A Multicenter, Prospective Clinical Trial With a Concurrent Control Evaluating Methotrexate Combined With Rituximab,Sintilimab and Pirtobrutinib vs. Investigator-Selected Standard of Care in Treatment-Naive PCNSL (PRIME-PCNSL)

In Treatment-Naive Patients With Primary Central Nervous System Lymphoma (PCNSL): A Multicenter, Prospective, Concurrent-Control Study of Methotrexate, , Rituximab,, Sintilimab ,Pirtobrutinib Versus Investigator-Selected Standard of Care

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

Study Overview

• Status: Recruiting
• Conditions: Primary Central Nervous System Lymphoma; PCNSL
• Intervention / Treatment: Drug: Pirtobrutinib, Sintilimab, Rituximab, Methotrexate; Drug: Standard of Care (Investigator Selected)

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 concurrent control cohort providing comparative evidence.

• Study Type: Interventional
• Enrollment (Estimated): 77
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Jia Wei, MD; Phone Number: 027-83663200; Email: jiawei@tjh.tjmu.edu.cn

Study Locations

• China
  • Fujian
    • Xiamen, Fujian, China
      • Recruiting
      • The First Affiliated Hospital of Fujian Medical University
      • Contact: Zhiyong Zeng; Phone Number: 0591-87981022; Email: zengzhiyong049@163.com
  • Hubei
    • Wuhan, Hubei, China, 430000
      • Recruiting
      • Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology
  • Jilin
    • Changchun, Jilin, China, 130033
      • Recruiting
      • China-Japan Union Hospital of Jilin University
      • Contact: Lintao Bi; Phone Number: 0431-84995222; Email: bilt@jlu.edu.cn
  • Shanxi
    • Taiyuan, Shanxi, China, 030012
      • Not yet recruiting
      • Shanxi Provincial People's Hospital
      • Contact: Jianxia He; Phone Number: 0351-4960081; Email: hejianxia125@163.com

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age >= 18 years.
2. Voluntarily signed informed consent.
3. ECOG Performance Status 0-3.
4. Expected survival > 3 months.
5. Histopathologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) restricted to the CNS or eyes (PCNSL).
6. Measurable lesion on contrast-enhanced MRI (>10x10 mm) or positive CSF cytology for leptomeningeal disease.
7. No prior systemic treatment for lymphoma (corticosteroids excepted).
8. Adequate bone marrow and organ function (ANC >=1.5x10^9/L, PLT >=80x10^9/L, Hb >=80 g/L; Bilirubin <=1.5xULN, AST/ALT <=2.5xULN; Creatinine <=1.5xULN or CrCl >=60 mL/min) .
9. Stable controlled comorbidities allowed (e.g., hypertension with blood pressure <=160/100 mmHg, type 2 diabetes with HbA1c <=8%, mild coronary heart disease without myocardial infarction in the past 6 months).
10. Basic communication ability to complete PROs questionnaires (no severe cognitive impairment).
11. Reproductive-aged females and males with childbearing potential: No pregnancy plans during the study and 3 months after treatment discontinuation; use effective contraception (abstinence, physical contraception, or hormonal contraceptives initiated >=3 months before first dose). Males prohibited from donating sperm during treatment and 3 months after discontinuation.
12. For Observational Cohort (Palliative Care Subgroup only): Pathologically confirmed DLBCL restricted to the CNS or eyes; Follow-up available for efficacy assessment (at least one CR evaluation) .

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),

1. myocardial infarction, unstable angina within 6 months before first dose; arrhythmia requiring treatment; LVEF <50%.
2. Primary cardiomyopathy.
3. 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).
4. Atrial fibrillation (EHRA grade ≥2b).
5. Refractory hypertension. 4.Active hepatitis B/C infection (HBV-DNA ≥ detection limit, HCV RNA positive) or syphilis. (Exceptions: HBV-DNA < detection limit, cured HCV).

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).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Interventional Cohort; Patients receive Rituximab, Methotrexate, Sintilimab, and Pirtobrutinib for 6 cycles (21 days/cycle).	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.
Active Comparator: Active Comparator Cohort; 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); 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	At the completion of induction treatment(approximately 18 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Sum of Complete Response (CR) and Partial Response (PR) rates.	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.	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.	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.	Up to 2 years.
Overall Survival (OS)	The time from confirmed diagnosis to death from any cause.	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).	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.	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	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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 .	Through study completion, an average of 1 year.

Collaborators and Investigators

• Sponsor: Tongji Hospital
• Collaborators: First Affiliated Hospital of Fujian Medical University; The General Hospital of Western Theater Command; China-Japan Union Hospital, Jilin University; Shanxi Provincial People's Hospital

Study record dates

Study Major Dates

• Study Start (Actual): December 25, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): June 30, 2029

Study Registration Dates

• First Submitted: December 30, 2025
• First Submitted That Met QC Criteria: January 9, 2026
• First Posted (Actual): January 20, 2026

Study Record Updates

• Last Update Posted (Actual): June 2, 2026
• Last Update Submitted That Met QC Criteria: May 30, 2026
• Last Verified: May 1, 2026

More Information

Terms related to this study

• Keywords: Methotrexate; Rituximab; Sintilimab; Pirtobrutinib; Real-World Evidence; Primary Central Nervous System Lymphoma (PCNSL)
• Additional Relevant MeSH Terms: Health Services Administration; Health Care Quality, Access, and Evaluation; Amino Acids, Peptides, and Proteins; Proteins; Heterocyclic Compounds; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Quality of Health Care; Quality Indicators, Health Care; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Serum Globulins; Globulins; Pterins; Pteridines; Aminopterin; Antibodies, Monoclonal, Murine-Derived; Rituximab; Methotrexate; Standard of Care; pirtobrutinib; sintilimab
• Other Study ID Numbers: TJ-IRB202512084

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No