Orelabrutinib, Sintilimab and Temozolomide in Relapsed or Refractory Central Nervous System Lymphoma

Exclusion Criteria

• •1. CNSL with systematic disease.
• •2. The pathological diagnosis was T-cell lymphoma.
• •3. Prior chemotherapy within 4 weeks or prior targeted small molecule therapy within 2 weeks , prior antibody-drug-conjugates within 10weeks, autologous stem cell transplant within 6 months, prior to the first day of study treatment, prior to the first day of study treatment.
• •4. Prior allogenic stem cell transplant.
• •5. Participation in another clinical study with an investigational product during the 4 weeks prior to the first day of study treatment.
• •6. External beam radiation therapy to the CNS within 14 days of the first day of study treatment.
• •7. Patient requires more than 8 mg of dexamethasone daily or the equivalent for control of CNS symptoms at the time of initiation of study therapy. Patients must taper off high dose corticosteroids for the control of CNS symptoms within 14 days after starting on study therapy.
• •8. History of intracranial hemorrhage or clinically significant stroke within 6 months prior to first day of study treatment
• •9. History of significant gastrointestinal disease that would limit absorption of oral medications.
• •10. Active concurrent malignancy requiring active therapy.
• •11. Prior therapy with a checkpoint inhibitor or BTK inhibitor.
• •12. Warfarin or any other Coumadin-derivative anticoagulant or vitamin K antagonists. Patients must be off warfarin-derivative anticoagulants for at least seven days prior to starting the study drug. Use of low molecular weight heparin and novel oral anticoagulants (eg. rivaroxaban, apixaban) is permitted if required.
• •13. Concurrent use of a moderate or strong inhibitor or inducer of the P450 isoenzyme CYP3A. Participants must be off P450/CYP3A inhibitors and inducers prior to starting the study drug.
• •14. Receipt of live attenuated vaccine within 30 days prior to the first day of study treatment. Note: Patients, if enrolled, should not receive live vaccine while receiving IP and up to 30 days after the last day of study treatment.
• •15. Suspicion of or confirmed progressive multifocal leukoencephalopathy
• •16. Active autoimmune disease (including autoimmune hemolytic anemia and immune thrombocytopenia purpura) requiring systemic treatment within the past two years (i.e. with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs). The following are exceptions to this criterion:
• •1. Patients with vitiligo or alopecia
• •2. Patients with hypothyroidism (e.g., due to Hashimoto syndrome) stable on hormone replacement
• •3. Any chronic skin condition that does not require systemic therapy
• •4. Patients without active disease in the last 5 years may be included but only after consultation with the study physician
• •5. Patients with celiac disease controlled by diet alone
• •6. Replacement therapy (e.g. thyroxine, insulin, or physiologic corticosteroids replacement therapy for adrenal or pituitary insufficiency, etc.)
• •17. Significant medical diseases or conditions, as assessed by the investigator, that would substantially increase the risk to benefit ratio of participating in the study. This includes, but is not limited to, acute myocardial infarction in the past 6 months, unstable angina, uncontrolled diabetes mellitus, significant active infections, severely immunocompromised state, and congestive heart failure, New York Heart Association Class III-IV.
• •18. Known bleeding diathesis (e.g. von Willebrand's disease), hemophilia, or active bleeding.
• •19. Known Human immunodeficiency virus (HIV) infection.
• •20. Known active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV) as determined by serologic tests and/or PCR.
• •21. History of invasive fungal infection, including invasive aspergillosis, or known active tuberculosis.
• •22. Major surgery ≤ 6 weeks prior to starting the trial treatment (or has not recovered from the side effects of such surgery) or plans to have surgery within 2 weeks of the first dose of the study drug.