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

NCT07678229 | Not Yet Recruiting Phase 3 DMC

• 1 other identifier: SHCA-NKT-Bridge26
• Study Type: interventional
• Target: 150
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Extranodal NK/T-cell Lymphoma

Keywords

Extranodal NK/T-cell lymphoma; Epstein-Barr virus; Sintilimab; Pegaspargase; Anlotinib; Methotrexate; Autologous hematopoietic stem cell transplantation

Outcome Measures

Primary Outcomes (1)

• Event-Free Survival Within 24 Months

  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.

  From randomization to the first protocol-defined EFS event or administrative censoring at 24 months after randomization

Secondary Outcomes (11)

• 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

Study Arms (2)

Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation

ACTIVE COMPARATOR

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.

Drug: GELAD regimen; Drug: MEDA regimen; Procedure: Autologous Hematopoietic Stem Cell Transplantation

Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation

EXPERIMENTAL

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.

Drug: LEAP regimen; Drug: High-dose methotrexate; Procedure: Autologous Hematopoietic Stem Cell Transplantation

Interventions

GELAD regimen DRUG

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.

Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation

MEDA regimen DRUG

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.

Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation

LEAP regimen DRUG

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.

Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation

High-dose methotrexate DRUG

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.

Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation

Autologous Hematopoietic Stem Cell Transplantation PROCEDURE

Participants achieving strict complete remission will undergo autologous hematopoietic stem cell transplantation according to institutional transplant procedures if eligible.

Arm A: Chemotherapy Induction Followed by Autologous HSCT Consolidation; Arm B: Immunotherapy Induction Followed by HD-MTX and Autologous HSCT Consolidation

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Rong Tao: lead

Study Sites (1)

Fudan University Shanghai Cancer Center,

Shanghai, Shanghai Municipality, 200433, China

Location

Related Publications (5)

• 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, Klapper W, Kovach AE, Kumar S, Lazar AJ, Lazzi S, Leoncini L, Leung N, Leventaki V, Li XQ, Lim MS, Liu WP, Louissaint A Jr, Marcogliese A, Medeiros LJ, Michal M, Miranda RN, Mitteldorf C, Montes-Moreno S, Morice W, Nardi V, Naresh KN, Natkunam Y, Ng SB, Oschlies I, Ott G, Parrens M, Pulitzer M, Rajkumar SV, Rawstron AC, Rech K, Rosenwald A, Said J, Sarkozy C, Sayed S, Saygin C, Schuh A, Sewell W, Siebert R, Sohani AR, Tooze R, Traverse-Glehen A, Vega F, Vergier B, Wechalekar AD, Wood B, Xerri L, Xiao W. The 5th edition of the World Health Organization Classification of Haematolymphoid Tumours: Lymphoid Neoplasms. Leukemia. 2022 Jul;36(7):1720-1748. doi: 10.1038/s41375-022-01620-2. Epub 2022 Jun 22.

  PMID: 35732829 RESULT

• 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; German Hodgkin's Study Group; Japanese Lymphorra Study Group; Lymphoma Study Association; NCIC Clinical Trials Group; Nordic Lymphoma Study Group; Southwest Oncology Group; United Kingdom National Cancer Research Institute. Recommendations for initial evaluation, staging, and response assessment of Hodgkin and non-Hodgkin lymphoma: the Lugano classification. J Clin Oncol. 2014 Sep 20;32(27):3059-68. doi: 10.1200/JCO.2013.54.8800.

  PMID: 25113753 RESULT

• 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 RESULT

• 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 RESULT

• 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 RESULT

MeSH Terms

Conditions

Lymphoma, Extranodal NK-T-Cell; Epstein-Barr Virus Infections

Interventions

Methotrexate

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms; Herpesviridae Infections; DNA Virus Infections; Virus Diseases; Infections; Tumor Virus Infections

Intervention Hierarchy (Ancestors)

Aminopterin; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Study Officials

• Rong Tao, MD & PhD

  Shanghai Cancer Center

  STUDY CHAIR

• Chuanxu Liu, MD & PhD

  Shanghai Cancer Center

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rong Tao, MD & PhD

CONTACT

008621-64175590; hkutao@hotmail.com

Chuanxu Liu, MD & PhD

CONTACT

008621-64175590; liuchaunxu@shca.or.cn

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Department head, professor

Study Record Dates

• First Submitted: June 16, 2026
• First Posted: July 1, 2026
• Study Start: July 1, 2026
• Primary Completion (Estimated): December 31, 2031
• Study Completion (Estimated): December 31, 2031
• Last Updated: July 21, 2026

Record last verified: 2026-07

Locations

CN (1)