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.

• 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.
• Etoposide Injection (Drug): Etoposide 60 mg/m\^2 is administered intravenously on Days 1 through 3 of each 21-day GELAD cycle.
• Dexamethasone (Drug): Dexamethasone 20 mg per day is administered intravenously on Days 1 through 4 of each 21-day GELAD cycle.
• 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.
• 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.
• 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.
• 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.

Primary outcomes

• 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%.

Secondary outcomes

• 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]: Complete response is assessed according to the Lugano 2014 response criteria. Participants who are not evaluable at the protocol-defined end-of-treatment assessment are considered not to have achieved complete response in the primary analysis.
• 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 response is defined as complete response or partial response according to the Lugano 2014 response criteria.
• Overall Survival [From the first GELAD dose through 60 months]: Overall survival is defined as the time from the first GELAD dose to death from any cause. Participants who are alive are censored at the date they were last known to be alive.
• Locoregional Control Rate at 12, 24, and 36 Months [At 12, 24, and 36 months after module assignment]: Description: Locoregional failure is defined as recurrence or progression within the primary radiotherapy region, involved cervical nodal region, or adjacent locoregional region. Locoregional control rates will be estimated at prespecified time points.
• Percentage of Baseline EBV DNA-Positive Participants Achieving Confirmed Plasma EBV DNA Clearance [From the first GELAD dose through 24 months]: Plasma EBV DNA below 500 copies/mL is defined as negative. Confirmed clearance is defined as conversion from positive to negative plasma EBV DNA with at least two consecutive negative measurements separated by at least 2 weeks.
• 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]: Adverse events, serious adverse events, grade 3 or higher adverse events, treatment-related adverse events, treatment discontinuations due to toxicity, and treatment-related deaths will be collected. Radiation-related acute and late toxicities and immune-related adverse events in PART C will be specifically evaluated.
• Percentage of PART C Participants in Treatment-Free Remission at 24 Months [24 months after PART C module registration]: Treatment-free remission at 24 months is defined as being alive and progression-free at 24 months after PART C module registration, having discontinued sintilimab for at least 6 months, and having received no additional anticancer therapy after discontinuation.

Sex: All, ages: 18 Years to 75 Years

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.

• Results publication: 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
• Results publication: 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

• Rong Tao, MD, Study chair, Fudan University
• Chuanxu Liu, MD, Principal investigator, Fudan University
• Xuejun Ma, MD, Principal investigator, Fudan University