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

Exclusion Criteria26

• 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.