A Prospective, Single-Arm, Multicenter, Phase II Clinical Study of Selinexor Combined With Reduced-Dose Radiotherapy in the Treatment of Early-Stage Extranodal NK/T-Cell Lymphoma
试验速览
- 阶段
- 2 期
- 状态
- 尚未招募
- 发起方
- 入组人数
- 34
- 试验地点
- 1
- 主要终点
- Complete response (CR) rate
研究概览
简要总结
Extranodal NK/T-cell lymphoma (ENKTCL) is an Epstein-Barr virus-associated non-Hodgkin lymphoma with high incidence in Asia and Latin America. Approximately 70% of patients present with early-stage (I-II) disease confined to the upper aerodigestive tract. Radiotherapy at 50-56 Gy is the standard curative treatment, but high-dose radiotherapy causes severe toxicities including oral mucositis and xerostomia, while radiotherapy alone yields high systemic recurrence rates. Previous studies have confirmed the efficacy of P-GEMOX induction chemotherapy, verified the feasibility of reduced-dose radiotherapy in patients achieving complete response after chemotherapy, and demonstrated the radiosensitizing effect of selinexor via inhibiting IRF3-BARD1-BRCA1-mediated DNA damage repair. Moreover, international evidence supports the efficacy of 40 Gy radiotherapy combined with chemotherapy. Accordingly, this study hypothesizes that selinexor combined with 40 Gy reduced-dose radiotherapy following P-GEMOX induction chemotherapy can achieve equivalent efficacy to standard-dose radiotherapy, while markedly decreasing radiotherapy-related toxicities. This trial innovatively applies selinexor as a radiosensitizer in ENKTCL, fulfills the unmet clinical demand for efficacy-preserving toxicity reduction, and is well supported by preliminary data.
详细描述
Extranodal NK/T-cell lymphoma (ENKTCL) is a distinct subtype of Epstein-Barr virus (EBV)-associated non-Hodgkin lymphoma, which shows a prominent geographical predilection with high incidence in Asia and Latin America. Clinically, around 70% of patients are diagnosed with early-stage (stage I-II) disease, and most lesions are localized to the nasal cavity and upper aerodigestive tract (UADT). Radiotherapy at a standard dose of 50-56 Gy is recommended as the curative first-line treatment for early ENKTCL in international guidelines. Nevertheless, high-dose radiotherapy inevitably induces severe adverse events, including oral mucositis, xerostomia, hypothyroidism and dysphagia, which severely impair patients' long-term quality of life. In addition, radiotherapy alone remains unsatisfactory due to a high risk of systemic recurrence, which is the leading cause of treatment failure.
Accumulating preliminary evidence supports rational treatment de-escalation for early ENKTCL. Previous research has validated the favorable efficacy and safety of the P-GEMOX chemotherapy regimen. A multicenter retrospective study including 202 early ENKTCL patients demonstrated that 4-6 cycles of P-GEMOX followed by standard-dose radiotherapy achieved an 83.2% complete response (CR) rate, with 3-year progression-free survival (PFS) of 74.6% and overall survival (OS) of 85.2%. Another retrospective cohort of 144 post-chemotherapy CR patients further confirmed the feasibility of reduced-dose radiotherapy: no significant differences in PFS and OS were observed between ≤50 Gy and >50 Gy groups, while grade 3-4 mucositis was markedly reduced. Recent international data also verified the long-term efficacy of 40 Gy chemoradiotherapy.
Our team previously identified the radiosensitizing effect of selinexor in vitro. Experiments on SNK-6 and YT cell lines showed that selinexor significantly enhances radiosensitivity by inhibiting the IRF3-BARD1-BRCA1 DNA damage repair pathway and inducing dsRNA accumulation. Based on these foundations, we hypothesize that selinexor combined with 40 Gy reduced-dose radiotherapy after P-GEMOX induction chemotherapy can achieve non-inferior efficacy compared with conventional 50-56 Gy radiotherapy, while substantially alleviating radiotherapy toxicity. This study innovatively applies XPO1 inhibitor selinexor as a radiosensitizer in ENKTCL for the first time, establishes a precision dose-reduction strategy targeting DNA damage repair, addresses the unmet clinical need of toxicity reduction without compromising efficacy, and is highly feasible with solid preclinical and clinical supporting data.
研究设计
- 研究类型
- Interventional
- 分配方式
- Na
- 干预模型
- Single Group
- 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
- •Aged 18 to 75 years, regardless of gender.
- •Pathologically confirmed extranodal NK/T-cell lymphoma (ENKTCL).
- •Ann Arbor stage I-II disease with primary lesion located in the nasal cavity or upper aerodigestive tract (UADT).
- •Eastern Cooperative Oncology Group (ECOG) performance status score of 0-
- •Treatment-naïve patients with no prior radiotherapy, chemotherapy or targeted therapy.
- •Adequate major organ function as follows:
- •Hematopoietic function: absolute neutrophil count (ANC) ≥1.5×10⁹/L, platelet count (PLT) ≥100×10⁹/L, hemoglobin (Hb) ≥90 g/L.
- •Hepatic function: total bilirubin (TBIL) ≤1.5×upper limit of normal (ULN), alanine transaminase (ALT) / aspartate transaminase (AST) ≤2.5×ULN.
- •Renal function: serum creatinine (Cr) ≤1.5×ULN, or creatinine clearance rate ≥60 mL/min.
- •Cardiac function: left ventricular ejection fraction (LVEF) ≥50%.
- •Expected overall survival ≥6 months.
- •Voluntarily sign the written informed consent form.
排除标准
- •Non-nasal type ENKTCL, or primary lesions outside the upper aerodigestive tract (UADT), including skin, gastrointestinal tract, lung and other sites.
- •Patients with Ann Arbor stage III-IV disease.
- •Central nervous system involvement.
- •History of prior malignant tumors, excluding non-melanoma skin cancer or cervical carcinoma in situ cured for more than 5 years.
- •Active infections, including active hepatitis B virus (HBV), hepatitis C virus (HCV) and human immunodeficiency virus (HIV) infection.
- •Severe complications, such as uncontrolled diabetes mellitus and severe cardiopulmonary diseases.
- •Pregnant or lactating women.
- •Hypersensitivity or contraindication to any investigational drugs in this study.
- •Concurrent participation in other interventional clinical trials.
研究组 & 干预措施
treatment arm
Patients will first receive 4 cycles of P-GEMOX induction chemotherapy. Pegaspargase at a dose of 2500 IU/m² (maximum dose not exceeding 3750 IU) is administered via intramuscular injection on Day 1 of each 21-day cycle. Gemcitabine 1000 mg/m² is given by intravenous infusion on Day 1 and Day 8 of each 21-day cycle. Oxaliplatin 130 mg/m² is administered intravenously on Day 1 of each 21-day cycle. A total of 4 cycles will be completed.
Following induction chemotherapy, patients will receive consolidation therapy consisting of selinexor combined with reduced-dose radiotherapy. Radiotherapy will be delivered at a total dose of 40 Gy in 20 fractions (2 Gy per fraction), once daily, 5 fractions per week, over 4 weeks. Radiation therapy will be performed using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). The target volume includes the gross tumor volume (GTV) of the primary lesion before chemotherapy, with a clinical target volume (CTV) margin ex
干预措施: Pegaspargase (PEG) Asparaginase (Drug)
treatment arm
Patients will first receive 4 cycles of P-GEMOX induction chemotherapy. Pegaspargase at a dose of 2500 IU/m² (maximum dose not exceeding 3750 IU) is administered via intramuscular injection on Day 1 of each 21-day cycle. Gemcitabine 1000 mg/m² is given by intravenous infusion on Day 1 and Day 8 of each 21-day cycle. Oxaliplatin 130 mg/m² is administered intravenously on Day 1 of each 21-day cycle. A total of 4 cycles will be completed.
Following induction chemotherapy, patients will receive consolidation therapy consisting of selinexor combined with reduced-dose radiotherapy. Radiotherapy will be delivered at a total dose of 40 Gy in 20 fractions (2 Gy per fraction), once daily, 5 fractions per week, over 4 weeks. Radiation therapy will be performed using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). The target volume includes the gross tumor volume (GTV) of the primary lesion before chemotherapy, with a clinical target volume (CTV) margin ex
干预措施: Gemcitabine (GEM) (Drug)
treatment arm
Patients will first receive 4 cycles of P-GEMOX induction chemotherapy. Pegaspargase at a dose of 2500 IU/m² (maximum dose not exceeding 3750 IU) is administered via intramuscular injection on Day 1 of each 21-day cycle. Gemcitabine 1000 mg/m² is given by intravenous infusion on Day 1 and Day 8 of each 21-day cycle. Oxaliplatin 130 mg/m² is administered intravenously on Day 1 of each 21-day cycle. A total of 4 cycles will be completed.
Following induction chemotherapy, patients will receive consolidation therapy consisting of selinexor combined with reduced-dose radiotherapy. Radiotherapy will be delivered at a total dose of 40 Gy in 20 fractions (2 Gy per fraction), once daily, 5 fractions per week, over 4 weeks. Radiation therapy will be performed using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). The target volume includes the gross tumor volume (GTV) of the primary lesion before chemotherapy, with a clinical target volume (CTV) margin ex
干预措施: Oxaliplatin (Drug)
treatment arm
Patients will first receive 4 cycles of P-GEMOX induction chemotherapy. Pegaspargase at a dose of 2500 IU/m² (maximum dose not exceeding 3750 IU) is administered via intramuscular injection on Day 1 of each 21-day cycle. Gemcitabine 1000 mg/m² is given by intravenous infusion on Day 1 and Day 8 of each 21-day cycle. Oxaliplatin 130 mg/m² is administered intravenously on Day 1 of each 21-day cycle. A total of 4 cycles will be completed.
Following induction chemotherapy, patients will receive consolidation therapy consisting of selinexor combined with reduced-dose radiotherapy. Radiotherapy will be delivered at a total dose of 40 Gy in 20 fractions (2 Gy per fraction), once daily, 5 fractions per week, over 4 weeks. Radiation therapy will be performed using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). The target volume includes the gross tumor volume (GTV) of the primary lesion before chemotherapy, with a clinical target volume (CTV) margin ex
干预措施: Selinexor (Drug)
treatment arm
Patients will first receive 4 cycles of P-GEMOX induction chemotherapy. Pegaspargase at a dose of 2500 IU/m² (maximum dose not exceeding 3750 IU) is administered via intramuscular injection on Day 1 of each 21-day cycle. Gemcitabine 1000 mg/m² is given by intravenous infusion on Day 1 and Day 8 of each 21-day cycle. Oxaliplatin 130 mg/m² is administered intravenously on Day 1 of each 21-day cycle. A total of 4 cycles will be completed.
Following induction chemotherapy, patients will receive consolidation therapy consisting of selinexor combined with reduced-dose radiotherapy. Radiotherapy will be delivered at a total dose of 40 Gy in 20 fractions (2 Gy per fraction), once daily, 5 fractions per week, over 4 weeks. Radiation therapy will be performed using intensity-modulated radiation therapy (IMRT) or volumetric modulated arc therapy (VMAT). The target volume includes the gross tumor volume (GTV) of the primary lesion before chemotherapy, with a clinical target volume (CTV) margin ex
干预措施: radiotherapy (Radiation)
结局指标
主要结局
Complete response (CR) rate
时间窗: From the day of initiation of treatment to 8 weeks after completion of radiotherapy.
CR was defined as complete response evaluated using MRI scan and PET-CT scan according to Lugano criteria.
次要结局
- Overall Response Rate (ORR)(From the day of initiation of treatment to 8 weeks after completion of radiotherapy.)
- two-year PFS rate(From the day of treatment as of 24 months)
- two-year OS rate(From the day of initiation of treatment as of 24 months)
- two-year local control rate (LCR)(From the day of initiation of treatment as of 24 months)
- Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability](From the day of initiation of treatment as of 24 months)
研究者
LIANG WANG
Director of Department of Hematology in Beijing Tongren Hospital
Beijing Tongren Hospital