This is an open-label, single-arm, multi-center Phase II clinical trial evaluating the efficacy and safety of a novel sequential regimen as first-line therapy for treatment-naïve patients with Extranodal NK/T-cell Lymphoma (ENKTL). The study consists of a Screening Phase, a Safety Lead-in Phase, and a Treatment Phase. During the Safety Lead-in Phase, 6 patients will be enrolled to receive a fixed dose of Sintilimab and Chidamide combined with Azacitidine to verify the dose (testing 100mg/d on days 1-3 versus days 1-5). Following the lead-in, all subjects will undergo a 2-cycle Immunotherapy Induction Phase with the SCA regimen (Sintilimab, Chidamide, and Azacitidine). Subsequently, treatment will be stratified based on response: patients achieving Complete Response (CR) or Partial Response (PR) will receive 4 additional cycles of SCA consolidation, while those with Stable Disease (SD) or Progressive Disease (PD) will switch to 4 cycles of P-GemOx chemotherapy. Upon completion of systemic therapy, all patients will undergo consolidative involved-field radiotherapy (≥50Gy).
Willingness to participate in the clinical study.
Age ≥ 18 years at the time of signing the Informed Consent Form (ICF).
Newly diagnosed ENKTL confirmed by histopathology at the study center.
Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2.
Aggressive natural killer cell leukemia.
Presence of hemophagocytic syndrome.
Primary central nervous system (CNS) lymphoma or secondary CNS involvement.
Patients with a known history of human immunodeficiency virus (HIV) infection and/or acquired immunodeficiency syndrome (AIDS).
Single group
SCA Induction followed by Response-Adapted Therapy
DrugDrug: Sintilimab, Chidamide, and Azacitidine (SCA Regimen) Safety Lead-in: Patients receive Sintilimab (fixed dose) and Chidamide (fixed dose) combined with Azacitidine at two dose levels (100mg/d on days 1-3 vs. days 1-5) to verify the combination dose. Induction Phase: All enrolled patients receive 2 cycles of SCA induction: Sintilimab (200mg, D1), Chidamide (30mg, biw, D1-21), and Azacitidine (100mg, D1-3/5 \[SCA\]). Cycle length is 21 days. Response-Adapted Consolidation: Patients achieving Complete Response (CR) or Partial Response (PR) continue with 4 cycles of the SCA regimen. Patients with Stable Disease (SD) or Progressive Disease (PD) switch to 4 cycles of P-GemOx chemotherapy (Pemetrexed + Gemcitabine + Oxaliplatin). Radiation: Involved-Field Radiotherapy (IFRT) Following the completion of immunotherapy or chemotherapy, all patients receive local radiotherapy (≥50Gy).
Complete Remission rate
he Complete Remission (CR) rate is defined as the proportion of participants who achieve a confirmed Complete Remission (CR) during the study treatment period. Tumor response will be assessed by the Investigator according to the Lugano Classification 2014 criteria for malignant lymphoma (or RECIL 2017 if applicable). Complete Remission (CR): Defined as the disappearance of all evidence of disease, including resolution of all target lesions, normalization of lymph nodes (based on size criteria), and metabolic complete response (Deauville Score 1-3) on Positron Emission Tomography-Computed Tomography (PET-CT) scans, if performed. Assessment Schedule: Efficacy assessments (including CT/MRI and PET-CT) will be performed at baseline, at the end of the Induction Phase (after 2 cycles), at the end of Consolidation/Chemotherapy Phase (after 4 additional cycles), and prior to radiotherapy. The best overall response during the systemic therapy phase will be used to calculate the CR rate.
objective response rate
the objective response rate (orr) is defined as the proportion of participants who achieve either a complete remission (cr) or a partial remission (pr) as their best overall response during the systemic treatment phase. assessments will be conducted by the investigator in accordance with the lugano classification 2014 criteria for malignant lymphoma (or recil 2017 if applicable). this measure evaluates the combined efficacy of the induction and consolidation regimens (sca and/or p-gemox) in reducing tumor burden prior to the administration of local radiotherapy. * complete remission (cr): disappearance of all target lesions, normalization of lymph nodes, and metabolic complete response (deauville score 1-3). * partial remission (pr): ≥50% decrease in the sum of the products of the perpendicular diameters of target lesions, taking into account the appearance of new lesions or flares in fdg-avid disease.
Partial Remission (PR) rate
The Partial Remission (PR) rate is defined as the proportion of participants who achieve a Partial Remission (PR) as their best overall response during the study treatment period. Tumor response will be assessed by the Investigator according to the Lugano Classification 2014 criteria (or RECIL 2017 if applicable). This endpoint measures the efficacy of the SCA induction regimen and subsequent response-adapted therapy (SCA consolidation or P-GemOx chemotherapy) in reducing the tumor burden in patients with previously untreated ENKTL. A PR is defined as a ≥50% decrease in the sum of the products of the perpendicular diameters of target lesions, taking into account the appearance of new lesions or flares in FDG-avid disease.
Progression-Free Survival
The Progression-Free Survival (PFS) is defined as the time from the date of initial treatment (first dose of the SCA regimen) to the date of disease progression or death from any cause, whichever occurs first. Disease progression will be determined by the Investigator based on radiological imaging (CT/MRI) and clinical assessment according to the Lugano Classification 2014 criteria (or RECIL 2017). Patients who do not experience the event (progression or death) at the time of data cutoff will be censored at the date of their last adequate disease assessment. Patients who initiate new anti-cancer therapy without documented progression will also be censored at the start date of the new therapy.
Duration of Response
The Duration of Response (DoR) is defined as the time from the date of first documented response (either Complete Remission or Partial Remission) to the date of disease progression or death from any cause, whichever occurs first. Disease progression will be determined by the Investigator based on radiological imaging and clinical assessment according to the Lugano Classification 2014 criteria (or RECIL 2017). Only participants who achieve a CR or PR are evaluable for this endpoint. Patients who do not experience the event (progression or death) at the time of data cutoff will be censored at the date of their last adequate disease assessment.
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