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. 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. 7. Life expectancy of at least 2 months. 8. Both female of childbearing potential and nonsterile male: must use highly effective
method of contraception for the duration of the study and ≥ 90 days after the last
dose of zanubrutinib. Female must also have a negative urine or serum pregnancy test ≤
7 days before initial treatment.
1. 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.
2. Male patients with a female partner of childbearing potential are eligible if
vasectomized or if they agree to the use of barrier contraception with other
methods described above during the study treatment period and for ≥ 90 days after
the last dose of zanubrutinib.
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;
1. 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.
2. 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.
3. 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.
15. 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)
16. Any uncontrolled active systemic infection or infection requiring systemic treatment
that was completed ≤ 7 days before the first dose of therapy. 17. 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)
18. 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. 19. Prior treatment with pemetrexed or a Bruton's tyrosine kinase (BTK) inhibitor for
lymphoma. 20. 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. 21. Hypersensitivity to zanubrutinib or pemetrexed or any of the other ingredients of the
applicable study drug
