Overview
This study is a multicenter, randomized, controlled phase III clinical trial aiming to investigate the efficacy and safety of Becotatug Vedotin induction therapy followed by concurrent chemoradiotherapy (CCRT) combined with neoadjuvant and adjuvant sintilimab, versus gemcitabine plus cisplatin (GP) induction chemotherapy followed by CCRT, in the treatment of high-risk locally advanced nasopharyngeal carcinoma (LANPC). The study plans to enroll 266 patients with high-risk NPC (AJCC 9th edition, anyT N2-3M0 or T4N1M0), who will be randomly assigned to the experimental group or the control group at a 1:1 ratio.The primary endpoint is 3-year event-free survival (EFS), and the secondary endpoints include overall survival (OS), local-regional failure-free survival (LRFFS), distant metastasis-free survival (DMFS), objective response rate (ORR), adverse events, and quality of life.
Description
This is a multicenter, randomized, controlled phase III clinical study targeting patients with high-risk locally advanced nasopharyngeal carcinoma (stage T1-4N2-3M0 or T4N1M0 per the 9th AJCC/UICC staging system), with a planned enrollment of 266 patients who will be randomized 1:1 into an experimental group and a control group under an open-label, stratified randomization design. The primary endpoint of the study is 3-year event-free survival (EFS), and the secondary endpoints include efficacy measures such as overall survival and locoregional recurrence-free survival, as well as safety and quality of life assessments; additionally, the study explores the predictive value of efficacy biomarkers including EGFR expression and combined positive score (CPS). The experimental group is administered neoadjuvant therapy with becotatug vedotin plus sintilimab for 3 cycles, followed by concurrent chemoradiotherapy with cisplatin combined with adjuvant sintilimab therapy for 9 cycles, while the control group receives induction chemotherapy with gemcitabine plus cisplatin (GP regimen) for 3 cycles followed by concurrent chemoradiotherapy with cisplatin. Intensity-modulated radiation therapy (IMRT) is uniformly adopted for all patients in both groups, with standardized target volume doses and normal organ dose constraints defined. The study has also formulated detailed protocols for drug dose adjustment and toxicity monitoring; treatment-related adverse events are graded and managed in accordance with the NCI-CTCAE v5.0 and RTOG/EORTC criteria, and the EORTC QLQ-C30 scale is used to evaluate patients' quality of life. The study aims to verify that the innovative treatment regimen of becotatug vedotin combined with sintilimab yields superior efficacy with a manageable safety profile compared with the conventional GP induction chemotherapy followed by chemoradiotherapy in patients with high-risk locally advanced nasopharyngeal carcinoma, thereby providing a novel treatment option for this patient population and supplementing high-level evidence-based medical evidence. Meanwhile, it explores relevant biomarkers to lay a foundation for individualized treatment.
Eligibility
Inclusion Criteria:
- Voluntarily participate in the study and sign the informed consent form in writing.
- Aged 18-70 years, male or non-pregnant female.
- Pathologically confirmed as nasopharyngeal non-keratinizing carcinoma (differentiated or undifferentiated type, i.e., WHO type II or III).
- Staged as anyT N2-3 or T4N1 (9th AJCC/UICC staging) without distant metastasis.
- ECOG performance status score of 0-1.
- Hemoglobin (HGB) ≥ 90 g/L, neutrophil count ≥ 1.5×10⁹/L, and platelet (PLT) count ≥ 100×10⁹/L.
- Liver function: Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal (ULN), and total bilirubin ≤ 1.5 times ULN.
- Normal renal function: Creatinine clearance rate ≥ 60 ml/min (calculated using the Cockcroft-Gault formula).
- Sexually active females of childbearing potential must agree to use effective contraceptive measures during treatment and for 1 year after the last administration of the study drug. Males who have sexual relations with females of childbearing potential must also agree to use effective contraceptive measures during treatment and for 1 year after the last administration of the study drug.
Exclusion Criteria:
- Aged \> 70 years or \< 18 years.
- Patients with recurrent or distant metastatic nasopharyngeal carcinoma.
- Pathologically confirmed as keratinizing squamous cell carcinoma (WHO type I).
- Patients who have previously received radiotherapy or systemic chemotherapy.
- Positive for hepatitis B surface antigen (HBsAg) with hepatitis B virus DNA \> 1000 copies/mL or 200 IU/mL.
- Positive for hepatitis C virus antibody (anti-HCV).
- Patients with active autoimmune diseases, excluding type 1 diabetes mellitus, hypothyroidism controlled by replacement therapy, and skin diseases that do not require systemic treatment (e.g., vitiligo, psoriasis, or alopecia).
- Patients who received systemic glucocorticoids (equivalent to prednisone \> 10 mg/day) or other immunosuppressive therapy within 28 days prior to signing the informed consent form. Patients who received systemic glucocorticoids equivalent to prednisone ≤ 10 mg/day, inhaled or topical glucocorticoids are eligible for enrollment.
- Patients with a history of active tuberculosis within the past year; patients with active tuberculosis that has been adequately treated for more than one year are eligible for enrollment. Patients with a history of other malignant tumors (except cured basal cell carcinoma or carcinoma in situ of the cervix).
- Patients with a history of interstitial lung disease.
- Patients who received live vaccines within 30 days prior to signing the informed consent form or plan to receive live vaccines in the near future.
- Pregnant or lactating females.
- Patients with a history of other malignant tumors within the past 5 years, except carcinoma in situ, adequately treated non-melanoma skin cancer, and papillary thyroid cancer.
- Patients with known hypersensitivity to any component of gemcitabine, cisplatin, becotatug vedotin, or sintilimab.
- Patients with known history of HIV infection.
- Any other conditions deemed by the investigator to potentially affect the patient's ability to sign the informed consent form, cooperate with and participate in the study, or interfere with the interpretation of results, including symptomatic heart failure, unstable angina pectoris, myocardial infarction, active infections requiring systemic treatment, mental illnesses, or family/social factors.
