a study of selinexor in combination with temozolomide and anti-pd-1 antibody in patients with relapsed/refractory primary central nervous system lymphoma

Conditions: Relapsed/Refractory Primary Central Nervous System Lymphoma

Summary: 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).


Eligibility criteria:
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) \ 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.