A Prospective, Open-label, Randomized Controlled Study Comparing Rituximab, Methotrexate, Cytarabine, and Penpulimab (R-MA-PD-1) Versus Rituximab, Methotrexate, and Cytarabine (R-MA) in Treatment-naive Patients With Primary Central Nervous System Lymphoma
This is a prospective, open-label, multicenter, randomized controlled study in treatment-naive patients with primary central nervous system lymphoma (PCNSL, DLBCL type). Eligible participants are randomized 1:1 to the experimental arm (R-MA-PD-1: rituximab, methotrexate, cytarabine plus penpulimab) or the control arm (R-MA: rituximab, methotrexate, cytarabine). Induction is administered every 21 days for 6 cycles, followed by risk- and response-adapted consolidation (ASCT or whole-brain radiotherapy) and penpulimab maintenance. The primary objective is to compare the 2-year progression-free survival rate between the two arms.
Primary central nervous system lymphoma is a rare, aggressive non-Hodgkin lymphoma, predominantly diffuse large B-cell lymphoma. High-dose methotrexate-based chemotherapy is the standard induction, but the optimal combination remains to be defined. Building on a prior single-arm phase II study of penpulimab plus R-MA (NCT05347641), this randomized controlled study evaluates whether adding the PD-1 inhibitor penpulimab to R-MA improves efficacy in treatment-naive PCNSL. Induction (both arms, every 21 days x 6 cycles): * Rituximab 375 mg/m2 (Day 0) * Methotrexate 3.5 g/m2 (Day 1) * Cytarabine (Ara-C): age \<60 or ECOG ≤2: 2 g/m2 q12h Day 2-3; age ≥60 or ECOG \>2: 1 g/m2 q12h Day 2 (from cycle 2) * Experimental arm only: Penpulimab 200 mg (Day 5) Consolidation (response- and age-adapted): patients \<60 years achieving PR/CR proceed to autologous stem cell transplantation (thiotepa + busulfan); patients ≥60 years or ASCT-ineligible receive penpulimab maintenance (CR) or whole-brain radiotherapy 36 Gy plus penpulimab maintenance (PR). Experimental-arm responders receive 8 cycles of penpulimab maintenance. Sample size: 58 participants (29 vs 29), based on 2-year PFS of 39% (R-MA) versus 70% (R-MA-PD-1), two-sided alpha 0.05, power 80%, 18-month enrollment, 30-month follow-up, 10% dropout (PASS 15.0).
Inclusion Criteria: 1. Fully understands the study and voluntarily signs informed consent. 2. Age 18 to 80 years. 3. Treatment-naive, pathologically (immunophenotypically) confirmed PCNSL (per 2016 WHO classification). 4. Diffuse large B-cell lymphoma originating in the CNS without other organ involvement, confirmed by PET-CT or contrast-enhanced CT. 5. Expected survival more than 3 months. 6. Laboratory: creatinine clearance ≥50 mL/min (Cockcroft-Gault); INR ≤1.5 x ULN or aPTT ≤1.5 x ULN (INR 2-3 allowed if on warfarin); LVEF ≥50%. 7. GFR ≥60 mL/min. 8. Participants of childbearing potential must agree to use effective contraception during the study and for 30 days after the last dose.
Exclusion Criteria: 1. Contraindication to any study drug. 2. Clinically significant liver disease, including viral or other hepatitis or cirrhosis (active HBV or active hepatitis C as defined). 3. HIV infection. 4. History of allergic disease, severe drug allergy, or known hypersensitivity to macromolecular protein preparations or any component of penpulimab. 5. Prior anti-PD-1/PD-L1/PD-L2, anti-CTLA-4 antibody, CAR-T, or any other agent targeting T-cell co-stimulation or checkpoint pathways. 6. Congestive heart failure (NYHA \>2); acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months. 7. Congenital long QT syndrome or QTcF \>480 ms. 8. Other malignancy within the past 5 years (except adequately treated in situ cervical carcinoma, basal cell skin carcinoma, in situ breast carcinoma, or a second primary cancer cured and recurrence-free for 5 years). 9. Pregnant or lactating women, or intending to become pregnant during the study. 10. History of clinically significant neurological or psychiatric disorder, or substance/drug abuse. 11. Clinically significant active infection.
[{"measure":"2-year progression-free survival (PFS) rate","timeFrame":"2 years from randomization"}]