A Phase 2 interventional study of Pirtobrutinib, Sintilimab, Rituximab, Methotrexate and Standard of Care (Investigator Selected) in PCNSL and Primary Central Nervous System Lymphoma, sponsored by Tongji Hospital. Recruiting at 4 sites in China. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-06-02.
Sponsored by Tongji Hospital · Phase 2, Interventional, and Treatment
The goal of this clinical trial is to evaluate the efficacy and safety of a four-drug combination regimen as first-line treatment for adults aged 18 years and older with newly diagnosed primary central nervous system lymphoma (PCNSL). The main questions it aims to answer are:
Does the combination of pirtobrutinib, sintilimab, rituximab, and high-dose methotrexate achieve a higher complete response rate than standard treatment for newly diagnosed PCNSL? What is the safety and tolerability profile of this four-drug combination regimen? Researchers will compare the experimental four-drug combination to investigator-selected standard-of-care regimens (all based on high-dose methotrexate) to see if the experimental regimen improves complete response rate, progression-free survival, and overall survival while maintaining an acceptable safety profile.
Participants will:
Be assigned to either the experimental group or the standard treatment group based on their personal preference Receive 6 cycles of induction therapy (21 days per cycle) with their assigned treatment regimen Undergo regular clinical assessments, including contrast-enhanced brain MRI scans, blood tests, and cerebrospinal fluid examinations Complete the EORTC QLQ-C30 quality-of-life questionnaire at baseline, mid-treatment, end of treatment, and follow-up visits Receive optional consolidation or maintenance therapy based on their response to induction treatment Be followed for up to 2 years after completing treatment to monitor for disease progression and long-term outcomes
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 concurrent control cohort providing comparative evidence.
Tongji Hospital is the lead sponsor of 373 studies on the registry; 204 are open to participants now.
Counted across the registry records on this site, refreshed daily.
Exclusion Criteria:
1.Prior treatment with PD-1/PD-L1 inhibitors or CTLA4 monoclonal antibodies. Uncontrolled active infection. 2.Uncontrolled or significant cardiovascular diseases: 3.Congestive heart failure (NYHA class III/IV),
5.HIV infection. 6.Prior organ transplantation or allogeneic stem cell transplantation. 7.Pregnant or lactating females. 8.Prior/current pulmonary fibrosis, interstitial pneumonia, pneumoconiosis, or radiation pneumonitis (unsuitable for study per investigator).
9.Autoimmune diseases requiring systemic treatment within 2 years. 10.For Observational Cohort (Palliative Care Subgroup only): Incomplete clinical data (e.g., no pathological report, inability to perform MRI/PET-CT assessment).
Patients receive Rituximab, Methotrexate, Sintilimab, and Pirtobrutinib for 6 cycles (21 days/cycle).
Drug: Pirtobrutinib, Sintilimab, Rituximab, Methotrexate
Patients eligible for curative-intent therapy will receive one of the following three guideline-recommended, high-dose methotrexate (HD-MTX)-based first-line regimens, selected by the treating physician based on patient age, performance status, comorbidities, and clinical judgment: MATRix Regimen: Rituximab 375 mg/m² IV on Day 0; Methotrexate 3.5 g/m² IV on Day 1; Cytarabine 2 g/m² IV twice daily on Days 2-3; Thiotepa 30 mg/m² orally on Day 4. Cycle length: 21 days, up to 6 cycles. RMT Regimen: Rituximab 375 mg/m² IV on Day 0; Methotrexate 3.5 g/m² IV on Day 1; Temozolomide 150 mg/m² orally once daily on Days 1-5. Cycle length: 21 days, up to 6 cycles. MR-BTKi Regimen: Rituximab 375 mg/m² IV on Day 0; Methotrexate 3.5 g/m² IV on Day 1; Covalent BTK inhibitor (Ibrutinib 560 mg qd, Zanubrutinib 160 mg bid, or Orelabrutinib 150 mg qd) orally on Days 1-21. Cycle length: 21 days, up to 6 cycles.
Drug: Standard of Care (Investigator Selected)
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.
Patients eligible for curative-intent therapy will receive one of the following three guideline-recommended, high-dose methotrexate (HD-MTX)-based first-line regimens, selected by the treating physician based on patient age, performance status, comorbidities, and clinical judgment: MATRix Regimen: Rituximab 375 mg/m² IV on Day 0; Methotrexate 3.5 g/m² IV on Day 1; Cytarabine 2 g/m² IV twice daily on Days 2-3; Thiotepa 30 mg/m² orally on Day 4. Cycle length: 21 days, up to 6 cycles. RMT Regimen: Rituximab 375 mg/m² IV on Day 0; Methotrexate 3.5 g/m² IV on Day 1; Temozolomide 150 mg/m² orally once daily on Days 1-5. Cycle length: 21 days, up to 6 cycles. MR-BTKi Regimen: Rituximab 375 mg/m² IV on Day 0; Methotrexate 3.5 g/m² IV on Day 1; Covalent BTK inhibitor (Ibrutinib 560 mg qd, Zanubrutinib 160 mg bid, or Orelabrutinib 150 mg qd) orally on Days 1-21. Cycle length: 21 days, up to 6 cycles.
Complete Response Rate (CRR)
Proportion of participants achieving Complete Response (CR) at the end of treatment. Efficacy is evaluated by both investigators and independent imaging personnel based on the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria.
Time frame: At the completion of induction treatment(approximately 18 weeks)
Overall Response Rate (ORR)
Sum of Complete Response (CR) and Partial Response (PR) rates.
Time frame: At the completion of induction treatment (approximately 18 weeks)
Duration of Response (DOR)
Time from documentation of tumor response (CR or PR) to disease progression or death.
Time frame: Up to 2 years.
Disease Control Rate (DCR)
The proportion of patients whose tumor is controlled (no progression or shrinkage), defined as the sum of Complete Response (CR), Partial Response (PR), and Stable Disease (SD) rates.
Time frame: At the completion of induction treatment (approximately 18 weeks)
Progression-Free Survival (PFS)
The time interval from the start of treatment to tumor progression (PD) or death from any cause.
Time frame: Up to 2 years.
Overall Survival (OS)
The time from confirmed diagnosis to death from any cause.
Time frame: Up to 5 years as per long-term follow-up mentions
Overall Survival Rate (OS Rate)
The percentage of surviving patients out of the total number of included patients (specifically assessed as 1-year OS rate in study objectives).
Time frame: 1 year.
Safety and Tolerability (Adverse Events)
Assessment of safety based on the severity grading of Adverse Events (AE) according to NCI CTCAE v5.0. This includes evaluation via physical examination, vital signs, performance status, ECG, laboratory tests, and AE severity.
Time frame: Throughout the study process, up to 30 days after the last dose.
Patient Reported Outcomes (PRO)
Assessed using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30). The questionnaire consists of 30 items, with scores ranging from 0 to 100. For functional scales (e.g., physical, role functioning) and the global health status, a higher score represents a better level of functioning or quality of life. For symptom scales/items (e.g., fatigue, nausea), a higher score represents a worse outcome or greater symptom burden
Time frame: Baseline, every 2 cycles (approximately week 6 and week 12) during treatment, at treatment completion (approximately week 18), and every 3 months during follow-up for up to 2 years
Correlation between Molecular Subtypes and Treatment Response (CRR)
To evaluate the correlation between molecular subtypes (defined by MYD88 L265P and CD79B mutation status) and the Complete Response Rate (CRR). Mutation status is assessed via Next-Generation Sequencing (NGS). Treatment response is assessed by investigators and independent radiologists using the International Primary CNS Lymphoma Collaborative Group (IPCG) criteria based on brain MRI .
Time frame: Through study completion, an average of 1 year.
Plan to share: No
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