Starting soon
Phase 2
GELAD-Based Response-Adapted Treatment for Early-Stage Extranodal NK/T-Cell Lymphoma
Condition(s) studied
Natural Killer/T-cell Lymphoma
Investigational drug(s) / intervention(s)
Gemcitabine (GEM): 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.
Etoposide Injection: Etoposide 60 mg/m\^2 is administered intravenously on Days 1 through 3 of each 21-day GELAD cycle.
Dexamethasone: Dexamethasone 20 mg per day is administered intravenously on Days 1 through 4 of each 21-day GELAD cycle.
pegaspargase: Pegaspargase 2000 U/m\^2, capped at 3750 U per dose, is administered intramuscularly on Day 1 of each 21-day GELAD cycle.
IMRT 50 Gy: Intensity-modulated radiotherapy is delivered at a total dose of 50 Gy in 25 fractions, 2.0 Gy per fraction, 5 fractions per week.
IMRT 40 Gy: Intensity-modulated radiotherapy is delivered at a total dose of 40 Gy in 20 fractions, 2.0 Gy per fraction, 5 fractions per week.
Sintilimab: 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.
Study 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.
Eligibility
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.
Primary outcome measure(s)
- 24-Month Progression-Free Survival Rate in PART A — From PART A randomization through 24 months
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.
- 24-Month Progression-Free Survival Rate in PART C — From PART C module registration through 24 months
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%.
Trial sites (1)
| Facility | City | Region | Status |
|---|
| Fudan University Shanghai Cancer Center |
Shanghai |
Shanghai Municipality |
|
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