A Multicenter Two-Cohort Study of Methotrexate, Rituximab, Sintilimab and Pirtobrutinib for Treatment-Naive PCNSL vs. Real-World Investigator-Selected Treatment (Observational Cohort) (PRIME-PCNSL)

Tongji Hospital

Status and phase: Enrolling; Phase 2

Conditions: PCNSL; Primary Central Nervous System Lymphoma

Treatments: Drug: Pirtobrutinib, Sintilimab, Rituximab, Methotrexate; Drug: Standard of Care (Investigator Selected)

Study type: Interventional

Funder types: Other

Identifiers

NCT07350850

TJ-IRB202512084

Details and patient eligibility

About

The goal of this clinical trial is to evaluate a new combination therapy for patients with newly diagnosed Primary Central Nervous System Lymphoma (PCNSL). The main questions it aims to answer are: (1) Does the combination of Methotrexate, Rituximab, Sintilimab, and Pirtobrutinib improve the Complete Remission Rate (CRR)? (2) Is this regimen safe and tolerable for patients? Researchers will compare this interventional group to a real-world observational group (receiving standard investigator-selected treatments) to see if the new combination improves treatment response and survival.

Full 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 real-world cohort providing comparative evidence.

Enrollment: 110 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

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).

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: Single Blind

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110 participants in 2 patient groups

Interventional Cohort

Experimental group

Description:

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

Treatment:

Drug: Pirtobrutinib, Sintilimab, Rituximab, Methotrexate

Real-World Observational Cohort

Active Comparator group

Description:

Participants in this cohort will receive investigator-selected standard-of-care treatments according to routine real-world clinical practice, without protocol-mandated intervention assignment. This includes: (1) Standard Treatment Subgroup: Regimens such as MATRix, RMT, or MR-BTKi. (2) Palliative Care Subgroup: Radiotherapy, low-dose chemotherapy, or supportive care.

Treatment:

Drug: Standard of Care (Investigator Selected)