Zanubrutinib With Pemetrexed to Treat Relapsed/Refractory Primary and Secondary Central Nervous System (CNS) Lymphomas

Inclusion Criteria:

1. Any of the following diseases histologically confirmed:

2. Primary CNS lymphoma or isolated secondary CNS involvement by diffuse large Bcell lymphoma with measurable disease

3. Cytologic diagnosis of B cell non-Hodgkin's lymphoma with measurable disease

4. Ocular lymphoma with histologic confirmation of ocular lymphoma and measurableintracranial tumor. Slit-lamp examination and vitreal or retinal biopsy will bedone to confirm ocular lymphoma.

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

6. Progressed during first-line chemotherapy and/or radiotherapy -OR- insufficientclinical response to previous therapy or relapsed after initial successful treatmentOR 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 repeattreatment exposure OR prior glucarpidase use due to high dose methotrexate delayedclearance and/or toxicity OR those who would have been glucarpidase candidates dueto delayed methotrexate clearance (plasma methotrexate concentrations greater than 2standard deviations of the mean methotrexate excretion curve specific for the doseof methotrexate administered or toxic plasma methotrexate concentrations (>1micromole per liter) in patients with delayed methotrexate clearance) due toimpaired renal function OR unable to receive high dose methotrexate induction onevery 2 week +/- 3 days schedule due to deconditioning and/OR need for physicalrehabilitation between the high dose methotrexate treatments

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

8. Adequate bone marrow and organ function demonstrated by:

9. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L

10. Platelets ≥ 75 x 10^9/L and no platelet transfusion within the past 14 daysprior to study enrollment

11. Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within thepast 14 days prior to study enrollment

12. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 timesthe upper limit of normal

13. Serum bilirubin ≤ 1.5 times the upper limit of normal; or total bilirubin ≤ 3times the upper limit of normal with direct bilirubin within the normal rangein patients with well documented Gilbert Syndrome

14. Creatinine Clearance (CrCl)> 45 mL/minute using Cockcroft-Gault formula

15. Ability to understand and sign written informed consent prior to study entry unlessthe subject suffers from cognitive or physical impairment due to their CNSmalignancy or due to a known underlying medical condition in which case consentcould be signed by proxy

16. Life expectancy of at least 2 months

17. Females of childbearing potential must use highly effective method of contraceptionfor 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 beforeinitial treatment.

• The investigator or a designated associate is requested to advise the patientshow 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. Femalesusing hormonal contraception should use barrier methods in addition.

• Male patients with a female partner of childbearing potential are eligible ifabstinent, vasectomized, or if they agree to the use of barrier contraceptionwith other methods described above during the study treatment period and for upto one week after the last dose of zanubrutinib. Agreement to use contraception during study participation

• Female patients of childbearing potential must practice highly effectivemethods of contraception.

• Male patients with female partners must be abstinent, vasectomized, or agree tothe use of barrier contraception in combination with other methods. Acceptablecontraception 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:

10. HIV positive with negative viral load and CD4 count > 400

11. Non-viremic Hepatitis C Virus (HCV)

12. 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 underobservation. Patients with a remote history (3 years or more) of malignancy areeligible for the protocol in the absence of active disease

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

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

5. Prior participation in chemotherapy, cytotoxic therapy, immunotherapy, radiationtherapy 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 immunosuppressivetreatment with the exception of dexamethasone, or low dose prednisone with a totaldose equivalent to 15 mg of prednisone a day or less for chronic conditions.Allogeneic stem cell transplant recipients as well as other organ transplantrecipients are excluded. Autologous stem cell transplant recipients will qualify ifrelapse occurs at one year after the stem cell transplantation. Short course ofdexamethasone up to 40 mg orally or intravenously daily with or without taper forCNS lymphoma symptom control is allowed.

9. Patients should not have active and/or ongoing autoimmune anemia and/or autoimmunethrombocytopenia (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 studytreatment; arterial or venous thrombotic or embolic event such as deep veinthrombosis or pulmonary embolism within 3 months before the start of studytreatment. Patients with upper extremity catheter-related deep venous thrombosiswill not be excluded.

13. Concurrent use of warfarin or other vitamin K antagonists (need to be stopped 7 daysprior 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 infectiousdisease specialist care. HIV positive patients have to agree for every 12-weekmonitoring of viral load. Patients with the emergence of HIV viral load on the trialtreatment will be referred to the infectious disease specialist and can continue onthe trial treatment unless recommended to stop by the infectious disease specialistand PI. If the viral load reaches 100,000 copies per milliliter or above, thepatient would be referred to an infectious disease specialist for and evaluation andwould be taken off the trial.

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

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

17. Currently active, clinically significant cardiovascular disease including thefollowing:

18. Myocardial infarction within 6 months before screening

19. Unstable angina within 3 months before screening

20. New York Heart Association class III or IV congestive heart failure

21. History of clinically significant arrhythmias (e.g., sustained ventriculartachycardia, ventricular fibrillation, torsades de pointes)

22. Any uncontrolled active systemic infection or infection requiring systemic treatmentthat was completed ≤ 7 days before the first dose of therapy

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

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

25. Prior treatment with pemetrexed or a Bruton's tyrosine kinase (BTK) inhibitor forlymphoma

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

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