Thiotepa in Combination With Pirtobrutinib (a BTK Inhibitor) and Sintilimab (a PD-1 Inhibitor) for Frail or Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma

Inclusion criteria

• Histopathologically confirmed relapsed primary central nervous system lymphoma (PCNSL) of B-cell lineage, or secondary central nervous system lymphoma (SCNSL) with a previously confirmed B-cell origin primary lesion but without evidence of active extracranial systemic involvement.
• The patients or their legal guardians provide voluntary written informed consent.
• Age>=18 years, both male and female.
• Karnofsky Performance Status (KPS) score>=40.
• Patients deemed unsuitable for methotrexate (MTX)-based systemic chemotherapy ("unfit"), including but not limited to: patients assessed as unsuitable for chemotherapy or frail according to a simplified Geriatric Assessment (sGA) criteria; patients with contraindications to MTX (e.g., renal insufficiency, serous cavity effusions, oral mucositis, etc.); or patients who refuse high-dose methotrexate (HD-MTX) chemotherapy.
• Life expectancy of greater than 3 months, as judged by the investigator.
• Patients with parenchymal lesions (>10*10mm ) on contrast-enhanced cranial MRI or those with leptomeningeal disease only, require cytological examination of cerebrospinal fluid (CSF) to confirm the presence of lymphoma cells and/or imaging findings consistent with CSF results. These assessments must be completed within 14 days prior to enrollment.
• If the patients have received prior anti-tumor therapy, all treatment-related non-hematologic toxicities must have recovered to Grade 1 or baseline (according to NCI CTCAE version 5.0, with the exception of alopecia).
• Bone marrow and organ function must meet the following criteria (without transfusion, G-CSF support, or corrective therapy within 14 days prior to informed consent):

• Hematological: Absolute neutrophil count (ANC) >=1.5*10^9/L (1500/mm^3), platelets >=75*10^9/L, hemoglobin>=8 g/dL (If bone marrow is involved, then platelets>=50*10^9/L, ANC >=1.0*10^9/L, and hemoglobin>=7 g/dL are acceptable).
• Hepatic: Total bilirubin <=1.5 × upper limit of normal (ULN); aspartate aminotransferase (AST) and alanine aminotransferase (ALT) <=2.5 × ULN.
• Renal: Serum creatinine <=1.5 × ULN or estimated creatinine clearance >=60 mL/min.
• Coagulation: INR <=1.5 × ULN; PT and APTT <=1.5 × ULN (unless the subject is receiving anticoagulant therapy and, at screening, PT and APTT are within the anticipated therapeutic range for the anticoagulant regimen).
• For the subjects of reproductive age women and fertile men, during the entire study period and within 3 months after the interruption of treatment, they must not have any conception plans with their partners. During the entire study period and within 3 months after the interruption of treatment, one of the following measures must be taken for effective contraception: abstinence, physical contraception (such as sterilization or condoms), and the use of hormonal contraceptive drugs (w hich must start at least 3 months before the first administration upon enrollment). For male subjects, sperm donation is prohibited from the start of treatment until 3 months after the cessation of treatment.
• Willingness and ability to undergo multiple MRI/CT scans and an expected ability to undergo lumbar puncture.

Ability to swallow oral medication without difficulty.

Exclusion criteria

• The patients with secondary central nervous system lymphoma (SCNSL) who have lesions outside the CNS and require systemic treatment.
• Received chemotherapy, radiotherapy, immunotherapy or antibody-based treatments for anti-tumor purposes within 4 weeks prior to the first administration (or within 5 half-lives), those who had used small molecule targeted drugs or traditional Chinese medicine with anti-tumor indications within 2 weeks, and those who had received monoclonal antibody conjugate drug treatments within 10 weeks.
• Receipt of any vaccine (including but not limited to vaccines for COVID-19, influenza, pneumonia, shingles, hepatitis B, etc.) within 4 weeks before taking the medicine for the first time.
• Concurrent enrollment in another interventional clinical study, or less than 4 weeks between the last dose of prior clinical trial treatment and the first dose in this study.
• Previous treatment with thiotepa, PD-1 inhibitors, or BTK inhibitors is not excluded by default but requires benefit-risk assessment by the investigator. Subjects with a history of Grade >=3 immune-related adverse events (per NCI CTCAE v5.0) attributed to these agents are excluded.
• History of active bleeding within 4 weeks before the first dose; need for therapeutic anticoagulation during the study (e.g., warfarin or vitamin K antagonists); or any condition associated with elevated bleeding risk or coagulopathy per investigator judgment (e.g., high-risk esophageal varices, active ulcer disease).
• Treatment with moderate or strong CYP3A4/5 inhibitors or inducers is required within 2 weeks before the first administration or during the study period.
• Concurrent presence of other malignant tumors requiring antineoplastic treatment.
• Having uncontrolled or significant cardiovascular diseases, including (but not limited to):

• Any of the following conditions occurring within 6 months before the first administration: congestive heart failure with New York Heart Association class >= 3, myocardial infarction, unstable angina pectoris, arrhythmia requiring treatment at screening, or left ventricular ejection fraction (LVEF) < 50%;
• Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restrictive cardiomyopathy, unclassified cardiomyopathy);
• A history of clinically significant QTc interval prolongation, second-degree type II atrioventricular block, third-degree atrioventricular block, or a QTc interval > 470ms (for females) and > 450ms (for males);
• Atrial fibrillation (EHRA class>= 2b);
• Poorly controlled hypertension, which is deemed unsuitable for study participation by the investigator.
• Active uncontrolled infection requiring intravenous antimicrobial treatment.
• Patients with active chronic hepatitis B, active chronic hepatitis C, or syphilis. Patients who test positive for hepatitis B surface antigen or hepatitis C virus antibody during the screening period must undergo further tests for HBV DNA titer (which must not exceed 1000 IU/ml) and HCV RNA (which must not exceed the lower detection limit of the assay) before being eligible for enrollment in the trial. Hepatitis B virus carriers, patients with hepatitis B stabilized after drug treatment, and patients with cured hepatitis C may be enrolled.
• Patients with a known history of HIV infection and/or AIDS.
• Clinically significant gastrointestinal abnormalities that may affect drug intake, transport, or absorption (e.g., inability to swallow, chronic diarrhea, intestinal obstruction), or total gastrectomy.
• Autologous transplantation within 3 months, or organ or allogeneic stem cell transplantation within 6 months, before signing the informed consent form.
• Pregnancy or lactation.
• Stroke or intracranial hemorrhage within 6 months before first dosing, excluding post-surgical sequelae of intracranial bleeding.
• History or current presence of pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, radiation pneumonitis, or similar conditions, deemed by the researcher as rendering the subject unsuitable for participation in the trial.
• Participants whom the investigator considers unsuitable for the study due to existing kidney, nerve/mental, liver, or endocrine diseases, or for any other reason judged by the researcher.
• Exclude patients with active autoimmune disease or a history of it, including but not limited to: immune-related neurologic disorders, multiple sclerosis, autoimmune (demyelinating) neuropathy, Guillain-Barré syndrome, myasthenia gravis, SLE, connective-tissue disease, scleroderma, inflammatory bowel disease (Crohn's or ulcerative colitis), hepatitis, TEN, Stevens-Johnson syndrome, antiphospholipid syndrome.

Note: allow subjects with vitiligo, eczema, type 1 diabetes, or endocrine disorders (e.g., thyroiditis on physiologic steroid replacement). Subjects with rheumatoid arthritis/other arthropathies, Sjögren's syndrome, controlled celiac disease, or psoriasis treated only topically, and those seropositive (ANA, anti-thyroid antibodies, etc.) must be assessed for target-organ involvement and need for systemic therapy; if neither is present, they may be enrolled.

• Major surgery within 28 days prior to the first study dose, as determined by the investigator.