CELL INTELLIGENCE · 肿瘤细胞治疗研究

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.

主要终点：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
次要终点：Percentage of Participants With Complete Response at the End of Treatment；Percentage of Participants With an Overall Response at the End of Treatment；Overall Survival；Locoregional Control Rate at 12, 24, and 36 Months；Percentage of Baseline EBV DNA-Positive Participants Achieving Confirmed Plasma EBV DNA Clearance；Number of Participants With Adverse Events as Assessed by CTCAE Version 5.0；Percentage of PART C Participants in Treatment-Free Remission at 24 Months

• 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.
• 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.
• 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.
• 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.

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.