23. Patient is unable to swallow tablets; has malabsorption, malabsorption syndrome, or a
comorbidity that affects gastric function; has undergone complete resection of the
stomach or small intestine; has ulcerative colitis or symptomatic inflammatory bowel
disease; or has partial or complete intestinal obstruction.

24. Women who are pregnant or lactating

25. Patient is found incapable of giving consent due to dementia or another such condition

26. Patient is found to be otherwise ineligible for the study by the Investigator or
sub-Investigator.

Note: Other protocol defined Inclusion/Exclusion criteria may apply.

Eligibility last updated 2/7/23. Questions regarding updates should be directed to the study team contact.