BRIDGE-NK: A Randomized, Open-Label, Prospective Phase III Study of Immunotherapy Induction Versus Chemotherapy Induction Followed by Autologous Hematopoietic Stem Cell Transplantation Consolidation in Newly Diagnosed Advanced Extranodal NK/T-Cell Lymphoma
试验速览
- 阶段
- 3 期
- 状态
- 招募中
- 发起方
- 入组人数
- 150
- 试验地点
- 1
- 主要终点
- Event-Free Survival Within 24 Months
研究概览
简要总结
This is a randomized, open-label, prospective, multicenter phase III superiority study in patients with newly diagnosed stage IV extranodal NK/T-cell lymphoma. The study compares two frontline induction strategies followed by consolidation with autologous hematopoietic stem cell transplantation in patients who achieve a protocol-defined strict complete remission.
Eligible participants will be randomized 1:1 to Arm A or Arm B, stratified by three-level PINK-E risk category. Arm A consists of one cycle of GELAD induction followed by three cycles of MEDA chemotherapy. Participants who achieve strict complete remission after key response assessment will proceed to autologous hematopoietic stem cell transplantation consolidation. Arm B consists of four cycles of LEAP induction with sintilimab, pegaspargase, and anlotinib. Participants who achieve strict complete remission will receive high-dose methotrexate CNS-directed consolidation followed by autologous hematopoietic stem cell transplantation consolidation if eligible.
The primary endpoint is event-free survival within 24 months after randomization. Secondary endpoints include progression-free survival, overall survival, overall response rate, complete remission rate, strict complete remission rate, autologous hematopoietic stem cell transplantation completion rate, cumulative incidence of relapse, grade 3 or higher adverse events, treatment discontinuation, treatment-related mortality, and plasma EBV-DNA clearance dynamics.
详细描述
Extranodal NK/T-cell lymphoma is an aggressive Epstein-Barr virus-associated lymphoma with poor outcomes in advanced-stage disease. High-dose methotrexate-containing asparaginase-based chemotherapy can induce responses but is limited by early toxicity, organ dysfunction, infection risk, and incomplete treatment delivery in patients with high tumor burden. PD-1 antibody-based immunotherapy combinations have shown promising activity and tolerability in advanced-stage disease, but randomized evidence comparing immunotherapy induction with chemotherapy induction in a frontline curative-intent strategy remains lacking.
This study is designed to evaluate whether immunotherapy induction followed by CNS-directed high-dose methotrexate consolidation and autologous hematopoietic stem cell transplantation can improve event-free survival compared with a conventional chemotherapy induction strategy followed by autologous hematopoietic stem cell transplantation. The comparison focuses on the entire treatment strategy, including induction depth, feasibility of subsequent consolidation, and early strategy failure, rather than isolated response to a single regimen.
Strict complete remission is defined as all of the following: complete metabolic remission on PET/CT according to Lugano 2014 criteria, negative plasma EBV-DNA, and negative EBER staining on repeat bone marrow biopsy for participants with baseline bone marrow involvement.
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 70 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Age 18 to 70 years at the time of signing informed consent.
- •Histologically confirmed extranodal NK/T-cell lymphoma according to the current classification criteria, with tumor tissue confirmed to be EBER positive. Central pathology review is recommended.
- •Stage IV disease according to Lugano 2014 staging criteria, with baseline staging including PET/CT and bone marrow evaluation.
- •Previously untreated disease, with no prior systemic anti-lymphoma therapy, radiotherapy, or other anti-tumor treatment for NKTCL.
- •At least one evaluable lesion assessable by PET/CT and/or contrast-enhanced CT/MRI.
- •Eastern Cooperative Oncology Group performance status score of 0 to
- •Adequate hematologic function during screening, defined as absolute neutrophil count ≥1.0 × 10^9/L, hemoglobin >80 g/L, and platelet count >50 × 10^9/L.
- •Adequate hepatic and renal function during screening, defined as alanine aminotransferase and aspartate aminotransferase ≤2 × upper limit of normal, total bilirubin ≤2 × upper limit of normal, and creatinine clearance ≥60 mL/min.
- •No severe uncontrolled coagulation disorder, and judged by the investigator to be able to receive pegaspargase-containing therapy.
- •Judged by the investigator to have no absolute contraindication to key components of the assigned treatment strategy, including irreversible contraindication to high-dose methotrexate, severe organ dysfunction precluding transplant evaluation, or other conditions clearly preventing completion of the protocol-defined strategy.
- •Written informed consent provided by the participant or legally authorized representative.
排除标准
- •Prior systemic anti-lymphoma therapy, radiotherapy, or investigational anti-tumor therapy.
- •Active central nervous system lymphoma involvement, including active brain parenchymal, meningeal, cerebrospinal fluid, or intraocular involvement.
- •Active infection requiring intensive care support, or infection judged by the investigator to be uncontrolled and likely to significantly interfere with protocol treatment.
- •Known history of acute or chronic pancreatitis, or any condition judged by the investigator to be an absolute contraindication to pegaspargase.
- •Fulminant disseminated intravascular coagulation, or severe coagulation disorder judged by the investigator to be uncorrectable in the short term and to substantially increase treatment risk.
- •Severe cardiac, pulmonary, hepatic, renal, or other major organ dysfunction that, in the investigator's judgment, would significantly interfere with protocol treatment.
- •Irreversible contraindication to high-dose methotrexate, including but not limited to marked renal failure, inability to receive standardized hydration, alkalization, leucovorin rescue, or methotrexate clearance monitoring, or any condition judged by the investigator to prevent safe administration of methotrexate within the protocol-defined strategy.
- •Active hepatitis C virus infection, human immunodeficiency virus infection, or active uncontrolled hepatitis B virus replication.
- •Uncontrolled severe hypertension, active bleeding, recent major thromboembolic event, or vascular high-risk condition judged by the investigator to preclude safe administration of anlotinib.
- •Pregnant or breastfeeding women, or participants of reproductive potential unwilling to use effective contraception during the study.
- •Any other medical, psychological, social, or compliance-related condition that, in the investigator's judgment, makes the participant unsuitable for this study.
研究组 & 干预措施
Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation
Participants randomized to Arm A will receive one 21-day cycle of GELAD induction followed by three 21-day cycles of MEDA chemotherapy. After completion of GELAD ×1 plus MEDA ×3, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will proceed to autologous hematopoietic stem cell transplantation consolidation if eligible. Participants who do not achieve strict complete remission and require non-protocol anti-tumor therapy will be managed according to the protocol-defined event rules.
干预措施: MEDA regimen (Drug)
Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation
Participants randomized to Arm B will receive four 21-day cycles of LEAP induction with sintilimab, pegaspargase, and anlotinib. After completion of LEAP ×4, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will receive high-dose methotrexate CNS-directed consolidation for up to 3 doses, followed by autologous hematopoietic stem cell transplantation consolidation if eligible.
干预措施: Autologous Hematopoietic Stem Cell Transplantation (Procedure)
Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation
Participants randomized to Arm B will receive four 21-day cycles of LEAP induction with sintilimab, pegaspargase, and anlotinib. After completion of LEAP ×4, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will receive high-dose methotrexate CNS-directed consolidation for up to 3 doses, followed by autologous hematopoietic stem cell transplantation consolidation if eligible.
干预措施: High-dose methotrexate (Drug)
Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation
Participants randomized to Arm A will receive one 21-day cycle of GELAD induction followed by three 21-day cycles of MEDA chemotherapy. After completion of GELAD ×1 plus MEDA ×3, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will proceed to autologous hematopoietic stem cell transplantation consolidation if eligible. Participants who do not achieve strict complete remission and require non-protocol anti-tumor therapy will be managed according to the protocol-defined event rules.
干预措施: GELAD regimen (Drug)
Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation
Participants randomized to Arm A will receive one 21-day cycle of GELAD induction followed by three 21-day cycles of MEDA chemotherapy. After completion of GELAD ×1 plus MEDA ×3, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will proceed to autologous hematopoietic stem cell transplantation consolidation if eligible. Participants who do not achieve strict complete remission and require non-protocol anti-tumor therapy will be managed according to the protocol-defined event rules.
干预措施: Autologous Hematopoietic Stem Cell Transplantation (Procedure)
Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation
Participants randomized to Arm B will receive four 21-day cycles of LEAP induction with sintilimab, pegaspargase, and anlotinib. After completion of LEAP ×4, participants will undergo key response assessment with PET/CT, plasma EBV-DNA testing, and repeat bone marrow biopsy with EBER staining if bone marrow was involved at baseline. Participants who achieve strict complete remission will receive high-dose methotrexate CNS-directed consolidation for up to 3 doses, followed by autologous hematopoietic stem cell transplantation consolidation if eligible.
干预措施: LEAP regimen (Drug)
结局指标
主要结局
Event-Free Survival Within 24 Months
时间窗: From randomization to the first protocol-defined EFS event or administrative censoring at 24 months after randomization
Event-free survival is defined as the time from the date of randomization to the first occurrence of any of the following events: disease progression; death from any cause; inability to complete the assigned protocol-defined treatment strategy due to severe adverse events, persistent organ toxicity, treatment-related complications, or other unacceptable toxicity; or failure to achieve strict complete remission at the key response assessment followed by initiation of non-protocol anti-tumor therapy. Participants without an EFS event at 24 months after randomization will be administratively censored at 24 months.
次要结局
- Progression-Free Survival(From randomization to disease progression, relapse, death, or last disease assessment, assessed up to 66 months)
- Overall Survival(From randomization to death or last confirmed survival status, assessed up to 66 months)
- Percentage of Participants With at Least One Serious Adverse Event(From the first dose of protocol treatment through 30 days after the last protocol treatment, and through Day +90 after autologous HSCT for transplanted participants, assessed up to 12 months.)
- Percentage of Participants With at Least One Grade 3 or Higher Adverse Event(From first dose of protocol treatment through 30 days after the last protocol treatment, and through Day +90 after autologous HSCT for transplanted participants, assessed up to 12 months)
- Percentage of Participants Who Permanently Discontinue a Key Component of the Assigned Treatment Strategy Due to Adverse Events(From first dose to permanent discontinuation of assigned protocol treatment, assessed up to 12 months)
- Strict Complete Remission Rate at Key Response Assessment(At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization)
- Percentage of Participants With Treatment-Related Mortality(From first dose through 30 days after the last protocol treatment, and through Day +90 after autologous HSCT for transplanted participants, assessed up to 12 months)
- Percentage of Baseline Plasma EBV-DNA-Positive Participants With Plasma EBV-DNA Clearance at the Key Response Assessment(At the key response assessment after completion of assigned induction treatment, approximately 12 to 20 weeks after randomization.)
- Overall Response Rate at Key Response Assessment(At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization)
- Percentage of Randomized Participants Who Complete Autologous Hematopoietic Stem Cell Transplantation(From randomization to completion of autologous HSCT, assessed up to 12 months)
- Cumulative Incidence of Relapse Among Participants Who Achieve Strict Complete Remission(From the date of first documented strict complete remission to relapse, death, or the last valid disease assessment, assessed up to 66 months after randomization.)
研究者
Rong Tao
Department head, professor
Fudan University