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

NCT07350850 | Recruiting Phase 2

• 1 other identifier: TJ-IRB202512084
• Study Type: interventional
• Target: 77
• Locations: 1 country
• Sites: 4

Brief Summary

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

Conditions

PCNSL; Primary Central Nervous System Lymphoma

Keywords

Primary Central Nervous System Lymphoma (PCNSL); Methotrexate; Rituximab; Sintilimab; Pirtobrutinib; Real-World Evidence

Outcome Measures

Primary Outcomes (1)

• 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 Outcomes (8)

• Overall Response Rate (ORR)

  At the completion of induction treatment (approximately 18 weeks)

• Duration of Response (DOR)

  Up to 2 years.

• Disease Control Rate (DCR)

  At the completion of induction treatment (approximately 18 weeks)

• Progression-Free Survival (PFS)

  Up to 2 years.

• Overall Survival (OS)

  Up to 5 years as per long-term follow-up mentions

Other Outcomes (1)

• Correlation between Molecular Subtypes and Treatment Response (CRR)

  Through study completion, an average of 1 year.

Study Arms (2)

Interventional Cohort

EXPERIMENTAL

Patients receive Rituximab, Methotrexate, Sintilimab, and Pirtobrutinib for 6 cycles (21 days/cycle).

Drug: Pirtobrutinib, Sintilimab, Rituximab, Methotrexate

Active Comparator Cohort

ACTIVE COMPARATOR

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)

Interventions

Pirtobrutinib, Sintilimab, Rituximab, Methotrexate DRUG

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.

Interventional Cohort

Standard of Care (Investigator Selected) DRUG

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.

Active Comparator Cohort

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age \>= 18 years.
• Voluntarily signed informed consent.
• ECOG Performance Status 0-3.
• Expected survival \> 3 months.
• Histopathologically confirmed Diffuse Large B-Cell Lymphoma (DLBCL) restricted to the CNS or eyes (PCNSL).
• Measurable lesion on contrast-enhanced MRI (\>10x10 mm) or positive CSF cytology for leptomeningeal disease.
• No prior systemic treatment for lymphoma (corticosteroids excepted).
• 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) .
• 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).
• Basic communication ability to complete PROs questionnaires (no severe cognitive impairment).
• 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.
• 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) .

You may not qualify if:

• 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),
• 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).
• Refractory hypertension. 4.Active hepatitis B/C infection (HBV-DNA ≥ detection limit, HCV RNA positive) or syphilis. (Exceptions: HBV-DNA \< detection limit, cured HCV).
• 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).
• 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).

Sponsors & Collaborators

• Tongji Hospital: lead
• 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

Study Sites (4)

The First Affiliated Hospital of Fujian Medical University

Xiamen, Fujian, China

RECRUITING

Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology

Wuhan, Hubei, 430000, China

RECRUITING

China-Japan Union Hospital of Jilin University

Changchun, Jilin, 130033, China

RECRUITING

Shanxi Provincial People's Hospital

Taiyuan, Shanxi, 030012, China

NOT YET RECRUITING

MeSH Terms

Interventions

pirtobrutinib; sintilimab; Rituximab; Methotrexate; Standard of Care

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds; Quality Indicators, Health Care; Quality of Health Care; Health Services Administration; Health Care Quality, Access, and Evaluation

Central Study Contacts

Jia Wei, MD

CONTACT

027-83663200; jiawei@tjh.tjmu.edu.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NON RANDOMIZED
• Masking: SINGLE
• Who Masked: OUTCOMES ASSESSOR
• Masking Details: While the participants and clinical investigators are aware of the treatment assignment (Open Label), Independent radiologists (from the central imaging group) will be completely blinded to patient grouping, clinical judgment, and laboratory results when evaluating the primary endpoint (Complete Remission).
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: chief physician

Model Details: Cohort 1 (Prospective Interventional): A single-arm cohort utilizing Simon's two-stage minimax design to evaluate the efficacy and safety of the Methotrexate, Rituximab, Sintilimab and Pirtobrutinib combination. Cohort 2 (Active Comparator）Intervention: Investigator-selected HD-MTX-based standard therapy:MATRix: Rituximab + HD-MTX + Ara-C + Thiotepa；RMT: Rituximab + HD-MTX + Temozolomide；MR-BTKi: Rituximab + HD-MTX + Ibrutinib/Zanubrutinib/Orelabrutinib.Cycle length: 21 days, up to 6 cycles.

Study Record Dates

• First Submitted: December 30, 2025
• First Posted: January 20, 2026
• Study Start: December 25, 2025
• Primary Completion (Estimated): December 31, 2028
• Study Completion (Estimated): June 30, 2029
• Last Updated: June 2, 2026

Record last verified: 2026-05

Data Sharing

• IPD Sharing: Will not share

Locations

CN (4)