Testing a four-drug regimen (methotrexate, rituximab, sintilimab, pirtobrutinib) versus investigator-selected care for newly diagnosed PCNSL

In Treatment-Naive Patients With Primary Central Nervous System Lymphoma (PCNSL): A Multicenter Two-Cohort Study of Methotrexate Combined With Rituximab, Sintilimab and Pirtobrutinib (Prospective Interventional Cohort) vs. Real-World Investigator-Selected Treatment (Observational Cohort)

This trial will try a combination of methotrexate, rituximab, sintilimab and pirtobrutinib as first treatment for adults with newly diagnosed primary central nervous system lymphoma to see if it increases complete remissions and is safe compared with standard doctor-selected treatments.

Quick facts

• Phase: Phase 2
• Study type: Interventional
• Enrollment: 110 (estimated)
• Ages: 18 Years and up
• Sex: All
• Sponsor: Tongji Hospital (Academic / other)
• Drugs / interventions: radiation, Rituximab, Sintilimab, Pirtobrutinib, Methotrexate
• Locations: 3 sites (Xiamen, Fujian and 2 other locations)
• Trial ID: NCT07350850 on ClinicalTrials.gov

What this trial studies

This is a multicenter Phase 2 program that enrolls treatment‑naive adults with primary central nervous system lymphoma into an interventional cohort receiving high‑dose methotrexate plus rituximab, the anti‑PD‑1 antibody sintilimab, and the reversible BTK inhibitor pirtobrutinib, alongside a real‑world observational cohort receiving investigator‑selected standard treatments. The study will measure complete remission rate as a primary outcome and will track safety, tolerability, and survival outcomes over follow‑up. The combination aims to pair the cytotoxic backbone of methotrexate and rituximab with improved CNS‑penetrant BTK inhibition and PD‑1 blockade to target common molecular drivers in PCNSL. Sites are enrolled across several major hospitals in China to capture real‑world comparator data alongside the experimental regimen.

Who should consider this trial

Good fit: Adults (≥18 years) with histologically confirmed treatment‑naive PCNSL (measurable CNS lesion or positive CSF cytology), ECOG 0–3, expected survival >3 months, and adequate organ and marrow function are ideal candidates.

Not a fit: Patients who have received prior systemic lymphoma therapy, have poor organ function, uncontrolled comorbidities, pregnancy, or severe cognitive impairment preventing consent or PRO completion are unlikely to benefit from this protocol.

Why it matters

Potential benefit: If successful, the regimen could raise complete remission rates and extend survival by combining better CNS drug penetration with immune‑directed therapy while maintaining manageable toxicity.

How similar studies have performed: BTK inhibitors and PD‑1 blockade have shown activity in CNS lymphoma in earlier or relapsed settings, but frontline combination of pirtobrutinib plus anti‑PD‑1 with methotrexate/rituximab is a novel approach without definitive prior Phase 3 confirmation.

Eligibility criteria

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).

Where this trial is running

Xiamen, Fujian and 2 other locations

• 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, China (Recruiting)
• Shanxi Provincial People's Hospital — Taiyuan, Shanxi, China (Not_yet_recruiting)

Study contacts

• Study coordinator: Jia Wei, MD

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