PCNSL, Primary Central Nervous System Lymphoma
Conditions
Keywords
Primary Central Nervous System Lymphoma (PCNSL), Methotrexate, Rituximab, Sintilimab, Pirtobrutinib, Real-World Evidence
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
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.
Interventions
DRUGPirtobrutinib, 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.
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.
Sponsors
Tongji Hospital
Shanxi Provincial People's Hospital
First Affiliated Hospital of Fujian Medical University
The General Hospital of Western Theater Command
China-Japan Union Hospital, Jilin University
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
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).
Intervention model description
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.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response Rate (CRR) | At the completion of induction treatment(approximately 18 weeks) | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) | At the completion of induction treatment (approximately 18 weeks) | Sum of Complete Response (CR) and Partial Response (PR) rates. |
| Duration of Response (DOR) | Up to 2 years. | Time from documentation of tumor response (CR or PR) to disease progression or death. |
| Disease Control Rate (DCR) | At the completion of induction treatment (approximately 18 weeks) | 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) | Up to 2 years. | The time interval from the start of treatment to tumor progression (PD) or death from any cause. |
| Overall Survival (OS) | Up to 5 years as per long-term follow-up mentions | The time from confirmed diagnosis to death from any cause. |
| Overall Survival Rate (OS Rate) | 1 year. | The percentage of surviving patients out of the total number of included patients (specifically assessed as 1-year OS rate in study objectives). |
| Safety and Tolerability (Adverse Events) | Throughout the study process, up to 30 days after the last dose. | 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. |
| Patient Reported Outcomes (PRO) | 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 | 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 |
Countries
China
Contacts
CONTACTJia Wei, MD
Outcome results
None listed