High-dose Methotrexate Combined with Thiotepa and Zanubrutinib in the Treatment of Newly Diagnosed PCNSL (MTZ)

Inclusion Criteria:

1. Men and woman who are 18 to 70 years of age
2. Histologically documented PCNSL
3. ECOG performance status ≤ 2
4. Life expectancy of \> 3 months
5. Imaging show at least one measurable lesion in the central nervous system.
6. Adequate bone marrow and organ function shown by:
7. Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
8. Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days
9. Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days
10. International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
11. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN
12. Serum bilirubin ≤ 1.5×ULN
13. Serum creatinine ≤ 2×ULN
14. Lipase ≤ 1.5 x LUN
15. Women of childbearing potential (WOCBP) and men must agree to use effective contraception when sexually active. Women of childbearing potential must have a negative serum pregnancy test within 7 days prior to the first dose of medication; women who are pregnant or breastfeeding are not eligible to participate in this study. Women of childbearing potential: from the time of signing the Informed Consent Form (ICF) until 30 days after the study ends, sexually active men: from the time of signing the ICF until 90 days after the study ends, must use contraceptive measures.
16. Must be able to tolerate MRI/CT scans
17. Must be able to tolerate lumbar puncture and/or Ommaya tap

Exclusion Criteria:

1. Diagnosed with a malignant tumor other than PCNSL or has received treatment, except for the following cases:

   1. Received curative treatment and has no known active disease at least 3 years or more before screening for enrollment.
   2. Fully treated non-melanoma skin cancer or malignant lentigo, with no evidence of disease.
   3. Fully treated carcinoma in situ, with no evidence of disease currently.
2. Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure (New York Heart Association \> Class 2), unstable angina, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification
3. Uncontrolled hypertension despite optimal medical management (per investigators assessment)
4. Patient has poorly controlled diabetes (per investigators assessment)
5. Patient is known to have an uncontrolled active systemic infection (\>CTCAE grade 2) and recent infection requiring intravenous anti-infective treatment that was completed ≤14 days before the first dose of study drug
6. Cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
7. Non-healing wound, ulcer or bone fracture in a short time
8. Known bleeding diathesis or hemophilia
9. Known history of infection with human immunodeficiency virus (HIV) or active stage of infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) . Active HBV infection must be confirmed by a positive test for HBV surface antigen or a positive test for hepatitis B core antibody with a positive determination of HBV DNA by polymerase chain reaction (PCR). For Hepatitis C virus (HCV), confirmation must be made by a positive test for HCV antibodies, unless the subject has been treated and has shown a sustained virological response. Note: Subjects with positive HCV antibodies who have been treated and have shown a sustained virological response (negative virus detection for at least 6 months after completing treatment) will not be excluded.
10. Patient underwent major systemic surgery ≤ 2 weeks prior to starting the trial treatment or who has not recovered from the side effects of such surgery
11. Unable to swallow capsules or disease significantly affecting gastrointestinal function
12. Life-threatening illness, medical conditions, or organ dysfunctions that may endanger the safety of the subject or put the study outcomes at risk.
13. Lactating or pregnant
14. Requires anticoagulation therapy with warfarin or equivalent vitamin K antagonists; requires treatment with potent CYP3A4/5 inhibitors.
15. Requires long-term use of dexamethasone ≥4mg/day or equivalent doses of corticosteroid formulations.
16. Requires treatment with immunosuppressive agents, including cyclosporine A, tacrolimus, and sirolimus. Patients must discontinue the use of immunosuppressive agents 28 days before receiving study medication.