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

This is an investigator-initiated, prospective, multicenter, response-adapted master protocol for previously untreated patients with stage IE or IIE extranodal NK/T-cell lymphoma of the upper aerodigestive tract.

All enrolled participants first receive two 21-day cycles of GELAD induction chemotherapy consisting of gemcitabine, etoposide, pegaspargase, and dexamethasone. Early response assessment is performed 14 to 21 days after completion of the second GELAD cycle and includes whole-body PET/CT, quantitative plasma EBV DNA, contrast-enhanced MRI or CT of the primary site, and nasal endoscopy.

Participants are subsequently assigned to one of three response-defined modules.

PART A includes participants who achieve complete metabolic response on PET/CT and have negative plasma EBV DNA. These participants are randomized centrally in a 1:1 ratio, stratified by NRI 0-1 versus NRI 2 or higher, to receive either 50 Gy in 25 fractions (A0, standard-dose radiotherapy) or 40 Gy in 20 fractions (A1, reduced-dose radiotherapy). Both groups subsequently receive two additional cycles of GELAD. PART A is designed as a noninferiority comparison. The primary endpoint is the 24-month progression-free survival rate from randomization. The prespecified noninferiority margin for the absolute difference in PFS24 between A1 and A0 is -10 percentage points. A total of 280 participants are planned for randomization in PART A.

PART B includes participants with partial response on PET/CT and negative plasma EBV DNA. These participants are not randomized and receive 50 Gy in 25 fractions followed by two additional cycles of GELAD. PART B serves as a prospective standard-treatment platform cohort and has no formal primary hypothesis test.

PART C includes participants with stable disease, local or regional progressive disease that remains within a field amenable to curative radiotherapy, or partial response with persistent positive plasma EBV DNA after two cycles of GELAD. Participants with distant progression or progression to stage III or IV disease are considered to have induction failure and do not enter PART C. Participants in PART C receive 50 Gy in 25 fractions followed by sintilimab 200 mg intravenously every 3 weeks. Sintilimab is administered for at least 24 weeks. Treatment 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 duration of sintilimab is 24 months or 35 cycles. PART C is a single-arm phase 2 module. Its primary endpoint is the 24-month progression-free survival rate from PART C module registration, evaluated against a prespecified null benchmark of 55%.

Approximately 620 participants are expected to be registered in the master protocol. Enrollment may be increased, based only on a blinded feasibility review of actual module-assignment proportions, to a maximum of 660 participants. Participants are followed every 3 months during the first 2 years after completion or discontinuation of protocol treatment, every 6 months during years 3 through 5, and annually thereafter.

Inclusion criteria

• 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.
• Fibrinogen at least 1.5 g/L.
• Left ventricular ejection fraction at least 50%.
• Ability to understand the study and provide written informed consent.
• Willingness to comply with protocol treatment, follow-up, laboratory testing, imaging assessments, and biospecimen collection.

Exclusion criteria

• 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.
• Current use of another investigational drug or participation in another interventional clinical trial within 4 weeks before enrollment.