A Clinical Study on the Efficacy and Safety of Methotrexate (MTX) or Thiotepa (for MTX Intolerance) or Temozolomide (TMZ) Combined With Orelabrutinib and Selinexor in Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma（SELINA）
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 25
- 试验地点
- 1
- 主要终点
- ORR
研究概览
简要总结
Clinical Study on the Efficacy and Safety of Methotrexate (MTX) or Thiotepa (for MTX intolerance) or Temozolomide (TMZ) Combined with Orelabrutinib and Selinexor in the Treatment of Relapsed/Refractory Primary or Secondary Central Nervous System Lymphoma
This study adopts an open-label, prospective, single-arm, single-center design aimed at evaluating the efficacy and safety of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor in the treatment of relapsed/refractory primary or secondary central nervous system lymphoma (r/r CNSL).
Primary Objective To evaluate the efficacy and safety of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor in the treatment of relapsed/refractory primary or secondary central nervous system lymphoma (r/r CNSL).
Secondary Objective To assess the benefit-risk balance of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor in combination with chemotherapy in the clinical management of relapsed/refractory primary or secondary central nervous system lymphoma (r/r CNSL).
Patients with relapsed/refractory primary or secondary CNSL (PCNSL/SCNSL) who meet the inclusion criteria will be enrolled. Previous study data indicate that the combination of orelabrutinib with methotrexate or temozolomide in the treatment of relapsed/refractory central nervous system lymphoma can achieve an ORR of 60%. It is anticipated that the addition of selinexor will increase the ORR to 75%. The treatment effect in r/r CNSL patients is expected to be superior to that of chemotherapy-based combination regimens (one-sided test). With a one-sided alpha = 0.025, beta = 0.1, and an expected enrollment completion within 12 months, along with a follow-up period of 24 months, the planned sample size is 23 patients. Accounting for a 10% dropout rate, the corrected sample size for this study is 25 patients.
Patients who meet the inclusion/exclusion criteria and provide signed informed consent will be enrolled in the experimental group. Each treatment cycle lasts 3 weeks. After 6 cycles of induction therapy, patients who do not achieve a PR or experience disease progression at any time will withdraw from the study and receive salvage therapy. Patients who achieve CR or PR will undergo autologous transplantation if they are young and eligible for transplantation. For patients with TP53 mutations, selinexor will be incorporated into the transplant conditioning regimen. Patients who are ineligible for transplantation will receive consolidative radiotherapy. After consolidative therapy, maintenance treatment with orelabrutinib may be administered based on treatment response and patient tolerance. For patients with TP53 mutations, selinexor will be added to orelabrutinib maintenance therapy. For patients with SD/PD, subsequent treatment will be determined by the investigator, followed by observation and follow-up for up to 3 years.
Experimental Group Regimen:
Induction Therapy: Orelabrutinib 150 mg once daily, selinexor 40 mg weekly, methotrexate 3.5 g/m² (for patients intolerant or resistant to methotrexate: temozolomide 150 mg/m² or thiotepa 30-40 mg/m² may be used as alternatives). Each cycle lasts 3 weeks, for a total of 6 cycles.
Maintenance Therapy:
Non-TP53mut patients without transplantation: After consolidative radiotherapy, maintenance therapy with orelabrutinib 150 mg once daily may be administered.
TP53mut patients without transplantation: After consolidative radiotherapy, maintenance therapy with orelabrutinib 150 mg once daily combined with selinexor 40 mg weekly may be administered.
详细描述
- Research Background
1.1 Significance of the Research Central nervous system lymphoma (CNSL) is a rare extranodal non-Hodgkin lymphoma characterized by high aggressiveness and poor prognosis. Over the past decades, high-dose methotrexate (HD-MTX)-based chemotherapy regimens (including combinations with rituximab, temozolomide, cytarabine, vincristine, etc.) have significantly improved the survival outcomes of CNSL patients . However, treatment options for relapsed/refractory primary and secondary central nervous system lymphoma (r/r CNSL) remain limited, necessitating the exploration of new combination therapies. This project aims to conduct a single-center, randomized, open-label, single-arm clinical trial of orelabrutinib combined with chemotherapy for r/r CNSL, analyzing patients' short- and long-term efficacy and chemotherapy-related toxic side effects, ultimately providing a reference for further optimizing the treatment of r/r CNSL.
1.2 Research Background Central nervous system lymphoma includes primary central nervous system lymphoma (PCNSL) and secondary central nervous system lymphoma (SCNSL). PCNSL is a relatively rare type of non-Hodgkin lymphoma (NHL) originating in the central nervous system (including the brain, eyes, spinal cord, and meninges) without involvement of other sites. It accounts for about 2%-4% of all intracranial tumors and 4%-6% of all NHLs, and its incidence has been gradually increasing in recent years . SCNSL refers to lymphoma that spreads to the CNS during or after treatment for systemic lymphoma. It can be diagnosed at the initial diagnosis of lymphoma or at relapse .
Over the past decades, HD-MTX-based chemotherapy regimens (including rituximab, temozolomide, cytarabine, vincristine, etc.) have significantly improved the survival prognosis of PCNSL patients, but the relapse rate exceeds 50%, and about 25% of patients fail initial treatment. The prognosis for r/r PCNSL is even worse . Furthermore, retrospective studies show that the median survival of previously treated SCNSL patients is approximately 6 months .
Due to the poor survival of patients, prospective studies for r/r CNSL patients are lacking; current knowledge is based on retrospective studies of cytotoxic drugs or combination regimens used to treat systemic lymphoma . In one retrospective study, 22 r/r CNSL patients who had initially received high-dose methotrexate-based chemotherapy were treated with a combination of rituximab, ifosfamide, and etoposide for 4 cycles. The ORR was 41%, CR rate was 37%, and the 2-year PFS was 21% .
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 14 Years 至 80 Years（Child, Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Patients must meet all of the following criteria to be enrolled in this study:
- •Fully understand this study and voluntarily sign the informed consent form;
- •Age: 14-80 years;
- •Life expectancy judged by the investigator to exceed 3 months;
- •B-cell origin central nervous system lymphoma (CNSL) confirmed by pathology or flow cytometry (histology or cytology);
- •Relapsed or refractory PCNSL or SCNSL: Must have received at least one prior systemic therapy for CNS lesions; number of relapses is not restricted;
- •Any non-hematological toxicity related to prior treatment should have recovered to Grade 1 or normal (according to NCI CTCAE version 5.0, except alopecia).
- •Bone marrow and organ function meeting the following criteria (no transfusion, no G-CSF use, no medication for correction within 14 days before screening):
- •Bone marrow function: Absolute neutrophil count ≥1.0x10⁹/L, platelets ≥50x10⁹/L, hemoglobin ≥60g/L;Liver function: Serum total bilirubin ≤1.5xULN (≤3.0xULN if liver metastases present); AST and ALT ≤ 2.5xULN (≤5.0xULN if liver metastases present);Coagulation function: International Normalized Ratio (INR) and activated partial thromboplastin time ≤1.5xULN;Renal function: Serum creatinine ≤1.5xULN or estimated creatinine clearance ≥30 mL/min (Male: Cr (mL/min) = (140 - age) x weight (kg) / (72 x serum creatinine (mg/dL)); Female: Cr (mL/min) = (140 - age) x weight (kg) / (85 x serum creatinine (mg/dL))).
- •Female subjects of childbearing potential and male subjects with reproductive ability, who have no pregnancy plan with their partners during the study period and for 3 months after treatment interruption, must use one of the following effective contraceptive methods throughout the study and for 3 months after treatment interruption: abstinence, physical contraception (e.g., ligation, condoms, etc.), hormonal contraceptive drugs started at least 3 months before the first dose in the study. Male subjects are prohibited from sperm donation from the start of treatment until 3 months after treatment cessation. The patient or their legal guardian voluntarily signs the informed consent form.
- •Good compliance, willing to adhere to the visit schedule, dosing plan, laboratory tests, and other trial procedures.
排除标准
- •Patients who meet any of the following criteria will not be allowed to enter this study:
- •Contraindication to any drug in the treatment regimen;
- •Subject has a history of active liver disease, including viral or other hepatitis or cirrhosis (Hepatitis B defined as HBV-DNA above the upper limit of normal; active Hepatitis C defined as seropositive for HCV antibody, but those with negative HCV-RNA can be enrolled);
- •Human Immunodeficiency Virus (HIV) infection;
- •Congestive heart failure (New York Heart Association Class >2); history of acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within the past six months;
- •Hereditary long QT syndrome or QTc >480ms (Note: QTc interval must be calculated using Fridericia's formula, QTcF = QT/(RR)^0.33);
- •Pregnant and lactating women, or those planning to become pregnant during the study period;
- •Clear history of neurological or psychiatric disorders, or history of psychotropic drug abuse or drug addiction;
- •Clinically significant active infection.
研究组 & 干预措施
selinexor
inductive treatment
-
Orelabrutinib 150mg qd + Selinexor 40mg qw
-
Combined chemotherapy (choose one):
-
MTX 3.5g/m² IV d0
-
Temozolomide 150mg/m² PO d1-5
-
Thiotepa 40mg/m² IV d3
-
Every 3 weeks for 6 cycles maintenance treatment
-
Non-transplant patients: Orelabrutinib ± Selinexor (based on TP53 mutation status)
干预措施: Selinexor+Orelabrutinib+Methotrexate/Thiotepa/Temozolomide (Drug)
结局指标
主要结局
ORR
时间窗: up to 6 months
Optimal response rates during the treatment period
次要结局
- 2-year Progression-Free Survival Rate(up to 2 years)