Primary Central Nervous System Lymphoma (PCNSL), Diffuse Large B Cell Lymphoma (DLBCL)
Conditions
Keywords
diffuse large b cell lymphoma, primary central nervous system lymphoma, pomalidomide, PD-1 inhibitor, XPO1 inhibitor, selinexor
Brief summary
Primary central nervous system diffuse large B-cell lymphoma (PCNSL-DLBCL) is a highly aggressive malignancy accounting for over 80% of primary CNS lymphomas, with an annual incidence of 0.4-0.6 per 100,000 people globally and a rising trend in immunocompetent patients. First-line high-dose methotrexate-based chemotherapy causes severe toxicities and nearly 50% of patients relapse within 1-2 years, developing relapsed/refractory (R/R) disease. Treatment options for R/R PCNSL are scarce, with low response rates, median survival of only 3-6 months, and 5-year survival below 5%. The blood-brain barrier and tumor heterogeneity further worsen outcomes. This prospective, multicenter, single-arm phase II study evaluates the efficacy and safety of pomalidomide, PD-1 inhibitor, and selinexor (PPS) in R/R PCNSL, aiming to provide a new effective treatment.
Detailed description
Primary central nervous system diffuse large B-cell lymphoma (PCNSL-DLBCL) is a highly aggressive and uncommon extranodal non-Hodgkin lymphoma that exclusively or predominantly involves the central nervous system. As the predominant subtype of primary central nervous system lymphomas, it accounts for more than 80% of all cases, representing a major clinical challenge in neuro-oncology. Epidemiological studies indicate a global annual incidence of 0.4 to 0.6 per 100,000 individuals, with a gradual increase observed in immunocompetent populations in recent decades. This rising incidence, coupled with its malignant biological behavior, has placed substantial pressure on clinical diagnosis and management. Currently, high-dose methotrexate (HD-MTX)-based combination chemotherapy remains the standard first-line treatment for PCNSL. Some patients may receive consolidation with local radiotherapy or autologous hematopoietic stem cell transplantation to improve disease control. Nevertheless, this therapeutic strategy has significant limitations. High-dose chemotherapy frequently induces severe adverse events, including myelosuppression, liver and renal toxicity, which are poorly tolerated by elderly patients or those with multiple comorbidities. Despite standardized first-line therapy, approximately 50% of patients experience disease relapse or progression within 1 to 2 years, eventually developing relapsed/refractory (R/R) PCNSL. For patients with R/R PCNSL, therapeutic options are extremely limited. Existing second-line chemotherapy regimens yield unsatisfactory and inconsistent efficacy, with objective response rates generally below 50%. The median overall survival is only 3 to 6 months, and the 5-year survival rate is less than 5%. In addition to poor survival outcomes, patients often suffer from headache, neurological deficits, cognitive impairment, and other neuropsychiatric symptoms, severely impairing quality of life. Furthermore, the physiological barrier of the blood-brain barrier prevents most conventional chemotherapeutic agents from reaching effective intratumoral concentrations. Meanwhile, the high genetic and phenotypic heterogeneity of tumor cells further compromises treatment efficacy and contributes to drug resistance. Collectively, the clinical demand for safe and effective treatments in R/R PCNSL remains drastically unmet. Therefore, we designed this prospective, multicenter, single-arm phase II clinical trial to systematically investigate the efficacy and safety of the triplet regimen consisting of pomalidomide, PD-1 monoclonal antibody, and selinexor (PPS) in patients with R/R PCNSL-DLBCL. This study aims to establish a novel and practical therapeutic approach, improve survival and quality of life, and fill the current therapeutic gap for this refractory patient population.
Interventions
DRUGPomalidomide
4 mg on days 1-14, every 3 weeks (q3w), for a total of 6 cycles
tislelizumab 200 mg on day 1, q3w, for a total of 6 cycles
DRUGXPO1 inhibitor
Selinexor: 60 mg on days 1, 8, and 15, q3w, for a total of 6 cycles
Sponsors
Beijing Tongren Hospital
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed primary central nervous system diffuse large B-cell lymphoma (PCNSL-DLBCL). * Disease progression or relapse after prior treatment with high-dose methotrexate and/or BTK inhibitors. * Age between 18 and 75 years. * ECOG performance status score 0-4. * Expected overall survival \> 3 months. * No known hypersensitivity to any study drug. * White blood cell count ≥ 3×10⁹/L; absolute neutrophil count ≥ 1.0×10⁹/L; platelet count ≥ 50×10⁹/L. * Serum creatinine ≤ 1.5 mg/dL; creatinine clearance ≥ 50 mL/min. * ALT and AST ≤ 3× upper limit of normal (ULN); total bilirubin ≤ 2× ULN. * Signed written informed consent.
Exclusion criteria
* Presence of another malignant tumor requiring active pharmacological or surgical intervention at present; * Female patients who are pregnant or breastfeeding; * Patients (male or female) of reproductive potential who are unwilling to use or fail to use effective contraceptive measures; * Known hypersensitivity to any study drug or any excipient ingredients of these products; * Active infection (determined by the investigator); * History of immunodeficiency, including positive HIV status, other acquired or congenital immunodeficiency disorders, or history of organ transplantation; * Documented history of neurological or psychiatric disorders, including epilepsy or dementia; * Documented history of autoimmune diseases (except Hashimoto's thyroiditis or thyroid dysfunction); * Any severe comorbidity that, in the investigator's judgment, would compromise patient safety or interfere with the completion of the study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| best overall response rate (ORR) as of 6 cycles of PPS | From the day of initiation of PPS treatment to 3 weeks after 6 cycles of PPS treatment (the length of each cycle is 3 weeks) | Overall response rate means sum of complete response rate and partial response rate |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Best Complete Response rate (CR) as of 6 cycles of PPS | From the day of initiation of PPS treatment to 3 weeks after 6 cycles of PPS treatment (the length of each cycle is 3 weeks) | CR was defined as complete response evaluated using MRI scan |
| Progression free survival (PFS) | From the day of initiation of PPS as of 24 months | PFS was defined from the date of initiation of PPS to the date fo confirmed disease progression or death of any reason |
| overall survival (OS) | From the day of initiation of PPS as of 24 months | OS was defined from the date of initiation of PPS to the date fo death |
| Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability] | From the day of initiation of PPS as of 24 months | measured using CTCAE version 5.0 |
Countries
China
Contacts
CONTACTLiang Wang, M.D.
CONTACTJia Cong, M.D.
PRINCIPAL_INVESTIGATORLiang Wang, M.D.
Beijing Tongren Hospital
Outcome results
None listed