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
Age >= 18 years.
Voluntarily signed informed consent.
ECOG Performance Status 0-3.
Expected survival > 3 months.
myocardial infarction, unstable angina within 6 months before first dose; arrhythmia requiring treatment; LVEF <50%.
Primary cardiomyopathy.
History of clinically significant QTc prolongation, second-degree type II/third-degree atrioventricular block, or QTc interval (Fridericia method) >470 msec (females) / >480 msec (males).
Atrial fibrillation (EHRA grade ≥2b).
Parallel
Pirtobrutinib, Sintilimab, Rituximab, Methotrexate
DrugParticipants 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.
Standard of Care (Investigator Selected)
DrugPatients 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.
Overall Response Rate (ORR)
Sum of Complete Response (CR) and Partial Response (PR) rates.
Duration of Response (DOR)
Time from documentation of tumor response (CR or PR) to disease progression or death.
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.
Progression-Free Survival (PFS)
The time interval from the start of treatment to tumor progression (PD) or death from any cause.
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 .
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Tongji Hospital
Lead sponsor
Shanxi Provincial People's Hospital
Collaborator
First Affiliated Hospital of Fujian Medical University
Collaborator
The General Hospital of Western Theater Command
Collaborator
China-Japan Union Hospital, Jilin University
Collaborator
