BRIDGE-NK: Immunotherapy Versus Chemotherapy Induction Followed by Autologous HSCT in Advanced NKTCL

Официальное название

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

Обзор

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.

Подробное описание

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.

Вмешательства

• Препарат GELAD regimen
  Gemcitabine 1.0 g/m² on day 1, etoposide 60 mg/m² on days 1-3, pegaspargase 2000 IU/m² on day 4, and dexamethasone 40 mg on days 1-4, repeated every 21 days for 1 cycle.
• Препарат MEDA regimen
  Methotrexate 3.0 g/m² on day 1 as a 3-hour intravenous infusion, etoposide 100 mg/m² on days 2-4, dexamethasone 40 mg on days 1-4, and pegaspargase 2500 IU/m² on day 4, repeated every 21 days for 3 cycles.
• Препарат LEAP regimen
  Sintilimab 200 mg intravenously on day 1, pegaspargase 2500 IU/m² on day 1 with a maximum single dose of 3750 IU, and anlotinib 8 mg orally on days 1-14, repeated every 21 days for 4 cycles.
• Препарат High-dose methotrexate
  Participants who achieve strict complete remission after LEAP induction will receive methotrexate 3.0 g/m² as a 3-hour intravenous infusion every 2 weeks for up to 3 doses, with hydration, urine alkalization, leucovorin rescue, and methotrexate concentration monitoring.
• Процедура Autologous Hematopoietic Stem Cell Transplantation
  Participants achieving strict complete remission will undergo autologous hematopoietic stem cell transplantation according to institutional transplant procedures if eligible.

Первичные конечные точки

• Event-Free Survival Within 24 Months [Срок оценки: From randomization to the first protocol-defined EFS event or administrative censoring at 24 months after randomization]

Вторичные конечные точки (11)

• Progression-Free Survival [Срок оценки: From randomization to disease progression, relapse, death, or last disease assessment, assessed up to 66 months]
• Overall Survival [Срок оценки: From randomization to death or last confirmed survival status, assessed up to 66 months]
• Percentage of Participants With at Least One Serious Adverse Event [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: From first dose to permanent discontinuation of assigned protocol treatment, assessed up to 12 months]
• Strict Complete Remission Rate at Key Response Assessment [Срок оценки: At key response assessment after assigned induction treatment, approximately 12-20 weeks after randomization]
• Percentage of Participants With Treatment-Related Mortality [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: 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 [Срок оценки: From randomization to completion of autologous HSCT, assessed up to 12 months]
• Cumulative Incidence of Relapse Among Participants Who Achieve Strict Complete Remission [Срок оценки: 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.]

Критерии участия

Критерии включения

• 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 3.
• 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.

Критерии исключения

• 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.

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Рандомизированное

Модель

Параллельные группы

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Fudan University Shanghai Cancer Center, — Шанхай

Публикации

• Alaggio R, Amador C, Anagnostopoulos I, Attygalle AD, Araujo IBO, Berti E, Bhagat G, Borges AM, Boyer D, Calaminici M, Chadburn A, Chan JKC, Cheuk W, Chng WJ, Choi JK, Chuang SS, Coupland SE, Czader M, Dave SS, de Jong D, Du MQ, Elenitoba-Johnson KS, Ferry J, Geyer J, Gratzinger D, Guitart J, Gujral S, Harris M, Harrison CJ, Hartmann S, Hochhaus A, Jansen PM, Karube K, Kempf W, Khoury J, Kimura H, PMID 35732829
• Cheson BD, Fisher RI, Barrington SF, Cavalli F, Schwartz LH, Zucca E, Lister TA; Alliance, Australasian Leukaemia and Lymphoma Group; Eastern Cooperative Oncology Group; European Mantle Cell Lymphoma Consortium; Italian Lymphoma Foundation; European Organisation for Research; Treatment of Cancer/Dutch Hemato-Oncology Group; Grupo Espanol de Medula Osea; German High-Grade Lymphoma Study Group; Germ PMID 25113753
• Li D, Liu C, Wan J, Zhang W, Ma Y, Zhu Y, Ma L, Tian S, Ding H, Tao R. Sintilimab, pegaspargase, and anlotinib as induction therapy for advanced-stage NKTCL: a multicenter phase II study. Blood Adv. 2026 Mar 3:bloodadvances.2025018720. doi: 10.1182/bloodadvances.2025018720. Online ahead of print. PMID 41774854
• Zhu Y, Tian S, Xu L, Ma Y, Zhang W, Wang L, Jin L, Liu C, Zhu C, Li Z, Hao S, Zhong H, Ding H, Tao R. GELAD chemotherapy with sandwiched radiotherapy for patients with newly diagnosed stage IE/IIE natural killer/T-cell lymphoma: a prospective multicentre study. Br J Haematol. 2022 Feb;196(4):939-946. doi: 10.1111/bjh.17960. Epub 2021 Nov 21. PMID 34806163
• Liu C, Ding H, Zhu Q, Liu P, Zhu Y, Wang L, Ma Y, Zhang W, Tian S, Zhang X, Jin L, Liu L, Li Z, Hao S, Tao R. Induction with MEDA regimen and consolidation with Auto-HSCT for stage IV NKTCL patients: A prospective multicenter study. Int J Cancer. 2022 Sep 1;151(5):752-763. doi: 10.1002/ijc.34055. Epub 2022 Jun 9. PMID 35489026

Идентификаторы

NCT: NCT07678229 · SHCA-NKT-Bridge26

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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