A Bayesian Adaptive Phase II Randomized Trial Comparing Ivonescimab, Ivonescimab Plus Nimotuzumab, Liposomal Mitoxantrone Plus Anti-PD-1 Antibody, and Liposomal Irinotecan Plus S-1 in Patients With PD-1-Resistant Recurrent or Metastatic Nasopharyngeal Carcinoma
This is a prospective, Bayesian adaptive, phase II clinical trial designed to evaluate the safety and efficacy of four treatment regimens in patients with recurrent (unamenable to local therapy) or metastatic nasopharyngeal carcinoma (NPC) who have failed after at least one prior platinum-containing standard regimen and anti-PD-1/PD-L1 therapy. The four treatment arms include: 1. Ivonescimab monotherapy, 2. Ivonescimab combined with nimotuzumab, 3. Liposomal mitoxantrone plus anti-PD-1 antibody, and 4. Liposomal irinotecan plus S-1.
• Histologically and/or cytologically confirmed recurrent or metastatic non-keratinizing nasopharyngeal carcinoma (either differentiated or undifferentiated subtype, corresponding to WHO type II or III).
• Age between 18 and 70 years.
• Performance Status (PS) score of 0 or 1.
• Disease progression after prior platinum-based doublet chemotherapy.
• Received at least one line of systemic therapy previously. (Progression occurring during or within 6 months after definitive concurrent chemoradiotherapy, neoadjuvant/adjuvant therapy, or treatment completion may be counted as first-line treatment.)
• Resistance to anti-PD-1 antibody therapy (either combination or sequential), including primary or secondary resistance（PD-1 exposure must be at least 6 weeks.）
• At least one measurable lesion according to RECIST 1.1 criteria.
• All acute toxicities from prior anti-tumor therapies have resolved to grade ≤1 (per NCI-CTCAE v5.0) or meet the specified inclusion/exclusion thresholds. (Certain toxicities such as alopecia, hair color changes, nail changes, fatigue, etc., which do not pose safety risks, are exempt.)
• Adequate organ function:
• Hematology: WBC ≥ 4000/μL, absolute neutrophil count ≥ 2000/μL, hemoglobin ≥ 9 g/dL, platelets ≥ 100,000/μL.
• Liver function: Total bilirubin ≤ 1.5 × upper limit of normal (ULN) (patients with Gilbert's syndrome and bilirubin ≤ 3 × ULN are eligible); AST and ALT ≤ 3 × ULN; alkaline phosphatase ≤ 3 × ULN; albumin ≥ 3 g/dL.
• Coagulation: INR, prothrombin time (PT), or activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN.
• Renal function: Serum creatinine ≤ 1.5 × ULN or creatinine clearance ≥ 60 mL/min calculated by Cockcroft-Gault formula. Proteinuria: Urine protein/creatinine ratio (UPC) \< 1.0. For UPC ≤ 0.5, no further testing is required; for UPC \> 0.5, 24-hour urine protein must be \< 1000 mg for eligibility.
⁃ Estimated life expectancy of at least 3 months.
⁃ Signed informed consent and willingness and ability to comply with study visits, treatment plans, laboratory tests, and other study procedures.