GELAD-Based Response-Adapted Treatment for Early-Stage Extranodal NK/T-Cell Lymphoma

NCT07768943 | Not Yet Recruiting Phase 2 DMC

• 1 other identifier: SHCA-NKTCL-RA26
• Study Type: interventional
• Target: 620
• Locations: 1 country
• Sites: 1

Brief Summary

This prospective, multicenter study evaluates a response-adapted treatment strategy for previously untreated patients with early-stage extranodal NK/T-cell lymphoma of the upper aerodigestive tract. All participants receive two cycles of GELAD induction chemotherapy, followed by early response assessment using positron emission tomography/computed tomography (PET/CT) and plasma Epstein-Barr virus (EBV) DNA. Subsequent treatment is determined by the early response. Participants with complete metabolic response and negative EBV DNA enter PART A and are randomized 1:1 to standard-dose radiotherapy (50 Gy) or reduced-dose radiotherapy (40 Gy); both groups subsequently receive two additional cycles of GELAD. Participants with partial response and negative EBV DNA enter PART B and receive standard 50 Gy radiotherapy followed by two additional cycles of GELAD. Participants with stable disease, local or regional progressive disease that remains amenable to curative radiotherapy, or partial response with positive EBV DNA enter PART C and receive 50 Gy radiotherapy followed by response-adapted sintilimab consolidation. The primary objective of PART A is to determine whether reduced-dose radiotherapy is noninferior to standard-dose radiotherapy with respect to the 24-month progression-free survival rate. The primary objective of PART C is to evaluate the 24-month progression-free survival rate with response-adapted sintilimab consolidation in patients with a high-risk early response.

Conditions

Natural Killer/T-cell Lymphoma

Keywords

Extranodal NK/T-cell lymphoma; Early-stage NK/T-cell lymphoma; GELAD; Response-adapted therapy; Radiotherapy de-escalation; Sintilimab; PD-1 blockade; PET/CT; Epstein-Barr virus DNA

Outcome Measures

Primary Outcomes (2)

• 24-Month Progression-Free Survival Rate in PART A

  Progression-free survival (PFS) is measured from the date of PART A randomization to the first documented disease progression, relapse, or death from any cause, whichever occurs first. Participants without a PFS event are censored at the date of the last adequate disease assessment. The 24-month PFS rate will be estimated using the Kaplan-Meier method. The primary treatment effect is the absolute difference in PFS24 between A1 (40 Gy) and A0 (50 Gy), calculated as A1 minus A0. Noninferiority is concluded if the lower bound of the two-sided 95% confidence interval for this difference is greater than -10 percentage points.

  From PART A randomization through 24 months

• 24-Month Progression-Free Survival Rate in PART C

  Progression-free survival (PFS) is measured from the date of PART C module registration, which occurs before radiotherapy, to the first documented disease progression, relapse, or death from any cause, whichever occurs first. Participants without a PFS event are censored at the date of the last adequate disease assessment. The 24-month PFS rate will be estimated using the Kaplan-Meier method and evaluated against the prespecified null benchmark of 55%.

  From PART C module registration through 24 months

Secondary Outcomes (7)

• Percentage of Participants With Complete Response at the End of Treatment

  At the protocol-defined end-of-treatment assessment, approximately 6 weeks plus or minus 2 weeks after the final protocol treatment

• Percentage of Participants With an Overall Response at the End of Treatment

  At the protocol-defined end-of-treatment assessment, approximately 6 weeks plus or minus 2 weeks after the final protocol treatment

• Overall Survival

  From the first GELAD dose through 60 months

• Locoregional Control Rate at 12, 24, and 36 Months

  At 12, 24, and 36 months after module assignment

• Percentage of Baseline EBV DNA-Positive Participants Achieving Confirmed Plasma EBV DNA Clearance

  From the first GELAD dose through 24 months

Study Arms (4)

PART A A0: Standard-Dose Radiotherapy

ACTIVE COMPARATOR

Participants who achieve complete metabolic response on PET/CT and negative plasma EBV DNA after two cycles of GELAD are randomized to standard-dose intensity-modulated radiotherapy (IMRT), 50 Gy in 25 fractions, followed by two additional 21-day cycles of GELAD.

Drug: Gemcitabine (GEM); Drug: Etoposide Injection; Drug: Dexamethasone; Drug: pegaspargase; Radiation: IMRT 50 Gy

PART A A1: Reduced-Dose Radiotherapy

EXPERIMENTAL

Participants who achieve complete metabolic response on PET/CT and negative plasma EBV DNA after two cycles of GELAD are randomized to reduced-dose IMRT, 40 Gy in 20 fractions, followed by two additional 21-day cycles of GELAD.

Drug: Gemcitabine (GEM); Drug: Etoposide Injection; Drug: Dexamethasone; Drug: pegaspargase; Radiation: IMRT 40 Gy

PART B: Standard Treatment Platform

OTHER

Participants with partial response on PET/CT and negative plasma EBV DNA after two cycles of GELAD receive IMRT, 50 Gy in 25 fractions, followed by two additional 21-day cycles of GELAD.

Drug: Gemcitabine (GEM); Drug: Etoposide Injection; Drug: Dexamethasone; Drug: pegaspargase; Radiation: IMRT 50 Gy

PART C: Sintilimab Consolidation

EXPERIMENTAL

Participants with stable disease, local or regional progressive disease that remains amenable to curative radiotherapy, or partial response with positive plasma EBV DNA after two cycles of GELAD receive IMRT, 50 Gy in 25 fractions, followed by sintilimab 200 mg intravenously every 3 weeks. Sintilimab is administered for at least 24 weeks and is discontinued after complete metabolic response and EBV DNA negativity have both been sustained for at least 24 weeks. The maximum duration is 24 months or 35 cycles.

Drug: Gemcitabine (GEM); Drug: Etoposide Injection; Drug: Dexamethasone; Drug: pegaspargase; Radiation: IMRT 50 Gy; Drug: Sintilimab

Interventions

Gemcitabine (GEM) DRUG

Gemcitabine 1.0 g/m\^2 is administered intravenously on Day 1 of each 21-day GELAD cycle. All participants receive two induction cycles. Participants in PART A A0, PART A A1, and PART B receive two additional GELAD cycles after radiotherapy.

PART A A0: Standard-Dose Radiotherapy; PART A A1: Reduced-Dose Radiotherapy; PART B: Standard Treatment Platform; PART C: Sintilimab Consolidation

Etoposide Injection DRUG

Etoposide 60 mg/m\^2 is administered intravenously on Days 1 through 3 of each 21-day GELAD cycle.

PART A A0: Standard-Dose Radiotherapy; PART A A1: Reduced-Dose Radiotherapy; PART B: Standard Treatment Platform; PART C: Sintilimab Consolidation

Dexamethasone DRUG

Dexamethasone 20 mg per day is administered intravenously on Days 1 through 4 of each 21-day GELAD cycle.

PART A A0: Standard-Dose Radiotherapy; PART A A1: Reduced-Dose Radiotherapy; PART B: Standard Treatment Platform; PART C: Sintilimab Consolidation

pegaspargase DRUG

Pegaspargase 2000 U/m\^2, capped at 3750 U per dose, is administered intramuscularly on Day 1 of each 21-day GELAD cycle.

PART A A0: Standard-Dose Radiotherapy; PART A A1: Reduced-Dose Radiotherapy; PART B: Standard Treatment Platform; PART C: Sintilimab Consolidation

IMRT 50 Gy RADIATION

Intensity-modulated radiotherapy is delivered at a total dose of 50 Gy in 25 fractions, 2.0 Gy per fraction, 5 fractions per week.

PART A A0: Standard-Dose Radiotherapy; PART B: Standard Treatment Platform; PART C: Sintilimab Consolidation

IMRT 40 Gy RADIATION

Intensity-modulated radiotherapy is delivered at a total dose of 40 Gy in 20 fractions, 2.0 Gy per fraction, 5 fractions per week.

PART A A1: Reduced-Dose Radiotherapy

Sintilimab DRUG

Sintilimab 200 mg is administered intravenously every 3 weeks after completion of radiotherapy in PART C. Treatment continues for at least 24 weeks. Sintilimab is discontinued when PET/CT complete metabolic response and plasma EBV DNA negativity have both been sustained for at least 24 weeks according to protocol-defined confirmation criteria. The maximum treatment duration is 24 months or 35 cycles.

PART C: Sintilimab Consolidation

Eligibility Criteria

• Age: 18 Years - 75 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age 18 to 75 years, inclusive.
• Histologically confirmed extranodal NK/T-cell lymphoma, nasal type, according to the 2022 World Health Organization classification.
• Diagnosis confirmed by institutional or central pathological review. Tumor tissue must be adequate for morphological assessment, immunohistochemistry, and Epstein-Barr virus-encoded RNA in situ hybridization.
• Lugano 2014 stage IE or IIE disease with a primary site in the upper aerodigestive tract, including but not limited to the nasal cavity, paranasal sinuses, nasopharynx, oropharynx, or oral cavity.
• At least one disease lesion evaluable by PET/CT at baseline.
• No previous chemotherapy, radiotherapy, immunotherapy, or other antitumor biological therapy for lymphoma.
• Eastern Cooperative Oncology Group performance status of 0 to 2.
• Adequate organ function, including:
• Absolute neutrophil count at least 1.0 x 10\^9/L.
• Platelet count at least 75 x 10\^9/L.
• Hemoglobin at least 90 g/L.
• No granulocyte colony-stimulating factor, platelet transfusion, or red blood cell transfusion within 14 days before enrollment.
• Total bilirubin no greater than 1.5 times the upper limit of normal.
• Alanine aminotransferase and aspartate aminotransferase no greater than 2 times the upper limit of normal.
• Serum creatinine no greater than 1.5 times the upper limit of normal.

You may not qualify if:

• Diagnosis not meeting the 2022 World Health Organization criteria for extranodal NK/T-cell lymphoma or not confirmed after pathological review.
• Lugano stage III or IV disease or distant organ involvement inconsistent with localized early-stage disease.
• Primary disease outside the upper aerodigestive tract or predominantly systemic or widespread extranodal disease.
• Previous lymphoma-directed chemotherapy, radiotherapy, immunotherapy, or other systemic antitumor treatment.
• Human immunodeficiency virus infection, active hepatitis C virus infection, or hepatitis B virus infection with HBV DNA greater than 10\^3/mL.
• History of pancreatitis or pancreatic disease considered unsuitable for pegaspargase treatment.
• Acute or systemic infection requiring intravenous anti-infective treatment.
• Severe complications including hemophagocytic lymphohistiocytosis or disseminated intravascular coagulation.
• Significant organ dysfunction, including respiratory failure, chronic congestive heart failure of New York Heart Association class II or higher, decompensated hepatic or renal dysfunction, uncontrolled hypertension or diabetes despite appropriate treatment, or cardiovascular or cerebrovascular thrombosis or bleeding within the previous 6 months.
• Active autoimmune disease or another condition considered by the investigator to make immune checkpoint inhibitor treatment unsuitable.
• Pregnancy or breastfeeding.
• Participants of reproductive potential who are unwilling to use adequate contraception.
• Known severe hypersensitivity to any study drug or its excipients.
• Another active malignancy within the previous 6 months requiring surgery, radiotherapy, or systemic anticancer therapy.
• Severe psychiatric disorder, poor adherence, or another condition that, in the investigator's judgment, would prevent completion of protocol treatment or follow-up.

Sponsors & Collaborators

• Fudan University: lead

Study Sites (1)

Fudan University Shanghai Cancer Center

Shanghai, Shanghai Municipality, 200032, China

Location

Related Publications (2)

• Tao R, Fan L, Song Y, Hu Y, Zhang W, Wang Y, Xu W, Li J. Sintilimab for relapsed/refractory extranodal NK/T cell lymphoma: a multicenter, single-arm, phase 2 trial (ORIENT-4). Signal Transduct Target Ther. 2021 Oct 27;6(1):365. doi: 10.1038/s41392-021-00768-0.

  PMID: 34702811 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

MeSH Terms

Conditions

Lymphoma, Extranodal NK-T-Cell

Interventions

Gemcitabine; Etoposide; Dexamethasone; pegaspargase; sintilimab

Condition Hierarchy (Ancestors)

Lymphoma, T-Cell; Lymphoma, Non-Hodgkin; Lymphoma; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Podophyllotoxin; Tetrahydronaphthalenes; Naphthalenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Polycyclic Compounds; Glucosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Steroids, Fluorinated

Study Officials

• Rong Tao, MD

  Fudan University

  STUDY CHAIR

• Chuanxu Liu, MD

  Fudan University

  PRINCIPAL INVESTIGATOR

• Xuejun Ma, MD

  Fudan University

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Rong Tao, MD

CONTACT

008621-64175590; hkutao@gmail.com

Chuanxu Liu, MD

CONTACT

008621-64175590; rtao@shca.org.cn

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Department head, professor

Model Details: This response-adapted master protocol includes a common induction period followed by response-defined treatment assignment. All participants initially receive two cycles of GELAD. After early PET/CT and plasma EBV DNA assessment, participants enter PART A, PART B, or PART C according to prespecified response criteria. Only PART A includes randomized allocation: participants with complete metabolic response and negative EBV DNA are randomized 1:1 to 50 Gy versus 40 Gy radiotherapy, with identical post-radiotherapy GELAD treatment. PART B and PART C are nonrandomized response-defined modules.

Study Record Dates

• First Submitted: August 12, 2026
• First Posted: August 17, 2026
• Study Start: September 1, 2026
• Primary Completion (Estimated): June 30, 2033
• Study Completion (Estimated): June 30, 2036
• Last Updated: August 17, 2026

Record last verified: 2026-08

Locations

CN (1)