R-MA-PD-1 Versus R-MA in Treatment-naive Primary CNS Lymphoma

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).

• Penpulimab (Biological): Anti-PD-1 monoclonal antibody, 200 mg intravenously on Day 5 of each induction cycle; continued as maintenance in responders.
• Rituximab (Drug): 375 mg/m2 intravenously on Day 0 of each induction cycle.
• Methotrexate (Drug): 3.5 g/m2 intravenously on Day 1 of each induction cycle.
• Cytarabine (Drug): Age <60 or ECOG ≤2: 2 g/m2 q12h on Days 2-3; age ≥60 or ECOG >2: 1 g/m2 q12h on Day 2 (from cycle 2).

Primary outcomes

• 2-year progression-free survival (PFS) rate [2 years from randomization]: PFS is defined as the time from randomization to first documented disease progression or relapse (per 2014 Lugano response criteria) or death from any cause, whichever occurs first, as determined by the investigator.

Secondary outcomes

• Complete response (CR) rate [From randomization through end of induction (6 cycles of 21 days each; up to 18 weeks)]: Proportion of patients with best overall response of CR by PET-CT during induction, per 2014 Lugano criteria.
• Objective response rate (ORR) [From randomization through end of induction (6 cycles of 21 days each; up to 18 weeks)]: Proportion of patients with best overall response of PR or CR during induction, per 2014 Lugano criteria.
• Overall survival (OS) [Up to 3 years from randomization]: Time from randomization to death from any cause.
• Duration of response (DOR) [Up to 3 years from randomization]: Time from first documented response to disease progression or death from any cause.
• Incidence of adverse events [From first dose until 30 days after last dose (induction 18 weeks + consolidation [ASCT/WBRT] + penpulimab maintenance 24 weeks)]: Incidence and severity of adverse events graded per CTCAE.

Sex: All, ages: 18 Years to 80 Years

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.