A Prospective Multicenter Response-Adapted Treatment Study Based on Early Response Assessment After GELAD Induction Chemotherapy in Early-Stage Extranodal NK/T-Cell Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 入组人数
- 620
- 试验地点
- 1
- 主要终点
- 24-Month Progression-Free Survival Rate in PART A
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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
- •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.
排除标准
- •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.
研究组 & 干预措施
PART A A0: Standard-Dose Radiotherapy
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.
干预措施: IMRT 50 Gy (Radiation)
PART A A1: Reduced-Dose Radiotherapy
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.
干预措施: IMRT 40 Gy (Radiation)
PART B: Standard Treatment Platform
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.
干预措施: IMRT 50 Gy (Radiation)
PART C: Sintilimab Consolidation
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.
干预措施: IMRT 50 Gy (Radiation)
PART A A1: Reduced-Dose Radiotherapy
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.
干预措施: Dexamethasone (Drug)
PART C: Sintilimab Consolidation
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.
干预措施: Etoposide Injection (Drug)
PART A A0: Standard-Dose Radiotherapy
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.
干预措施: pegaspargase (Drug)
PART C: Sintilimab Consolidation
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.
干预措施: pegaspargase (Drug)
PART C: Sintilimab Consolidation
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.
干预措施: Gemcitabine (GEM) (Drug)
PART A A0: Standard-Dose Radiotherapy
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.
干预措施: Dexamethasone (Drug)
PART B: Standard Treatment Platform
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.
干预措施: pegaspargase (Drug)
PART A A0: Standard-Dose Radiotherapy
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.
干预措施: Gemcitabine (GEM) (Drug)
PART A A1: Reduced-Dose Radiotherapy
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.
干预措施: Gemcitabine (GEM) (Drug)
PART A A0: Standard-Dose Radiotherapy
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.
干预措施: Etoposide Injection (Drug)
PART B: Standard Treatment Platform
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.
干预措施: Dexamethasone (Drug)
PART A A1: Reduced-Dose Radiotherapy
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.
干预措施: pegaspargase (Drug)
PART B: Standard Treatment Platform
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.
干预措施: Etoposide Injection (Drug)
PART A A1: Reduced-Dose Radiotherapy
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.
干预措施: Etoposide Injection (Drug)
PART B: Standard Treatment Platform
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.
干预措施: Gemcitabine (GEM) (Drug)
PART C: Sintilimab Consolidation
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.
干预措施: Dexamethasone (Drug)
PART C: Sintilimab Consolidation
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.
干预措施: Sintilimab (Drug)
结局指标
主要结局
24-Month Progression-Free Survival Rate in PART A
时间窗: 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
时间窗: 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%.
次要结局
- 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)
- Number of Participants With Adverse Events as Assessed by CTCAE Version 5.0(From the first study treatment through the protocol-defined safety follow-up after the final study treatment, up to approximately 26 months)
- Percentage of PART C Participants in Treatment-Free Remission at 24 Months(24 months after PART C module registration)
研究者
Rong Tao
Department head, professor
Fudan University