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

Prior treatment

• Diagnosed with a malignant tumor other than PCNSL or has received treatment, except for the following cases:
  • Received curative treatment and has no known active disease at least 3 years or more before screening for enrollment.
  • Fully treated non-melanoma skin cancer or malignant lentigo, with no evidence of disease.
  • Fully treated carcinoma in situ, with no evidence of disease currently.
• 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
• Cerebrovascular accident, deep vein thrombosis or pulmonary embolism within 3 months before the start of study treatment
• 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
• Requires anticoagulation therapy with warfarin or equivalent vitamin K antagonists; requires treatment with potent CYP3A4/5 inhibitors.
• Requires long-term use of dexamethasone ≥4mg/day or equivalent doses of corticosteroid formulations.
• 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.

Other illness

• 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
• Uncontrolled hypertension despite optimal medical management (per investigators assessment)
• Patient has poorly controlled diabetes (per investigators assessment)
• Non-healing wound, ulcer or bone fracture in a short time
• Known bleeding diathesis or hemophilia
• 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.
• Unable to swallow capsules or disease significantly affecting gastrointestinal function
• Life-threatening illness, medical conditions, or organ dysfunctions that may endanger the safety of the subject or put the study outcomes at risk.

Other

• Lactating or pregnant

• Men and woman who are 18 to 70 years of age
• Histologically documented PCNSL
• ECOG performance status ≤ 2
• Life expectancy of \> 3 months
• Imaging show at least one measurable lesion in the central nervous system.
• Adequate bone marrow and organ function shown by:
• Absolute neutrophil count (ANC) ≥ 1.5 x 10\^9/L
• Platelets ≥ 75 x 10\^9/L and no platelet transfusion within the past 14 days
• Hemoglobin (Hgb) ≥ 8 g/dL and no red blood cell (RBC) transfusion within the past 14 days
• International Normalized Ratio (INR) ≤ 1.5 and PTT (aPTT) ≤ 1.5 times the upper limit of normal
• Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3×ULN
• Serum bilirubin ≤ 1.5×ULN
• Serum creatinine ≤ 2×ULN
• Lipase ≤ 1.5 x LUN
• 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.
• Must be able to tolerate MRI/CT scans
• Must be able to tolerate lumbar puncture and/or Ommaya tap