Selinexor Combined With Reduced-Dose Radiotherapy For Early-Stage Extranodal NK/T-Cell Lymphoma

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Extranodal NK/T-cell Lymphoma
• Intervention / Treatment: Drug: Pegaspargase (PEG) Asparaginase; Drug: Gemcitabine (GEM); Drug: Oxaliplatin; Drug: Selinexor; Radiation: radiotherapy

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Estimated): 34
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Liang Wang, M.D.; Phone Number: +861058266633; Email: wangliangtrhos@126.com
• Study Contact Backup: Name: Jia Cong; Phone Number: +861058268442; Email: congjia21@163.com

Study Locations

• China
  • Beijing, China, 100730
    • Beijing Tongren Hospital, Capital Medical University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• 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 0-2.
• 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.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: 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

Drug: Pegaspargase (PEG) Asparaginase; 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 for a total of 4 cycles.; Drug: Gemcitabine (GEM); Gemcitabine 1000 mg/m² is given by intravenous infusion on Day 1 and Day 8 of each 21-day cycle for a total of 4 cycles.; Drug: Oxaliplatin; Oxaliplatin 130 mg/m² is administered intravenously on Day 1 of each 21-day cycle for a total of 4 cycles.; Drug: Selinexor; Following induction chemotherapy, patients will receive consolidation therapy consisting of selinexor combined with reduced-dose radiotherapy. Selinexor 40 mg will be administered orally twice weekly (Monday and Thursday, Tuesday and Friday, or Wednesday and Saturday). Selinexor will be given concurrently with radiotherapy for a total of 8 doses.; Radiation: radiotherapy; ollowing 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 expansion of 1-2 cm.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complete response (CR) rate	CR was defined as complete response evaluated using MRI scan and PET-CT scan according to Lugano criteria.	From the day of initiation of treatment to 8 weeks after completion of radiotherapy.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate (ORR)	Overall response rate means sum of complete response rate and partial response rate.	From the day of initiation of treatment to 8 weeks after completion of radiotherapy.
two-year PFS rate	PFS was defined from the date of initiation of treatment to the date fo confirmed disease progression or death of any reason	From the day of treatment as of 24 months
two-year OS rate	OS was defined from the date of initiation of treatment to the date fo death	From the day of initiation of treatment as of 24 months
two-year local control rate (LCR)	local control was defined as no local disease relapse or progression	From the day of initiation of treatment as of 24 months
Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]	measured using CTCAE version 5.0	From the day of initiation of treatment as of 24 months

Collaborators and Investigators

• Sponsor: Beijing Tongren Hospital
• Investigators: Principal Investigator: Liang Wang, Beijing Tongren Hospital

Study record dates

Study Major Dates

• Study Start (Estimated): May 15, 2026
• Primary Completion (Estimated): December 31, 2027
• Study Completion (Estimated): April 30, 2029

Study Registration Dates

• First Submitted: April 21, 2026
• First Submitted That Met QC Criteria: April 21, 2026
• First Posted (Actual): April 28, 2026

Study Record Updates

• Last Update Posted (Actual): April 28, 2026
• Last Update Submitted That Met QC Criteria: April 21, 2026
• Last Verified: April 1, 2026

More Information

Terms related to this study

• Keywords: radiotherapy; extranodal NK/T-cell lymphoma; selinexor; reduced-dose radiotherapy; XPO1 inhibitor
• Additional Relevant MeSH Terms: Neoplasms; Neoplasms by Histologic Type; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoma, T-Cell; Lymphoma, Extranodal NK-T-Cell; Organic Chemicals; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Therapeutics; Hydrolases; Enzymes; Enzymes and Coenzymes; Coordination Complexes; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Amidohydrolases; Oxaliplatin; Gemcitabine; Asparaginase; Radiotherapy; selinexor; pegaspargase
• Other Study ID Numbers: TRhos-NKTCL-XPO1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No