This study is a prospective, single-arm, open label, Phase Ib/II clinical study to evaluate the safety and efficacy of selinexor in combination with temozolomide and anti-PD-1 monoclonal antibody in patients with relapsed/refractory primary central nervous system lymphoma(PCNSL). Phase Ib used a "3+3" dose-climbing design to confirm the safety, maximum-tolerated dose (MTD,if any) and recommended phaseII dose (RP2D) of selinexor in combination with fixed dose of temozolomide and anti-PD-1 monoclonal antibody for 6 cycles. Phase II was a comprehensive evaluation of efficacy and safety. Subjects who achieved complete remission or partial remission were treated with anti-PD-1 monoclonal antibody maintenance therapy until disease progression or recurrence, intolerance of toxicity, death, loss of follow-up, withdrawal of notification (whatever happened first).

Inclusion Criteria:

• Aged between 18 and 75 (inclusive).

• Participants must be able to understand and be willing to sign a written informed consent document.

• Eastern Cooperative Oncology Group performance status 0 to 3.

• Life expectancy of ≥ 3 months (in the opinion of the investigator).

• Primary central nervous system lymphoma (PCNSL) of B-cell origin confirmed by pathology (histology or cytology)

• Measurable disease was defined as at least ≥1.0cm in short-diameter by enhanced MRI.

• Recurrent/refractory PCNSL: Must have received at least one systemic treatment with methotrexate-based treatment.

• Any non-hematological toxicity associated with previous treatment should return to grade 1 or normal (except hair loss according to NCI CTCAE version 5.0)

• Bone marrow and organ function meet the following criteria (no blood transfusion within 14 days prior to screening, no G-CSF, no medication correction) :

  1. Bone marrow function: absolute value of neutrophils ≥1.5×10^9/L, platelets ≥80×10^9/L, hemoglobin ≥80 g/L;
  2. Liver function: serum total bilirubin ≤1.5×ULN (≤3.0×ULN, if there is liver metastasis); Glutamic oxalic aminotransferase (AST) and glutamic pyruvic aminotransferase (ALT) ≤2.5×ULN (≤5.0×ULN, if there is liver metastasis);
  3. Coagulation function: International standardized ratio (INR) and activated partial thrombin time ≤1.5×ULN;
  4. Renal function: serum creatinine ≤1.5×ULN or estimated creatinine clearance ≥60 mL/min (male: Cr (ml/min) = (140-age) × body weight (kg) /72× serum creatinine concentration (mg/dl); Female: Cr (ml/min) = (140- age) × body weight (kg) /85× serum creatinine concentration (mg/dl)

• Women of reproductive potential must agree to use highly effective methods of birth control during the period of therapy and for 6 months after the last dose of the study drug. Men who are sexually active must agree to use highly effective contraception during the period of therapy and for 6 months after the last dose.

• Can accept multiple MRI/CT and lumbar puncture examination.

• Swallowing oral tablets/capsules without difficulty.

• Good compliance, willing to follow the visit schedule, dosing schedule, laboratory examination and other test procedure.

Exclusion Criteria:

• Pathological diagnosis was T cell lymphoma.
• Anti-tumor therapy with chemotherapy, radiotherapy, immunotherapy or antibody drugs, or Chinese herbal medicine with anti-tumor indications, small-molecule targeted therapy within 2 weeks, monoclonal antibody-coupled drugs or cytotoxin therapy within 10 weeks, and autologous stem cell transplantation within 6 months before the first administration.
• Participation in another clinical study with an investigational product during the 4 weeks prior to the first day of study treatment.
• Patients who use systemic adrenal corticosteroids for more than 5 days within 14 days prior to medication or who need to take >10mg of dexamethasone or equivalent drugs daily to control CNS disease.
• Active concurrent malignancy requiring active therapy.
• Prior treatment with temozolomide or anti-PD-1, anti-PD-L1, or anti-PD-L2 drugs within 6 months prior to initial administration
• Have uncontrolled or significant cardiovascular disease, including (but not limited to) : Any of the following: congestive heart failure (NYHA Class III or IV);myocardial infarction; unstable angina; or the presence of an arrhythmia requiring treatment at the time of screening with a left ventricular ejection fraction (LVEF) < 50% in the 6 months prior to initial dosing; Primary cardiomyopathy (e.g., dilated cardiomyopathy, hypertrophic cardiomyopathy, arrhythmogenic right ventricular cardiomyopathy, restricted cardiomyopathy, undefined cardiomyopathy); A clinically significant history of prolonged QTc, grade II type II atrioventricular block or grade III atrioventricular block, or QTc interphase (method F) > 470 msec (female) or > 480msec (male);Atrial fibrillation (EHRA grade ≥2b);Patients with unmanageable hypertension were deemed unsuitable for participation in the study.
• Uncontrolled infections or infections that require intravenous antibiotic treatment.
• Chronic hepatitis B carriers with active hepatitis B or C infection (hepatitis B: acute hepatitis B, untreated chronic hepatitis B virus infection, HBV-DNA≥ the detection limit of each center; Hepatitis C: HCV RNA positive) or syphilis. Notes: Non-active HBV surface antigen (HBsAg) carriers, subjects with active HBV infection and persistent anti-HBV inhibition (HBV DNA < each center detection limit), and subjects cured of HCV can be enrolled.
• Human immunodeficiency virus (HIV) infection
• Clinically significant gastrointestinal abnormalities that may affect drug intake, transport, or absorption (such as active gastrointestinal inflammation, chronic diarrhea, intestinal obstruction, etc.), or total gastrectomy or gastric banding surgery.
• Prior allogenic stem cell transplant.
• For female subjects, they are currently pregnant or breastfeeding.
• Allergy to the investigational drug or excipient.
• The patient has active mental illness, alcohol, drug or substance abuse.
• The presence of any life-threatening disease, medical condition, or organ system dysfunction that the investigator believes may affect the patient's safety or compliance with the study procedure.
• There are other conditions that the investigator considers inappropriate to participate in this clinical trial.