Selinexor, High-dose Methotrexate, and Rituximab Combined With Radiotherapy for Newly Diagnosed, Transplant-ineligible Patients With Central Nervous System Lymphoma: An Open-label, Single-arm, Multicenter Phase II Study

Selinexor, High-dose Methotrexate, and Rituximab Combined With Radiotherapy for Newly Diagnosed, Transplant-ineligible Patients With Central Nervous System Lymphoma: An Open-label, Single-arm, Multicenter Phase II Study

This phase II clinical trial is designed to evaluate a novel combination treatment for patients with newly diagnosed central nervous system lymphoma (CNSL) who are not candidates for stem cell transplantation. The study will assess the safety and effectiveness of combining selinexor (an oral selective nuclear export inhibitor) with high-dose methotrexate and rituximab chemotherapy, followed by low-dose whole-brain radiotherapy (WBRT). Selinexor has shown promise in enhancing the effects of chemotherapy and radiation in blood cancers.

Patients enrolled in this open-label, single-arm, multicenter study will receive up to six 21-day treatment cycles. Those who respond well will undergo reduced-dose WBRT and continue selinexor as maintenance therapy. The study will measure how many patients respond to the treatment (overall response rate), how long the response lasts (progression-free survival), overall survival, and safety.

This research aims to provide a less toxic and more effective option for treating CNSL in patients who are older or medically unfit for transplantation.

This is a prospective, investigator-initiated, open-label, single-arm, multicenter phase II clinical trial designed to evaluate the efficacy and safety of a combination regimen consisting of selinexor, high-dose methotrexate (HD-MTX), and rituximab, followed by low-dose whole-brain radiotherapy (WBRT), in patients with newly diagnosed primary or secondary central nervous system lymphoma (PCNSL or SCNSL) who are not eligible for autologous stem cell transplantation (ASCT).

Selinexor is a first-in-class, selective inhibitor of nuclear export (SINE) targeting XPO1/CRM1. By blocking nuclear export, selinexor restores nuclear localization and activity of multiple tumor suppressor proteins and growth regulatory factors. Preclinical studies suggest that selinexor may enhance the antitumor activity of chemotherapy and radiotherapy, particularly in hematologic malignancies. Its role in CNSL is supported by its ability to cross the blood-brain barrier and sensitize lymphoma cells to treatment.

Eligible patients will receive six 21-day cycles of combination therapy: rituximab 375 mg/m² IV on day 0, HD-MTX 3.5 g/m² IV over 4 hours on day 1, and selinexor 80 mg orally once weekly (days 1, 8, and 15). Tumor response will be assessed every three cycles. Patients achieving at least partial response (PR) will proceed to consolidative low-dose WBRT (23.4 Gy in 13 fractions), followed by maintenance selinexor (80 mg orally once weekly) until disease progression or unacceptable toxicity.

The primary endpoint is the overall response rate (ORR) based on the Lugano 2014 criteria. Secondary endpoints include complete response rate (CRR), progression-free survival (PFS), overall survival (OS), and safety/tolerability assessed by CTCAE v5.0.

A total of 26 patients will be enrolled. This study aims to provide an effective treatment option for transplant-ineligible CNSL patients and to explore the potential synergistic effects of selinexor with chemotherapy and radiotherapy.

Inclusion Criteria:

1. Age ≥ 18 years, male or female.

2. Histologically confirmed primary CNS lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL) with CNS-only involvement.

3. Ineligible for autologous stem cell transplantation based on clinical assessment or patient refusal.

4. At least one measurable brain lesion ≥1 cm in diameter, or positive cerebrospinal fluid (CSF) cytology/flow cytometry for patients with leptomeningeal disease.

5. Eastern Cooperative Oncology Group (ECOG) performance status of 0-3.

6. Adequate organ function, including:

   • Absolute neutrophil count (ANC) ≥ 1.0 × 10⁹/L
   • Platelets ≥ 75 × 10⁹/L
   • Hemoglobin ≥ 80 g/L
   • Total bilirubin ≤ 1.5 × ULN (or ≤ 3 × ULN if liver involvement)
   • ALT and AST ≤ 2.5 × ULN (or ≤ 5 × ULN if liver involvement)
   • Creatinine clearance ≥ 30 mL/min (Cockcroft-Gault formula)
   • INR ≤ 1.5 × ULN; APTT within 10 seconds of normal

7. Estimated life expectancy of ≥ 3 months.

8. Negative serum pregnancy test for women of childbearing potential.

9. Ability to understand and willingness to sign a written informed consent form.

Exclusion Criteria:

1. CNS involvement limited to intraocular lymphoma only.

2. Prior systemic therapy for CNS lymphoma.

3. SCNSL with active systemic (non-CNS) disease involvement.

4. Uncontrolled intracranial hypertension.

5. Clinically significant or unstable cardiovascular disease, including:

   • Myocardial infarction within 6 months
   • Unstable angina within 3 months
   • Uncontrolled arrhythmias (e.g., ventricular tachycardia/fibrillation)
   • Congestive heart failure NYHA class ≥ III
   • LVEF < 50% by echocardiography

6. Other severe uncontrolled medical conditions, including active infections requiring systemic therapy.

7. Known active hepatitis B (HBV), hepatitis C (HCV), or HIV infection.

8. Active gastrointestinal dysfunction that interferes with the ability to swallow or absorb oral medication.

9. Prior treatment with selective inhibitor of nuclear export (SINE) compounds, including selinexor.

10. Concurrent malignancy, except for adequately treated basal/squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ of the cervix, prostate, or breast.

11. Pregnant or breastfeeding women, or subjects unwilling to use medically accepted effective contraception during the study and for 6 months after the last dose.

12. Any condition which, in the investigator's judgment, would make the patient unsuitable for study participation.