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
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 发起方
- 入组人数
- 58
- 试验地点
- 5
- 主要终点
- 2-year progression-free survival (PFS) rate
研究概览
简要总结
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.
详细描述
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).
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Fully understands the study and voluntarily signs informed consent.
- •Age 18 to 80 years.
- •Treatment-naive, pathologically (immunophenotypically) confirmed PCNSL (per 2016 WHO classification).
- •Diffuse large B-cell lymphoma originating in the CNS without other organ involvement, confirmed by PET-CT or contrast-enhanced CT.
- •Expected survival more than 3 months.
- •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%.
- •GFR ≥60 mL/min.
- •Participants of childbearing potential must agree to use effective contraception during the study and for 30 days after the last dose.
排除标准
- •Contraindication to any study drug.
- •Clinically significant liver disease, including viral or other hepatitis or cirrhosis (active HBV or active hepatitis C as defined).
- •HIV infection.
- •History of allergic disease, severe drug allergy, or known hypersensitivity to macromolecular protein preparations or any component of penpulimab.
- •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.
- •Congestive heart failure (NYHA >2); acute myocardial infarction, unstable angina, stroke, or transient ischemic attack within 6 months.
- •Congenital long QT syndrome or QTcF >480 ms.
- •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).
- •Pregnant or lactating women, or intending to become pregnant during the study.
- •History of clinically significant neurological or psychiatric disorder, or substance/drug abuse.
- •Clinically significant active infection.
研究组 & 干预措施
R-MA-PD-1 (Experimental)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), cytarabine (D2-3 or D2 by age/ECOG), plus penpulimab 200 mg (D5), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation and penpulimab maintenance.
干预措施: Penpulimab (Biological)
R-MA (Active Comparator)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), and cytarabine (D2-3 or D2 by age/ECOG), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation (ASCT or WBRT).
干预措施: Methotrexate (Drug)
R-MA (Active Comparator)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), and cytarabine (D2-3 or D2 by age/ECOG), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation (ASCT or WBRT).
干预措施: Rituximab (Drug)
R-MA-PD-1 (Experimental)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), cytarabine (D2-3 or D2 by age/ECOG), plus penpulimab 200 mg (D5), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation and penpulimab maintenance.
干预措施: Methotrexate (Drug)
R-MA (Active Comparator)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), and cytarabine (D2-3 or D2 by age/ECOG), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation (ASCT or WBRT).
干预措施: Cytarabine (Drug)
R-MA-PD-1 (Experimental)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), cytarabine (D2-3 or D2 by age/ECOG), plus penpulimab 200 mg (D5), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation and penpulimab maintenance.
干预措施: Cytarabine (Drug)
R-MA-PD-1 (Experimental)
Rituximab 375 mg/m2 (D0), methotrexate 3.5 g/m2 (D1), cytarabine (D2-3 or D2 by age/ECOG), plus penpulimab 200 mg (D5), every 21 days for 6 induction cycles, followed by response- and age-adapted consolidation and penpulimab maintenance.
干预措施: Rituximab (Drug)
结局指标
主要结局
2-year progression-free survival (PFS) rate
时间窗: 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.
次要结局
- Complete response (CR) rate(From randomization through end of induction (6 cycles of 21 days each; up to 18 weeks))
- Objective response rate (ORR)(From randomization through end of induction (6 cycles of 21 days each; up to 18 weeks))
- Overall survival (OS)(Up to 3 years from randomization)
- Duration of response (DOR)(Up to 3 years from randomization)
- Incidence of adverse events(From first dose until 30 days after last dose (induction 18 weeks + consolidation [ASCT/WBRT] + penpulimab maintenance 24 weeks))
研究者
WEI XU
Chief Physician, Department of Hematology
The First Affiliated Hospital with Nanjing Medical University