This study is being conducted to evaluate the safety and efficacy of the combination of pemetrexed and zanubrutinib (called induction therapy) followed by zanubrutinib treatment alone (also called maintenance therapy) in people who have relapsed or refractory (RR) primary central nervous system lymphoma (PCNSL) or isolated central nervous system relapse of B cell lymphoma (SCNSL). Assessments include how well people respond to this treatment, whether their disease gets better or worse, and their survival. Safety of this treatment and its side effects also will be assessed.

Pemetrexed, when used by itself, is beneficial and is a standard of care therapy for RR PCNSL and can be used to treat SCNSL. Zanubrutinib is an oral drug that is approved by the Food and Drug Administration (FDA) as safe and effective to treat certain lymphoma types.

Inclusion Criteria:

1. Any of the following diseases histologically confirmed:

   1. Primary CNS lymphoma or isolated secondary CNS involvement by diffuse large B cell lymphoma with measurable disease
   2. Cytologic diagnosis of B cell non-Hodgkin's lymphoma with measurable disease
   3. Ocular lymphoma with histologic confirmation of ocular lymphoma and measurable intracranial tumor. Slit-lamp examination and vitreal or retinal biopsy will be done to confirm ocular lymphoma.

2. Karnofsky performance status (KPS) ≥ 30% (≥ 50% for patients ≥ 60 years-old)

3. Progressed during first-line chemotherapy and/or radiotherapy -OR- insufficient clinical response to previous therapy or relapsed after initial successful treatment OR unable to tolerate previous therapy defined as Grade 3+ acute kidney injury (AKI) and/or transaminase elevation according to CTCAE v 5.0 criteria preventing repeat treatment exposure OR prior glucarpidase use due to high dose methotrexate delayed clearance and/or toxicity OR those who would have been glucarpidase candidates due to delayed methotrexate clearance (plasma methotrexate concentrations greater than 2 standard deviations of the mean methotrexate excretion curve specific for the dose of methotrexate administered or toxic plasma methotrexate concentrations (>1 micromole per liter) in patients with delayed methotrexate clearance) due to impaired renal function OR unable to receive high dose methotrexate induction on every 2 week +/- 3 days schedule due to deconditioning and/OR need for physical rehabilitation between the high dose methotrexate treatments

4. No systemic lymphoma by positron emission tomography (PET) CT or CT scan of the chest, abdomen, and pelvis with contrast

5. Adequate bone marrow and organ function demonstrated by:

   1. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
   2. Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 14 days prior to study enrollment
   3. Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days prior to study enrollment
   4. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limit of normal
   5. Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3 times the upper limit of normal with direct bilirubin within the normal range in patients with well documented Gilbert Syndrome
   6. Creatinine Clearance (CrCl)> 45 mL/minute using Cockcroft-Gault formula

6. Ability to understand and sign written informed consent prior to study entry unless the subject suffers from cognitive or physical impairment due to their CNS malignancy or due to a known underlying medical condition in which case consent could be signed by proxy

7. Life expectancy of at least 2 months

8. Females of childbearing potential must use highly effective method of contraception for the duration of the study and ≥ 30 days after the last dose of zanubrutinib. Female must also have a negative urine or serum pregnancy test ≤ 7 days before initial treatment.

   • The investigator or a designated associate is requested to advise the patients how to achieve highly effective birth control (failure rate of less than 1%), e.g., intrauterine device (IUD), intrauterine hormone-releasing system (IUS), bilateral tubal occlusion, vasectomized partner and sexual abstinence. Females using hormonal contraception should use barrier methods in addition.
   • Male patients with a female partner of childbearing potential are eligible if abstinent, vasectomized, or if they agree to the use of barrier contraception with other methods described above during the study treatment period and for up to one week after the last dose of zanubrutinib.

   Agreement to use contraception during study participation

   • Female patients of childbearing potential must practice highly effective methods of contraception.
   • Male patients with female partners must be abstinent, vasectomized, or agree to the use of barrier contraception in combination with other methods. Acceptable contraception methods are included in the study protocol.
   • Patients using hormonal contraceptives (e.g., birth control pills or devices) must use a barrier method of contraception (e.g., condoms) as well.

9. For patients with Infectious disease, must have:

   1. HIV positive with negative viral load and CD4 count > 400
   2. Non-viremic Hepatitis C Virus (HCV)
   3. HBcAb (Hepatitis B core positive) and HBsAg negative

Exclusion Criteria:

1. Serious uncontrolled concurrent illness or comorbid condition

2. Other active systemic malignancy except for basal cell carcinoma of the skin, cervical carcinoma in situ or very low and low risk prostate cancer under observation. Patients with a remote history (3 years or more) of malignancy are eligible for the protocol in the absence of active disease

3. Concurrent chronic systemic immune therapy, targeted therapy not indicated in this study protocol

4. Unable to comprehend the study requirements or who are not likely to comply with the study protocol

5. Prior participation in chemotherapy, cytotoxic therapy, immunotherapy, radiation therapy or therapeutic protocols within 2 weeks of protocol treatment

6. Pregnant (confirmed by serum or urine β-HCG) or lactating

7. Transaminases > 3 times above the upper limits of the institutional normal

8. Patients must not have pre-existing immunosuppression, concurrent immunosuppressive treatment with the exception of dexamethasone, or low dose prednisone with a total dose equivalent to 15 mg of prednisone a day or less for chronic conditions. Allogeneic stem cell transplant recipients as well as other organ transplant recipients are excluded. Autologous stem cell transplant recipients will qualify if relapse occurs at one year after the stem cell transplantation. Short course of dexamethasone up to 40 mg orally or intravenously daily with or without taper for CNS lymphoma symptom control is allowed.

9. Patients should not have active and/or ongoing autoimmune anemia and/or autoimmune thrombocytopenia (e.g., idiopathic thrombocytopenia purpura).

10. Non-healing wound, ulcer or bone fracture

11. Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia

12. Cerebrovascular accident or intracranial hemorrhage within 6 months of the study treatment; arterial or venous thrombotic or embolic event such as deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment. Patients with upper extremity catheter-related deep venous thrombosis will not be excluded.

13. Concurrent use of warfarin or other vitamin K antagonists (need to be stopped 7 days prior to starting on trial drug)

14. Infectious disease: HIV positive patients with positive viral load and CD4+ count < 400 are excluded. HIV patients must have established and consistent infectious disease specialist care. HIV positive patients have to agree for every 12-week monitoring of viral load. Patients with the emergence of HIV viral load on the trial treatment will be referred to the infectious disease specialist and can continue on the trial treatment unless recommended to stop by the infectious disease specialist and PI. If the viral load reaches 100,000 copies per milliliter or above, the patient would be referred to an infectious disease specialist for and evaluation and would be taken off the trial.

15. Patients with presence of HCV antibody are eligible if HCV RNA is undetectable and if they are willing to undergo monitoring for HCV reactivation every 12 weeks. HCV patients will be taken off trial if there is 1 log increase in viral load after the initial detection of HCV viral load regardless of liver function tests (LFTs). Patients will be referred promptly to hepatology specialist with the first detectable viral load.

16. Patients with detectable hepatitis B surface antigen (HBsAg) are excluded. Patients with viral hepatitis B core antibody (HBcAb) positivity, but absence of HBsAg, are eligible if HBV DNA is undetectable and if they are willing to undergo monitoring for Hepatitis B Virus (HBV) reactivation every 12 weeks. HBV patients will be taken off trial if there is 1 log increase in viral load after the initial detection of HBV viral load regardless of LFTs. Patients will be referred promptly to hepatology specialist with the first detectable viral load.

17. Currently active, clinically significant cardiovascular disease including the following:

    1. Myocardial infarction within 6 months before screening
    2. Unstable angina within 3 months before screening
    3. New York Heart Association class III or IV congestive heart failure
    4. History of clinically significant arrhythmias (e.g., sustained ventricular tachycardia, ventricular fibrillation, torsades de pointes)

18. Any uncontrolled active systemic infection or infection requiring systemic treatment that was completed ≤ 7 days before the first dose of therapy

19. Participants who received a strong cytochrome P450 (CYP) 3A inhibitor or inducer within 7 days prior to the first dose of protocol anti-fungal prophylaxis, or participants who require continuous treatment with a strong CYP3A inhibitor/inducer (i.e., except for any medication to be specifically mentioned in this protocol)

20. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the patient's safety, or put the study at undue risk. Participants with suspicious radiologic evidence of aspergillosis infection (i.e., chest CT and/or brain MRI) will not be eligible unless confirmatory laboratory testing of Beta-D glucan and aspergillus antigen are negative

21. Prior treatment with pemetrexed or a Bruton's tyrosine kinase (BTK) inhibitor for lymphoma

22. Vaccination with a live or attenuates vaccine within 28 days prior to the first dose of zanubrutinib. Live or attenuated vaccines are not allowed during treatment with zanubrutinib

23. Hypersensitivity to zanubrutinib or pemetrexed or any of the other ingredients of the applicable study drug