R-MTX-zanbrutinib in Secondary CNS Lymphoma

Inclusion Criteria:

• Men and women ≥ 18, and ≤75 years of age
• Histologically documented systemic diffuse large B-cell lymphoma(DLBCL)
• Central nervous system (CNS) relapse (meningeal or /and intraparenchymal) with orwithout systemic lymphoma manifestations
• All patients need to have received at least one and ≤4 lines of prior therapy systemiclymphoma directed therapy.
• ECOG performance score 0-3
• Participants must have adequate bone marrow and organ function shown by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L, Hemoglobin (Hgb) ≥ 9 g/dL,Platelets ≥ 75 x 109/L(≥ 50 x 109/L if bone marrow involvement)
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 timesthe upper limit of normal, total bilirubin ≤ 2 times the upper limit of normal
• International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upperlimit of normal
• serum creatinine (mg/dL)) ≤ 1.5 times the upper limit of normal ; calculatedcreatinine clearance(CrCl) ≥ 40ml/min using the Cockcroft-Gault equation
• Expected survival greater than 3 months
• Did not receive targeting agents within 10 days or receive chemortherapy,radiotherapy, or monoclonal antibody within 3 weeks
• Woman of reproductive potential must agree to use highly effective methods of birthcontrol during the period of therapy and for 30 days after the last dose of the studydrug. Men who are sexually active must agree to use highly effective contraceptionduring the period of therapy and for 3 months after the last dose
• Ability of participants or Legally Authorized Representative (LAR) to understand andthe willingness to sign a written informed consent document

Exclusion Criteria:

• Newly diagnosed DLBCL with CNS involvement
• Previous treatment with Bruton's Tyrosine Kinase (BTK) inhibitors
• Received targeting agents within 10 days or received chemortherapy, radiotherapy, ormonoclonal antibody within 3 weeks
• Patient has significant abnormalities on screening electrocardiogram (EKG) and activeand significant cardiovascular disease such as uncontrolled or symptomaticarrhythmias, congestive heart failure, hypertension, valvular disease, pericarditis,or myocardial infarction within 6 months of screening
• History of severe bleeding diseases
• Patient is using warfarin or any other Coumadin-derivative anticoagulant or vitamin Kantagonists. Patients must be off warfarin-derivative anticoagulants for at leastseven days prior to starting the study drug. Low molecular weight heparin is allowed.Patients with congenital bleeding diathesis are excluded
• Patient is taking a drug known to be a moderate and strong inhibitor or inducers ofthe P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducersfor at least two weeks prior to starting the study drug
• Patient is known to have human immunodeficiency virus (HIV) infection
• Patient is known to have a history of active or chronic infection with hepatitis Cvirus (HCV) or hepatitis B virus (HBV) as determined by serologic tests
• Patient is known to have an uncontrolled active systemic infection
• Patients with serous cavity effustion
• Patient underwent major systemic surgery ≤ 4 weeks prior to starting the trialtreatment or who has not recovered from the side effects of such surgery
• Women who are pregnant or nursing (lactating)
• The patient is unwell or unable to participate in all required study evaluations andprocedures