Becotatug Vedotin Plus PD-1 Monoclonal Antibody and Radiotherapy for Unresectable Locally Recurrent Nasopharyngeal Carcinoma

**Detailed Description**

This is an open-label, single-arm, single-center Phase II clinical study. The study will enroll patients with unresectable locally recurrent nasopharyngeal carcinoma. Eligible patients will receive two cycles of induction therapy with becotatug vedotin plus a PD-1 monoclonal antibody, followed by intensity-modulated radiotherapy. During and after radiotherapy, patients will continue PD-1 monoclonal antibody maintenance treatment until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-defined discontinuation criteria.

The study is designed to evaluate the efficacy and safety of this sequential treatment strategy. The primary endpoint is objective response rate assessed by RECIST v1.1. Secondary endpoints include locoregional recurrence-free survival, progression-free survival, distant metastasis-free survival, 12-month and 24-month progression-free survival rates, overall survival, disease control rate, duration of response, treatment-related adverse events assessed according to NCI-CTCAE v5.0, and quality of life.

Inclusion criteria

• Voluntarily participates in the study and provides written informed consent.
• Aged 18-70 years, male or non-pregnant female, with an expected survival of ≥3 months and an ECOG performance status of 0 or 1.
• Histologically or cytologically confirmed locally recurrent nasopharyngeal carcinoma, differentiated or undifferentiated carcinoma, corresponding to WHO type II or III, with clinical stage rT2-4N0-3M0, rIA-III according to the AJCC 9th edition.
• Recurrence occurring more than 12 months after completion of initial radiotherapy, with no systemic or local antitumor treatment during this interval.
• At least one measurable lesion according to RECIST v1.1.
• Hemoglobin ≥90 g/L, white blood cell count ≥4.0 × 10⁹/L, and platelet count ≥100 × 10⁹/L.
• Adequate liver function: total bilirubin <2.0 × ULN; AST and ALT ≤2.5 × ULN in the absence of liver metastasis, or ALT or AST ≤3.0 × ULN in the presence of liver metastasis; ALP ≤1.5 × ULN, or ≤2 × ULN in the presence of liver metastasis; serum albumin ≥30 g/L.
• Adequate coagulation function: INR or PT and APTT ≤1.5 × ULN, except for patients receiving anticoagulant therapy, whose anticoagulation level should be within the therapeutic range. These laboratory parameters should be closely monitored by the investigator if the patient is receiving anticoagulant therapy.
• Adequate renal function, defined as serum creatinine ≤1.5 × ULN, or creatinine clearance ≥50 mL/min if serum creatinine is >1.5 × ULN. Creatinine clearance should be calculated using the corrected Cockcroft-Gault formula.
• Female and male patients of childbearing potential must agree to use adequate contraception during treatment and for 180 days after the last dose.

Exclusion criteria

• Patients with surgically resectable locally recurrent disease, including rT2 disease limited to the superficial parapharyngeal space and located more than 0.5 cm from the internal carotid artery, or rT3 disease limited to the floor of the sphenoid sinus and located more than 0.5 cm from the internal carotid artery and cavernous sinus.
• Nasopharyngeal necrosis, radiation-induced brain injury, severe cervical fibrosis, or other CTCAE v5.0 Grade ≥3 radiation-related complications, with extremely high radiotherapy risk as assessed by the investigator.
• Grade ≥2 peripheral neuropathy according to CTCAE v5.0.
• Receipt of systemic chemotherapy within 3 weeks before the first dose of study drug; small-molecule targeted therapy within 2 weeks or 5 half-lives, whichever is longer, before the first dose; antitumor biologic therapy, macromolecular targeted therapy, immunotherapy, or major surgery within 4 weeks before the first dose, except for minor surgery within 2 weeks with complete recovery.
• Residual toxicity from prior antitumor therapy, including immunotherapy, targeted therapy, chemotherapy, or radiotherapy, except alopecia, fatigue, and Grade 2 hypothyroidism, or clinically significant laboratory abnormalities greater than Grade 1 according to CTCAE v5.0.
• Uncontrolled or poorly controlled cardiac disease, including congestive heart failure (CHF) Grade ≥2 according to CTCAE v5.0 or New York Heart Association classification, myocardial infarction, unstable angina, history of ventricular tachycardia or torsades de pointes, or arrhythmia requiring treatment within 6 months before enrollment; QTcF >450 ms in males or >470 ms in females; complete left bundle branch block; or third-degree atrioventricular block. QTcF = QT/(RR^0.33).
• Pulmonary embolism or deep vein thrombosis within 3 months before the first dose of study drug, except catheter-related thrombosis from an infusion port or PICC line.
• Known history of malignancy, except for radically treated basal cell carcinoma of the skin, superficial bladder cancer, squamous cell carcinoma of the skin, carcinoma in situ, or papillary thyroid carcinoma, unless the patient has received potentially curative treatment and has had no disease recurrence within 5 years after treatment initiation.
• Any severe or uncontrolled systemic disease, including uncontrolled or poorly controlled hypertension, such as systolic blood pressure >160 mmHg or diastolic blood pressure >100 mmHg, or diabetes mellitus with HbA1c >8%.
• Active bleeding, history of coagulation disorder, or treatment with coumarin anticoagulants.
• Known hypersensitivity to any component or excipient of becotatug vedotin, including citric acid monohydrate, sodium citrate dihydrate, trehalose dihydrate, sodium chloride, and polysorbate 80; or known Grade ≥3 hypersensitivity reaction to prior anti-EGFR drugs, including investigational study drugs, or other monoclonal antibodies.
• Known active hepatitis B or hepatitis C. Active hepatitis B is defined as known HBsAg positivity and HBV DNA ≥500 IU/mL. Active hepatitis C is defined as known hepatitis C antibody positivity and quantitative HCV RNA above the lower limit of detection. Other severe liver diseases, including chronic autoimmune liver disease, primary biliary cirrhosis or sclerosing cholangitis, alcoholic liver disease, or nonalcoholic steatohepatitis (NASH), are also excluded.
• Severe uncontrolled infection; known human immunodeficiency virus (HIV) infection with positive HIV antibody; diagnosis of acquired immunodeficiency syndrome (AIDS); active autoimmune disease, except type 1 diabetes mellitus, hypothyroidism controlled by replacement therapy, and skin diseases not requiring systemic therapy, such as vitiligo, psoriasis, or alopecia; prior allogeneic tissue or organ transplantation, stem cell or bone marrow transplantation, or prior solid organ transplantation.
• Active bacterial, viral, fungal, rickettsial, or parasitic infection requiring systemic anti-infective therapy, unless treated and resolved before study drug administration.
• Receipt of a live viral vaccine within 30 days before the first dose of study drug.
• History of or concurrent interstitial pneumonia, severe chronic obstructive pulmonary disease with respiratory failure, severe pulmonary insufficiency, symptomatic bronchospasm, or similar pulmonary conditions.
• Receipt of immunology-based therapy for any reason, including chronic systemic steroid therapy equivalent to >10 mg/day prednisone within 7 days before the first dose of study drug or at any time during the study. Inhaled or topical steroids, systemic corticosteroids equivalent to ≤10 mg/day prednisone, and short-term corticosteroids equivalent to >10 mg/day prednisone, such as premedication before contrast administration, are permitted.
• Uncontrolled pleural, abdominal, pelvic, or pericardial effusion requiring drainage at least once per month.
• Positive pregnancy test or breastfeeding. Female and male patients who do not plan to use adequate contraception during treatment and for 180 days after the last dose are excluded.
• Any other disease, clinically significant laboratory abnormality, severe medical or psychiatric condition, or substance abuse including alcoholism that, in the investigator's opinion, may compromise patient safety, study integrity, patient participation, or interfere with the study objectives and outcome analysis.