NCT07350850

A Multicenter Two-Cohort Study of Methotrexate, Rituximab, Sintilimab and Pirtobrutinib for Treatment-Naive PCNSL vs. Real-World Investigator-Selected Treatment (Observational Cohort)

In Treatment-Naive Patients With Primary Central Nervous System Lymphoma (PCNSL): A Multicenter Two-Cohort Study of Methotrexate Combined With Rituximab, Sintilimab and Pirtobrutinib (Prospective Interventional Cohort) vs. Real-World Investigator-Selected Treatment (Observational Cohort)

• Status: Recruiting
• Phase: Phase 2
• Study type: Interventional
• Enrollment: 110 (estimated)
• Sponsor: Tongji Hospital · Academic / Other
• Sex: All
• Age: 18 Years
• Healthy volunteers: Not accepted

Summary

The goal of this clinical trial is to evaluate a new combination therapy for patients with newly diagnosed Primary Central Nervous System Lymphoma (PCNSL). The main questions it aims to answer are: (1) Does the combination of Methotrexate, Rituximab, Sintilimab, and Pirtobrutinib improve the Complete Remission Rate (CRR)? (2) Is this regimen safe and tolerable for patients? Researchers will compare this interventional group to a real-world observational group (receiving standard investigator-selected treatments) to see if the new combination improves treatment response and survival.

Detailed description

Primary Central Nervous System Lymphoma (PCNSL) is a rare extranodal non-Hodgkin lymphoma with poor prognosis, characterized by MYD88 L265P/CD79B mutations and PD-L1/PD-L2 overexpression. Current first-line therapies based on high-dose methotrexate (HD-MTX) have limitations including high recurrence rates, poor blood-brain barrier penetration, and significant toxicity. Pirtobrutinib, a highly selective reversible BTK inhibitor, exhibits superior CNS penetration and safety profiles compared to covalent BTK inhibitors. Sintilimab (anti-PD-1) enhances anti-tumor immunity by blocking PD-1/PD-L1 axis. This study evaluates the efficacy and safety of the quadruple combination (methotrexate+rituximab + sintilimab + pirtobrutinib ) in treatment-naive PCNSL, with a real-world cohort providing comparative evidence.

Conditions

• PCNSL
• Primary Central Nervous System Lymphoma

Interventions

Type	Name	Description
DRUG	Pirtobrutinib, Sintilimab, Rituximab, Methotrexate	Participants in this single-arm prospective cohort will receive the investigational combination therapy: Rituximab (375 mg/m\^2, IV, Day 0), Methotrexate (3.5 g/m\^2, IV, Day 1; adjusted to 1.0 g/m\^2 for elderly/frail patients), Sintilimab (200 mg, IV, Day 1), Pirtobrutinib (200 mg, PO, Days 1-21). Treatment cycles repeat every 21 days for up to 6 cycles.
DRUG	Standard of Care (Investigator Selected)	Participants in the Real-World Observational Cohort receive investigator-selected treatments based on clinical guidelines. 1.Specific regimens include: 1. MATRix: Methotrexate (3.5g/m², d1), Cytarabine (2g/m², d2-3), Rituximab (375mg/m², d0), and Thiotepa (30mg/m², d4) every 21 days . 2. RMT: Methotrexate (3.5g/m², d1), Rituximab (375mg/m², d0), and Temozolomide (150mg/m², d1-5) every 21 days . 3. MR-BTKi: Methotrexate (3.5g/m², d1), Rituximab (375mg/m², d0), and a covalent BTK inhibitor (Ibrutinib 560mg qd, Zanubrutinib 160mg bid, or Orelabrutinib 150mg qd) . 2.Palliative Care Subgroup: Radiotherapy, low-dose chemotherapy, or supportive care .Radiotherapy: Low-dose Whole Brain Radiotherapy (WBRT ≤ 30Gy). Low-dose Chemotherapy: Reduced-dose Methotrexate (e.g., 1.0g/m²) or other single-agent chemotherapy. Best Supportive Care: Management of symptoms and complications without intensive anti-tumor agents.

Timeline

• Start date: 2025-12-25
• Primary completion: 2028-12-31
• Completion: 2029-06-30
• First posted: 2026-01-20
• Last updated: 2026-03-09

Locations

3 sites across 1 country: China