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）

1. 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% . Temozolomide is a well-tolerated oral alkylating agent that has shown activity in other brain tumors, with CNS concentrations about 20% lower than corresponding blood concentrations . A prospective study showed that temozolomide monotherapy for r/r CNSL patients achieved an ORR of only 31% . It is known that in CNSL tumor cells, the B-cell receptor pathway and MYD88 gene often mutate, leading to sustained activation of the nuclear factor-kappa B (NF-κB) signaling pathway . Bruton's tyrosine kinase (BTK) is a key regulatory molecule in the B-cell receptor pathway and is considered one of the ideal targets for treating lymphoma with sustained NF-κB pathway activation . For CNSL, a preclinical study reported that ibrutinib achieves high drug levels in the brain, suggesting that the BTK inhibitor ibrutinib might be effective against central lymphoma . Subsequently, two clinical trials found that the objective response rate (ORR) in relapsed PCNSL patients receiving ibrutinib combined with chemotherapy could reach 75% . These results suggest that BTK inhibitors combined with existing chemotherapy regimens may help improve patient ORR and ultimately enhance the survival prognosis of these patients. However, due to ibrutinib's off-target effects which cause relatively high toxicity events, applying a new-generation BTK inhibitor with longer efficacy and lower toxicity is significant and may be more suitable for combination therapy in r/r CNSL patients. Orelabrutinib is a second-generation BTK inhibitor. Due to its excellent efficacy and low toxicity, it has been approved for adult patients with mantle cell lymphoma (MCL) who have received at least one prior therapy; adult patients with chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) who have received at least one prior therapy; and relapsed/refractory marginal zone lymphoma (MZL) . A phase II clinical study found that in r/r PCNSL patients, the median cerebrospinal fluid (CSF) concentration of orelabrutinib was 28.7 ng/ml (range, 11.8-52.7 ng/ml), with a median CSF/plasma free ratio of 59.8% (range 46.09%-86.67%). This result indicates that orelabrutinib can effectively cross the blood-brain barrier (BBB) . Furthermore, Yang C et al. reported that an orelabrutinib combination regimen (orelabrutinib + lenalidomide + RMT) achieved an ORR of 86.7% in 15 r/r PCNSL patients, with a median PFS of 9.8 months . Thus, orelabrutinib has potential application prospects in the treatment of r/r CNSL, and the efficacy and safety of orelabrutinib combination regimens for treating r/r CNSL warrant further exploration. Selinexor is a Selective Inhibitor of Nuclear Export (SINE), belonging to a new class of targeted anticancer drugs. Its mechanism of action involves specifically inhibiting Exportin 1 (XPO1), blocking the transport of tumor suppressor proteins, growth regulators, and anti-inflammatory proteins from the nucleus to the cytoplasm. This causes the accumulation of these key proteins within the nucleus, thereby inducing cancer cell apoptosis and inhibiting tumor growth. Therefore, this study plans to conduct a single-center, randomized, open-label, single-arm clinical trial of methotrexate (MTX) or thiotepa (for MTX intolerance) or temozolomide (TMZ) combined with orelabrutinib and selinexor for the treatment of 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.
2. Study Design

2.1 Overall Design This study adopts an open-label, prospective, single-arm, single-center design aimed at evaluating the efficacy and safety of orelabrutinib combined with chemotherapy in r/r CNSL.

2.2 Definition of Study Endpoints

Primary Endpoint Objective Response Rate (ORR)

Secondary Endpoints 2-year Progression-Free Survival (PFS) rate; Overall Survival (OS); Complete Response (CR) rate; Safety.

Safety endpoints: Incidence and grade of adverse events (AEs) and serious adverse events (SAEs); ECOG performance status, vital signs, physical examination, laboratory test indicators, electrocardiogram (ECG), echocardiogram, etc.; Incidence of thrombotic events.

Exploratory Endpoints Blood and cerebrospinal fluid concentrations of selinexor;

Cerebrospinal fluid and peripheral blood ctDNA:

Collect patient cerebrospinal fluid (4ml each time) at four time points: pre-treatment, before cycle 2, end of treatment, and at disease progression.

Peripheral blood anticoagulant sample (4ml), once during follow-up; Extract circulating tumor DNA (ctDNA), using capture and next-generation sequencing technology, Capp-seq for detection, analyzing the correlation of ctDNA with tumor burden, molecular mutations, molecular response, and for prognosis, treatment response, relapse, and drug resistance. Single-cell sequencing will be performed on some patients for deeper research.

2.3 Determination of Sample Size

Based on historical data showing an ORR of approximately 41% for chemotherapy combination regimens in r/r CNSL patients, combined with research and current clinical needs, where ibrutinib combined with chemotherapy showed 69% efficacy in r/r CNSL, and considering orelabrutinib's higher concentration across the blood-brain barrier and potentially better effect, it is hypothesized that this study's ORR will increase to 75%. The treatment effect in r/r CNSL patients is expected to be superior to that of chemotherapy combination regimens (one-sided test). With a one-sided alpha = 0.025, beta = 0.1, an expected enrollment completion within 12 months, and 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.